, Indomethacin

1. Chemical and PhysicalCharacteristics

1.1 NameChemical Abstracts Services Registry Number53-86-1

UPAC Systematic Chemical Name1-( 4-Chlorobenzoyl)-5-methoxy-2-methyl-lH-indole-3-acetic acid

Synonyms1-( 4-Chlorobenzoyl)-5-methoxy-2-methylindo-lo-3-acetic acid; 1-(p-chlorobenzoyl)-5-meth-

oxy-2-methyl-3-indolylacetic acid; 1-(p-chloro-benzoyl)-5-methoxy-2-methylindole-3 acetic acid

1.2 Structural and molecular formulae and

relative molecular mass

CH2COOHCH30

, CH3N

O..nCIC19H16CIN04 Relative molecular mass: 357.81

1.3 Physical and chemical properties

From Budavari et al. (1996) and Reynolds andPrasad (1982), unless otherwise stated.

DescriptionWhite to yeIlow-tan, odourless crystallne powder

Meltng-pointIndomethacin exhibits polymorphism, with amelting-point of -155°C for one form and-162°C for the other.

SolubíltySoluble in ether, acetone and castor oil; practi-caIly insoluble in water

Spectroscopy dataAbsorbance spectrum in ethanol has maxima at230,260 and 319 nm

StabíltyStable in neutral or slightly acid media; decom-posed by strong alkali.

Impuritesa,-Substituted monoglyceryl esters of 4-chlorobenzoic acid and indomethacin areformed through chemical interaction of thedrug with glycerin present in suppositories.

Only trace or undetectable amounts of these

and other impurities were recorded after analy-sis of bulk samples or after formulation as cap-sules (Curran et al., 1980).

1.4 Technical products

Amuno, Argun, Artracin, Artrinovo, Artrivia,Bonidon, Catlep, Chibro-Amuno, Chrono-Indocid-75, Confortid, Dolcidium-PL, Dolovin,Durametacin, Elmetacin, Idomethine,Imbrilon, Inacid, Indacin, Indocid, Indocil,Indocin, Indocollyre, Indomecol, Indomed,Indomee, Indometacin, Indometacine,Indomethacine, Indomethine, Indomod, Indo-Phlogont, Indoptic, Indorektal, Indo-Rectalmin, Indo- Tablinen, Indoxen, Indren,Inflazon, Infrocin, Inteban SP, Lausit, Metacen,Metastril, Methazine, Metindal, Mezolin,

Mikametan, Mobilan, Reumacide, Rheumacin

LA, Sadoreum, Tannex, Vonum.

2. Occurrence, Production, Use,Analysis and Human Exposure

2.1 OccurrenceIndomethacin is not known to occur naturaIly.

2.2 ProductionIndomethacin may be synthesized by severalroutes (Shen & Winter, 1977), which aregenerally modifications of the originalprocedure (Shen et al., 1963) in which5-methoxy-2-methylindole-3-acetic acid was-

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used as the starting material. Technical details

about its current commercial production werenot available to the Working Group.

2.3 UseThe only known use of indomethacin is as apharmaceutical agent. The drug is formulatedas capsules or suppositories (Watanabe et aI.i1993). Experimental formulations of the drug

are being investigated (Tsuji et aI.i 1993).Indomethacin has analgesic, anti-inflammatoryand anti-pyretic properties and is usedextensively in the treatment of rheumatic disor-ders at doses of 25 mg and 50 mg two to fourtimes dailyup to 100-200 mg daily (WaIler, 1983).

2.4 Analysisln general, methods for the analysis ofindomethacin are restricted to its determina-tion in pharmaceutical preparations and in

body fluids. Most of the methods involve high-performance liquid chromatography. Indo-

methacin can be determined in pharmaceuticalpreparations in the presence of other non-

steroidal anti-inflammatory drugs (NSAIDs)

(Rau et al., 1991). Methods exist for its deter-mination in plasma and urine (Hubert &Crommen, 1990; Singh et al., 1991; Johnson &Ray, 1992).

2.5 Human exposureIndomethacin is a commonly used NSAID(Griffn et al., 1991; Langman et al., 1994).Since its introduction in 1962, it has beenused extensively for the treatment of acute

and chronic arthritis and other inflammatorydisorders. Although indomethacin is normallytaken by mouth, it can be administered rectallyin order to reduce the occurrence of gastro-

intestinal side-effects. This approach has beeninvestigated in pers ons with familal adenoma-tous polyposis and remaining rectal segments(Hirata et al., 1994; Hirota et aL., 1996).When it is used for the treatment of rheumato-logical disease, similar clinical benefits are seenwith oral and rectal doses of indomethacin,

although most patients prefer the oral route ofadministration (Huskisson et aL., 1970).

Indomethacin is currently available infive dosage formulations: a sterile solution

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containing 1 mg for intravenous administra-tion, a conventional gelatin capsule, (25 or 50 mg)

for oral administration, a 75-mg sustained

release capsule; an oral suspension containing25 mg indomethacin per 5 ml and a 50-mg sup-pository for rectal use (Bilups & Bilups, 1992).

3. Metabolism, Kinetics and GeneticVariation

3.1 Human studies3.1.1 Metabolism

ln adults, indomethacin undergoes extensive

hepatic biodegradation by O-demethylation

and N-deacylation reactions (Duggan et al.i1972), and only a small amount is excreted inthe urine unchanged (Helleberg, 1981) (Fig. 1).These metabolites lack anti-inflammatory activity(Shen, 1965).

Indomethacin is demethylated to formdemethylindomethacin through the cyto-chrome P450 micros omal pathway (Duggan etal.i 1972). Leemann et al. (1993) showed inhum an liver microsomes, that a single cyto-chrome P450 monooxygenase plays a criticalrole in the elimination of indomethacin by theliver. Analysis of inhibition by indomethacin incomparison with other of NSAIDs suggested

that a common isoenzyme, CYP2C9, catalysesoxidation of NSAIDS by hum an liver.

3.1.2 Pharmacokinetics

The pharmacokinetics of indomethacin inhumans has been extensively studied andreviewed (Alvan et al., 1975; HeIleberg, 1981;Waller, 1983; Yeh, 1985).

(a) AbsorptionConventional indomethacin capsules are read-ily and completely absorbed after oral adminis-tration, with an estimated mean bioavailabiltyof 85-122% (Duggan et al., 1972; Alvan et al.,1975; Kwan et aL., 1976; Yeh, 1985). Con-comitant ingestion of foods may affect theabsorption of indomethacin: total absorption isgreater and the rate of absorption is generaIly

quicker in fasting th an in non-fasting subjects

when delays of up to 4 h have been reported(Arnold & Brynger, 1970; Turakka & Airaksinen,1974). Absorption of indomethacin from

Indomethacin

Figure 1. 1-(p-Chlorobenzyl)-5-methoxy-2-methylindole-3-acetic acid (indomethacin) andits main metabolites

Ci

Indomethacin

/ ~H

CH3

i!CH3

Dech lorobenzoyl indomethaci n

CI

Demethyl benzoyl i ndomethaci n

~ /CH3

Demeth yl-dech 10 robenzoyl i n dometh a ci n

50-mg gelatin capsules was nearly twice as longwhen taken with food th an in fasting subjects

(Rothermich, 1966; Emori et al., 1976). Dietshigh in carbohydrates appear to delay absorp-

tion most, foIlowed by high-protein andhigh-lipid diets (WaIlusch et al., 1978). The pres-ence of antacids or antidiarrhoeal medications

may also decrease the rate of absorption oforaIly administered indomethacin (Rothermich,1966; Emori et al., 1976). The overaIl bioavail-abilty of indomethacin, is not however,influenced by the presence of food (Kwan et al.,1976; WaIlusch et aL., 1978), and similarvalues are reported in fasting and non-fasting

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subjects (Alvan et al., 1975). Despite the possibleeffects on absorption, indomethacin and otherNSAIDs are commonly taken with meals orantacids in order to les sen the gastric side-effects.

Comparisons of the bioavailabilty andpharmacokinetic profies of sustained-releaseindomethacin and conventional capsules havebeen reported (Helleberg, 1981; Yeh et aL., 1982;WaIler, 1983). The 75-mg sustained-release cap-sule contains 25 mg of an immediate-release

fraction, and the remaining 50 mg are polymer-coated to ensure graduaI release. The formula-tion is administered once or twice daily, asopposed to the less convenient three timesdaily dosing regime with conventional 25- or50-mg capsules.

Use of the sustained-release formulation isassociated with a slower rate of absorption andlower peak plasma concentrations, althoughthe ove raIl plasma concentration-time rela-tionship is generaIly comparable to that of theconventional oral formulation. WaIler (1983)

reported peak plasma times of 2.0 :t 0.9 h withthe sustained-release capsule and 1.0 :t 0.4 h

with conventional capsules, and a 55% reduc-tion in peak plasma concentrations. Schoog etal. (1981), however, in a cross-over study, foundsignificant differences in the plasma concentra-tion-time curves with 75-mg sustained-releaseand conventional capsules. The greatest differ-ences were seen between 1 and 5 h after admin-istration.

The peak plasma levels associated withrectal administration are generally lower

th an those with orally administered indo-

methacin capsules and are achieved earlier(HoIt & Hawkins, 1965), although at least oneauthor has disagreed on this point (Alvan et al.,1975). Studies with volunteers showed that themaximal plasma concentrations of indomethacinafter administration of suppositories (50-100 mg)were achieved within 60-80 min, with meanpeak plasma concentrations of 1.5-2.8 Ilg/ml(HoIt & Hawkins, 1965; Arnold & Brynger,1970; Kwan et al., 1976). The ove raIl bio-

availabilty of rectally delivered indomethacinis similar to that of orally administered ormula-tions, with values ranging from 80 to 100%(Alvan et aL. 1975; Kwan et al., 1976).

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Circadian variation in the pharmacokineticsof indomethacin has been described (Clench etal., 1981; Aronson et al., 1993). ln nine healthyvolunteers, absorption of a single 100-mg oraldose of indomethacin was more rapid when itwas taken at 7:00 or II:00 h than at 15:00,

19:00 or 23:00 h (Clench et al., 1981). Diurnalvariations in the rate of gastric emptying maypartiaIly explain this effect, since the rate is sig-nificantly slower in the evening. Similarly, the

transport mechanisms in the small bowel,

where most indomethacin is absorbed, may bemore efficient before midday. No diurnalvariation was reported after rectal administra-tion of a 100-mg suppository (Taggart et aL.,1987).

(b) DistributionLike most other acidic NSAIDs, indomethacinreadily binds to human serum albumin andother plasma proteins (Hucker et al., 1966;

HuItmark et aL., 1975; Rane et aL., 1978; Zini etal., 1979), with binding affinities similar tothose of other NSAIDs (HuItmark et aL., 1975).The lack of binding to erythrocytes reported ineadier studies (McArthur et al., 1971) was laterdisproved (Bruguerolle et aL., 1986), when amore sensitive detection technique was used. lnthis study, uptake of indomethacin by erythro-cytes represented approximately 2.4% of thetotal blood indomethacin levels in both youngand older volunteers.

The numbers of indomethacin-binding siteson hum an serum albumin have been calculatedto be between four (Hultmark et al., 1975) and15 (Hvidberg et aL., 1972), with an associationconstant of 0.86 x 103 litre/mol (Hvidberg et al.,1972), and the actual percentage of indo-methacin bound to albumin has been reportedto range from 92 to 99% (Mason & McQueen,1974; HuItmark et aL., 1975). All of the studiesshowed consistent binding over the therapeuticdose range of indomethacin and at higher lev-els (Hucker et al., 1966; Hvidberg et al., 1972;Mason & McQueen, 1974; Hultmark et al.,1975). At therapeutic doses, binding to albu-

min is independent of concentration (Rane etal., 1978).

Binding of indomethacin is not aItered inuraemic patients with chronic renal failure

Indomethacin

(Sjoholm et aL., 1976); however, decreased pro-tein binding has been observed in cancer

patients with active disease, probably reflectinglower serum albumin levels in those patients(Raveendran et aL., 1992).

lndomethacin readily penetrates body tis-sues (Hucker et aL., 1966; Kohler et al., 1981)and has been recovered in synovial fluid fromrheumatoid arthritis patients (Caruso, 1971;Emori et aL., 1973) and in fatty tissue, muscleand bone (Kohler et aL., 1981). lndomethacinenters the synovial fluid slowly and exceeds

plasma levels after 5 h (Emori et al., 1973). Onlytrace amounts of indomethacin have beendetected in saliva (Rothermieh, 1971) and inbrain tissue (Hucker et al., 1966). lndomethacinreadily crosses the human placenta (Traeger etaL., 1973; Moise et al., 1990) and is distributedin fetal tissues (Parks et aL., 1977). Placental

transfer is independent of gestational age

(Moise et al., 1990).ln women given indomethacin for pain

relief, post partum negligible levels of indo-methacin have been recovered from breast milk(Takyi, 1970; Lebedevs et al., 1991). ln onestudy, six of seven breast-fed infants had

plasma indomethacin concentrations of0( 20 iig/ml, below the detection limit of theassay, after maternaI doses of 0.94-4.3 mg/kgbw per day (Lebedevs et aL., 1991). Since theaverage milk:plasma ratio of indomethacin insubjects with measurable levels was only 0.37,it was concluded that only small amounts ofindomethacin could be ingested via breastmilk.

(c) EliminationMost administered indomethacin is excreted inthe urine either unchanged or in the form ofconjugated and unconjugated metaboliteswhich include demethylindomethacin, dechloro-benzoylindomethacin and demethyldechloro-benzoylindomethacin (Duggan et aL., 1972).After oral administration, these metabolites rep-resent 19-42% of the dose recovered in faeces,whereas an average of nearly 60% appears in theurine as the parent drug and its glucuronide

conjugates (Hucker et al., 1966; Duggan et al.,1972; Kwan et al., 1976). ln these studies, theamount of unchanged indomethacin in urine

was between less than 5% and up to 18%. Nodifferences in the excretion pattern of indo-

methacin or its metabolites were found afteroral, rectal or intravenous administration (Kwanet al., 1976).

lndomethacin is also eliminated in bile,where it undergoes extensive enterohepaticrecycling (Kwan et al., 1978). Once dischargedinto the bile, indomethacin is subsequently

hydrolysed and re-enters the circulationthrough the gastrointestinal tract (Hucker et aL.,1966). It has been estimated that 24-115% of agiven dose is reabsorbed into the circulation bythis mechanism (Kwan et aL., 1976). The spo-radie nature of bilary clearance may be respon-sible for the wide fluctuations in plasma

indomethacin levels and plasma half-livesreported in the literature. The lack of correla-tion between plasma indomethacin levels andclinieal therapeutie effects further supports thistheory. Bilary recycling and the presence ofunchanged indomethacin in bile may con-trib-ute to the production of intestinal les ions insome patients.

A two-compartment, open kinetic modelhas been proposed to describe the pharmacoki-netie profies of individuals partieipating in sin-gle-dose studies and patients undergoing long-term therapy. Dissolution of indomethacin

from the plasma follows a biexponentialpattern, with an initial rapid phase lasting upto 8 h foIlowed by a slower secondary phase

lasting 2.6-11 h (Alvan et al., 1975).Linear pharmacokineties have been demon-

strated with oral doses of 25-75 mg, withtypical peak plasma concentrations of1.1-4.4 iig/ml within 30-60 min (Emori et aL.,1976). The half-life in plasma is extremely

variable, ranging from 2 to i i h, perhaps

because of entewhepatie cycling (Flower et al.,1985). Comparable measurements of the areaunder the curve of plasma concentration-timewere observed in subjects given 25 mg indo-methacin orally or intravenously (Alvan et aL.,1975). Marked variabilty in the peak plasma

concentration between subjects and in the samesubjects tested on three separate occasions werereported by Emori et al. (1976), while few dif-ferences in plasma levels have been noted byother investigators (Alvan et al., 1975).

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No evidence of altered elimination patternsafter long-term treatment with indomethacinhave been documented.

(d) Effects of ageThe total plasma clearance rates of indo-methacin in adults are highly variable, rangingfrom 44 to 109 ml/h per kg bw (Alvan et al.,1975); in premature infants, a substantiaIlylower clearance rate of 7.6 :: 3.0 ml/h per kg bwhas been reported after intravenous administra-tion (Vert et al., 1980). ln children aged oneyear, the total clearance of indomethacin is sub-stantiaIly higher, at about 192 ml/h per kg bw(Olkkola et al., 1989). Indomethacin has beenwidely used as a non-surgical treatment ofpatent ductus arteriosus in premature infants, atoral doses of 0.1-0.3 mg/kg bw. Plasma half-livesare considerably longer in premature newborns(11-90 h) th an in adults, and wide variation isseen (Bhat et aL., 1979, 1980; Bianchett et aL., 1980).

Some investigators have postulated that theplasma half-lie is inversely correlated with ges-tational age (Evans et aL., 1979; Vert et al.,1980). Decreased renal function or lower hepat-

ic metabolism may explain the lower rate ofelimination of indomethacin in premature

infants. Alternatively, the differences related inhalf-life related to gestational age may corre-spond to maturation of drug metabolism sys-tems (Evans et al., 1981).

The pharmacokinetics of indomethacin inthe elderly population has been described

(Traeger et al., 1973; Kunze et aL., 1974;McElnay et al., 1992). No differences in absorp-tion rate or peak plasma levels were seen

between young volunteers and groups ofhealthy elderly subjects (McElnay et al., 1992).One study, however, reported twofold higherlevels in elderly patients than in young adultsafter a single 75-mg dose of indomethacin(Bruguerolle et al., 1986), although the elimina-tion rate of indomethacin was the same in thetwo groups. The clinical relevance of these datamay be that untoward effects after indo-methacin administration occur more frequentlyin patients over 60 years of age (Castleden &Pickles, 1988).

Age does not appear to influence the pro-tein-binding capacity of indomethacin. After

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oral administration, more th an 90% of a doseof indomethacin is bound to protein (Hultmarket al., 1975) comparable values were found inpremature newborns (Evans et aL., 1979), fuIl-term infants (Friedman et al., 1978) and theelderly (BrugueroIle et aL., 1986).

Some age-related alterations in excretioncapacity have been noted. ln one study, lowerlevels of unchanged indomethacin were recov-ered with increasing age, which were correlatedwith a reduction in renal function (Kunze et aL.,1974). The elimination kinetics in this group,were not affected, however. A 40% reduction inrenal clearance of indomethacin was observedin a study of 12 healthy 36-50-year-old subjectsin comparison with 15 healthy 19-34-year-old

subjects (Wichlinski et aL., 1983). This studysuggests that a reduction in renal clearance

may accompany advancing age.

3.2 Experimental modelsAs in humans, biodegradation of indomethacinin most animal species involves deacylationand demethylation pathways (Harman et al.,1964; Hucker et al., 1966). While there is noevidence of demethylation reactions or metabo-lites in hamsters, both metabolic pathways

have been shown in the rats, rabbits andguinea-pigs (Rowe & Carless, 1982). ln mon-keys, extensive metabolism of indomethacininto dechlorobenzoylindomethacin and excre-tion in the urine have been reported, whereas

in rats indomethacin is metabolized principallyinto demethylindomethacin (Yesair et al.i 1970a).

Interspecies variations in the metabolism ofdrugs and in their binding affinities to plasmaprotein must be considered before data on the

pharmacokinetics of indomethacin can beextrapolated. Marked differences in the absorp-tion, plasma half-life, metabolism and excre-tion rate of indomethacin have been docu-

mented among animal species and in compari-son with humans (Yesair et al., 1970a).The plas-ma concentration is also influenced by theroute of administration (Hucker et al., 1966).

ln an early study, higher plasma levels of14C-indomethacin were reported in dogs and

rats th an in rhesus monkeys or guinea-pigsafter intravenous administration. The tissuedistribution of the radiolabel was highest in

Indomethacin

guinea-pigs, which had a faster plasma clear-ance rate than the other species. The plasma

half-lives of indomethacin were several hoursin rats and minutes in monkeys and dogs

(Hucker et al.! 1966). ln horses, a peak plasmalevel of about 125 ng/ml was se en within 1 hafter a 250-mg oral dose of indomethacin

(Philips et al., 1980).ln horses given 100 mg indomethacin rec-

tally, maximal urinary levels were observed 2 hlater, with peak concentrations of 19-81 ¡ig/ml(Delbeke et al.! 1991). ln rabbits, peak plasmalevels appeared within 30-45 min after rectaladministration of a 100-mg indomethacinsuppository (Kuroda et aL., 1983), comparableto the time in humans. ln beagle dogs, gastricacidity influenced the absorption rate of a sus-tained-release indomethacin capsule: low gastricacid resulted in faster absorption, but bioavail-abilty was reduced (Yamada et al., 1990).

As in humans, placental transfer ofindomethacin has been documented. Whengiven during late gestation, indomethacin read-ily crosses the placenta in rats (Sharpe et aL.,1975), rabbits (Parks et al., 1977) and sheep(Levin et aL., 1979; Anderson et aL., 1980). lnone study in rats, the maternaI indomethacinplasma levels were 37-66 times higher th anfetallevels when the drug was administered ondays II and 12 of gestation, whereas only a

three- to fourfold difference between maternaIand fetal values was seen when it was given onday 21 (Klein et aL., 1981). Progressive decreasesin the maternal:fetal ratio of the concentrationof indomethacin plasma with advancing gesta-tional age have been confirmed in rats(Momma & Takao, 1987). ln other animal mod-els, such as the rabbit and sheep, fetal plasmalevels exceeded maternallevels when the drugwas given late in gestation (Parks et al., 1977;Harris & Van Petten, 1981).

Differences in the protein binding capacity

of maternaI and fetal blood may affect indo-methacin transport throughout gestation. lnrabbits, Parks et al. (1977) noted that the fetallevels of indomethacin increased as the maternaIlevels increased and there was always a sub-stantial difference between the maternaI andfetal concentrations, probably due to proteinbinding of indomethacin. Anderson et al. (1980)

found no difference in maternaI and fetal plasmaprotein binding affinity in sheep. Evidence to

support the theory that the plasma half-life ofindomethacin is inversely correlated with gesta-tional age was provided in a study in neonatal rats,in which an age-related increase in cytochromeP450 activity was reported (Clozel et aL., 1986).

The increase in microsomal activity may bepartially explained by an increased affinity ofthe enzyme for its substrate with age. An alter-native theory is that the low affinity in theneonate is due to the presence of competitiveinhibitors, as has been shown in neonatal rab-bit liver (Evans et aL., 1981).

The kidneys play a significant role in theelimination of indomethacin in some animalspecies, except dogs. ln dogs, at least 80% of anadministered dose of 14C-indomethacin was

excreted in the faeces as the parent compound,and large amounts were also present in bile. Itwas estimated that about 50% of the amount ofindomethacin excreted in bile is reabsorbed bythe intestines in dogs (Hucker et aL., 1966).Enterohepatic recycling has been desCfibed in

both rats (Hucker et aL., 1966; Yesair et al.,1970a,b) and monkeys (Yesair et aL., 1970a).Most excreted indomethacin is reabsorbedslowly by the intestine in rats (Hucker et al.,1966; Liss et al., 1968; Yesair et al., 1970b) andis thought to be involved in the occurrence ofintestinallesions in this species (Baer et aL., 1974).

3.3 Genetic variation ~No genetic variation in the pharmacokinetics

of indomethacin has been described among dif-ferent population groups.

4. Cancer-preventive Effects

4.1 Human studies4.1.1 Studies of cancer occurrence

(a) Colorectal cancerThere are no studies that specificaIly address therisk for colorectal cancer after use ofindomethacin alone. Studies that included sep-arate estimates of NSAIDs other than aspirinand those in which aspirin and other NSAIDs

were considered together are summarized in thechapter on aspirin.

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(b) Breast cancerlndomethacin was included in a hypothesis-

generating cohort study designed to screen 215

drugs for possible carcinogenicity, which cov-ered more than 140 000 subscribers enroIled inJuly 1969 to August 1973 in a prepaid medicalcare programme in northern California (USA).Computer records of persons to whom at leastone drug prescription had been dispensed werelinked to cancer records from hospitals and thelocal cancer registry. The observed numbers ofcancers were compared with expected numbers,standardized for age and sex, for the entirecohort. Three publications summarized thefindings for foIlow-up periods of up to sevenyears (Friedman & Ury, 1980), nine years(Friedman & Ury, 1983) and 15 years (Selby etaL., 1989). Among 4867 persons who receivedindomethacin, there was a significant (p .( 0.01)deficit of breast cancer (12 observed, 26

expected) in the seven-year foIlow-up. No nega-tive or positive association with use of indo-methacin was reported in the 15-year foIlow-up.

4.1.2 Studies of other relevant end-points

(a) Sporadic adenomatous polyps in the colonThere are no controlled studies of the risk forsporadic adenomatous polyps of the colon anduse of indomethacin alone. Studies of combinednon-aspirin NSAIDs in this respect are summa-rized in the chapter on aspirin.

(b) Adenomatous polyps in patients withfamilal adenomatous polyposis

Hirata et al. (1994) reported on two patientswith familal adenomatous polyposis who hadresidual polyps in the rectal remnant afterundergoing total colectomy and ileoproc-toscopy. They were treated with 50-mg indo-methacin suppositories once or twice daily andshowed regression of polyps (both size andnumbers) within three months. ln one patient,polyps recurred after cessation of therapy andregressed again with reinstitution.

Eight patients with familal adenomatouspolyposis who had undergone total colectomywith ileorectal anastomosis were given a 50-mgindomethacin suppository once or twice dailyfor four or eight weeks (Hirota et al., 1996). ln

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six patients, the polyps regressed, but recurredon cessation of therapy.

(c) Case studies of treatment for desmoidtumours

WaddeIl and Gerner (1980) reported threepatients with refractory desmoid tumours whoresponded to indomethacin. Waddell et aL.(1983) described two additional patients withdesmoid tumours, one of whom responded toindomethacin. Klein et al. (1987) reported sixpatients treated with indomethacin for thesetumours: one regressed completely, but noresponse was seen in the other five patients. Offour patients with desmoid tumours treated byTsukada et aL. (1992), one had complete remis-sion of the tumour, but the others did not

respond. Itoh et al. (1988) reported one patientwith recurrent abdominal desmoid tumours

who did not respond to indomethacin. Thus, of16 patients reported, six responded to indo-methacin.

4.2 Experimental models4.2.1 Experimental animaIs

(a) ColonStudies on the prevention of colon carcinogen-

esis in rats treated with indomethacin are sum-marized in Table 1.

Eight-week-old male Donryu rats receivedintraperitoneal injections of 20 mg;g bwmethylazoxymethanol acetate once a week forsix weeks. One group of rats received anintrarectal instilation of a I-ml solution ofindomethacin (macrogolum powder; 7.5 mglgbw) once a week on weeks 27, 28 and 29. Onecontrol group received instilations of 1.0 mlwater (vehicle control), and another wasuntreated. Colon tumours were counted inweek 30. The incidence of colon tumours inindomethacin-treated rats (15/30) was signifi-cantly lower than that in the vehicle control

group (19/23) and in the untreated controls(26/30) (p .( 0.05). lndomethacin treatmentreduced the me an number of colon tumoursper tumour-bearing rat (2.0) from that in thevehicle control group (3.5) and in untreated

contraIs (3.3) (p 0: 0.05). Treatment also reducedthe incidence of small intestine adenocarcinomas

Table 1. Prevention of colon tumourigenesis by indomethacinSpecies, strain, sex No. of Carcinogen (dose) Indomethacin Preventive efficacy Reference

animals/group Dose (route) Treatment relativeto carcino~ ...

Rat, Donryu, male 30 MAM (20 mg/kg bw) 7.5 mg/kg bw Afer Incidence, 42% (p -: 0.05); Kudo et al. (1980)

(intrarectally) multiplicity, 39%

Rat, Sprague-Dawley male 10 DMH (30 mg/kg bw) 20 mg/I (water) 3 d after Multiplicity, 83% (p -: 0.01) Pollard & Luckert (1980)

12 d after Multiplîcity, 65% (p -: 0.01)

35 d after Multiplicity, 77% (p -: 0.01)

0.2 mg/kg bw Afer Multiplîcity, 48% (NS)

(gavage)

Rat, Sprague-Dawley, male 7/8 NDMA-OAc (13 mg/kg 20 mg/I (water) Afer Multiplîcity, 90% (p -: 0.05) Pollard & Luckert (1981a)

bw)

Rat, Lobund Sprague-Dawley, 9 DMH (30 mg/kg bw) 20 mg/I (water) Afer Incidence, 75% (p -: 0.01); Pollard & Luckert (1981 b)

male multiplicity, 83% (p = 0.01)

7 MAM (30 mg/kg bw) 20 mg/I (water) Afer Incidence, 81 % (p -: 0.01);multiplicity, 89% (p -: 0.01)

Rat, F344, female 29 MNU (2 mg/rat) 2.5 mg/kg After Incidence, 55% (p -: 0.002); Narisawa et al. (1981)

(intraperitoneal) multiplicity, 59% (p -: 0.02)

Rat, F344, female 30 MNU (2 mg/rat) 20 ppm (water) After Incidence, 75% (p -: 0.01); Narisawa et al. (1982)

multiplîcity, 78% (p -: 0.01)

30 10 ppm (water) Afer Incidence, 79% (p -: 0.01);multiplicity, 80% (p -: 0.01)

Rat, F344, female 27 MNU (3 x 4 mg/rat) 10 ppm (water) During Incidence, 58% (p -: 0.05) Narisawa et al. (1983)

27 2-30 weeks Incidence 76% (p -: 0.01)

27 11 weeks after None

Rat, Lobund Sprague-Dawley, 10-27 DMH (2 x 30 mg/kg 20 ppm (water) Afer Incidence, 81% Poila rd & Luckert (1983)

male bw) Incidence, 79%

MAM (30 mg/kg bw) 1 Er0.08('..

~I::

1 g.

NDEA (100 mg/kg 20 ppm (water)bw); MNU (20 mg/kgbw); NBHBA (500

ppm); DMH (40 mg/kgbw); NBHP (1000ppm)

MAM, methylazoxymethanol acetate; DMH, 1,2-dimethylhydrazine; NS, not significant; NDMA-OAc, N-nitrosodimethylacetoxyamine; F344, Fischer 344; MNU, N-methyl-N-nitrosourea;1-HA, 1-hydroxyanthraquinone; NDEA, N-nitrosodiethylamine; NBHBA, N-nitrosobutyl(4-hydroxybutyl)amine; NBHP, N-nitrosobis-2-hydroxypropylamine

§ 1

Table 1 (contd)Species, strain, sex No. of Carcinogen (dose) Indomethacin

animals/group Dose (route) Treatment relativeto carcinogen

Rat, Sprague-Dawley, male 30 DMH (20 mg/kg bw) 20 mg/L (water) During and after

Rat, Sprague-Dawley, male 50 NDMA-OAc (2 mg/kg 10 ppm (water) Duringbw) Afer

During and after

Rat, ACI/N, male 14 1-HA (1.5% in the 16 ppm (water) During and afterdiet)

Rat, F344, male 19-20 After

Preventive efficacy Reference

Incidence, 36% (p .: 0.005)

NoneMultiplicity, 32% (p .: 0.05Multiplicity, 55% (p .: 0.05

Incidence of colon adenoma +carcinoma, 100% (p .: 0.002); ofcolon adenoma +adenocarcinoma, 100%

(p .: 0.01); of squamous cellpapillomas of the forestomach,72% (p .: 0.01)

Adenoma incidence, 100%Tumour incidence, 100%

(p .: 0.05)

Metzger et al. (1984)

Narisawa et al. (1984a)

Tanaka et al. (1991)

Shibata et al. (1995)

s;~n::¡,~§:oo?:en

o..n¡,~("ro..""..ro..ro~..õ'~

Indomethacin

to 4/30, from 10/23 in vehicle controls and

12/30 in untreated con troIs (p ~ 0.05) (Kudo etaL., 1980).

Male Sprague-Dawley rats received fiveweekly intragastric administrations of 30 mg/kgbw 1,2-dimethylhydrazine as a solution of thehydrochloride in sterile saline, freshly preparedbefore administration. Three groups of 10 ratswere given 20 mg/ltre indomethacin in thedrinking-water ad libitum starting 3, 12 or 35days after the last dose of 1,2-dimethylhy-

drazine, and three control groups were giventap-water that had been neither chlorinatednor acidified. The numbers of colon tumourswere counted 20 weeks after the start of car-cinogen treatment. Treatment with indo-methacin reduced the number of tumours perrat from 5.3 to 0.9 (p = 0.002) when given threedays after the carcinogen, from 2.6 to 0.9(p = 0.0065) when given after 12 days and from2.2 to 0.5 (p = 0.007) when given after 35 days.ln the last group, the number of rats with

tumours was reduced from 9/10 to 4/9

(p = 0.0016). Indomethacin treatment had noeffect on body weight, and no les ion was

observed in any other organ. ln a second pro-

tocol, two groups of 10 rats received intragastrieadministrations of 1,2-dimethylhydrazine as

above. Seven days after the fifth dose, onegroup received daily intragastric administra-tions of 0.25 mg/kg bw indomethacin obtainedfrom commercial capsules (Indocin~), and thesecond group received an intragastrie adminis-tration of the vehicle (10/ cornstarch). Twentyweeks after the onset of treatment, a nonsignif-ieant reduction in the number of tumours perrat, from 2.7 to 1.4, was seen (p = 0.08) (Pollard& Luckert, 1980).

Two groups of seven and eight male wean-ling Sprague-Dawley rats received a singleintraperitoneal injection of 13 mg/kg bwN-nitrosomethyl(acetoxymethyl)amine. Twoweeks later, the first group was given 20 mg/ml(3 mg/kg bw) indomethacin in the drinking-water for 18 weeks, at whieh time the experi-ment was terminated. The number of rats withtumours was reduced from 6/8 to 1/7 in thefirst experiment and from 8/10 to 0/5 in thesecond. (The statistieal signifieance of thesedifferences was not reported.) The number of

intestinal tumours per rat was reduced from 1.5to 0.14 (p ~ 0.05). ln a duplicate experiment

with groups of five indomethacin-treated and10 control rats, the number of tumours per ratwas reduced from 1.4 to none (Pollard &Luckert, 1981a).

Weanling male Lobund strain Sprague-Dawley rats received a single dose of 30 mg/kgbw 1,2-dimethylhydrazine by gavage; 34 dayslater, indomethacin was given in the drinking-water (20 mg/l) and continued until the end ofthe experiment at 20 weeks. Indomethacin

treatment reduced the incidence of colon

tumours from 9/10 to 2/9 (p ~ 0.01) and themultiplicity of tumours from 1.30 to 0.22(p = 0.01). Indomethacin also reduced the aver-age body weight by 7% (p ~ 0.05). ln a secondexperiment, rats were injected subcutaneously

with methylazoxymethanol acetate (30 mg/kgbw) and 7 or 35 days later given indomethacinin the drinking-water (20 mgll. The numbersof intestinal tumours in indomethacin-treatedand untreated rats were determined at week 20.Treatment with indomethacin seven days aftercarcinogen treatment reduced the incidence

from 7/9 to 1/7 (p ~ 0.01) and the multiplicityfrom 1.3 to 0.14 (p ~ 0.01). Treatment 35 daysafter carcinogen treatment reduced the inci-dence from 3/5 to 0/5 and the multiplicity from1.4 to O. No significant reduction in body-

weight gain was seen with either protocol(Pollard & Luckert, 1981 b).

Nine-week-old female Fischer 344 rats weregiven an intrarectal instilation of a 0.5-mlsolution (2 mg) of 13.3 mg/kg bw N-methyl-N-nitrosourea three times a week in weeks 1-5.Groups of 29 and nine rats received intraperi-toneal injections of 2.5 mg/kg bw indo-methacin solution three times a week in weeks

11-25. AnimaIs in the first group were kiled at25 weeks, and those in the second group were

subjected to endoscopie examination and keptfor an additional 10 weeks. A third group of

nine rats was given indomethacin in weeks

26-35.The tumour incidences in the threegroups were 9/29,3/9 and 7/9, respectively, andthe numbers of tumours per rat were 0.45, 0.33and 1.0, respectively. Three control groups of20, 30 and nine rats were treated withN-methyl-N-nitrosourea as ab ove; one group

161

IARC Handbooks of Cancer Prevention

then received intraperitoneal injections of0.1 ml of the vehicle (methylceIlulose); the

other two groups were not treated. The tumourincidences in the three groups were 14/20,

20/30 and 6/9, respectively, and the numbers oftumours per rat were 1.1, 1.0 and 1.3 (p valuenot given). Thus, indomethacin did not inhibitexisting tumours when administered between25 and 35 weeks (Narisawa et al., 1981).

Three groups of 30 female Fischer 344 ratsreceived intrarectal instilations of 2 mgN-methyl-N-nitrosourea in weeks 1-5. Twogroups were given indomethacin at concentra-tions of 20 or 10 mg/l (20 or 10 ppm) in weeks11-25 (consumption of water was not docu-

mented); the third group was given tap-water.AIl rats were kiled at week 26. Three rats giventhe high dose of indomethacin died before theend of treatment and a total of 8/90 rats died ofpneumonia or lung abscess. ln rats treated with20 mg/l (20 ppm) of indomethacin, a reductionin the incidence of colon tumours was seen,

from 18/27 to 4/24 (p -( 0.01) and a reductionin the multiplieity from 1.04 to 0.23 tumoursper rat (p ? 0.01). With a dose of 10 mg/l (10ppm) indomethacin, the reduction in inci-dence was from 18/27 to 4/28 (p -( 0.01) andthe reduction in multiplieity from 1.04 to 0.21

(p -( 0.01) (Narisawa et al., 1982).Colonie tumours were induced in female

Fischer 344 rats by intrarectal administration of4 mg per rat of a freshly prepared 0.5-ml solu-tion of N-methyl-N-nitrosourea on days 3, 5

and 7. Indomethacin was given at a concentra-tion of 0.001 % (10 ppm) in drinking-water forvarious periods. The incidence of tumours incontrol rats kiled at week 31 was 12/27.

Administration of indomethacin on days 1-7reduced the incidence to 5/27 (p -( 0.05), andadministration in weeks 2-30 to week30 reduced the incidence to 3/28 (p -( 0.01).The reduction in the incidence (6/28) of colontumours when indomethacin was given inweeks 11-30 was not signifieant. The incidenceof colon tumours in rats given indomethacinin weeks 2-30 and kiled on week 41 (10/22)

was significantly higher (p -( 0.01) than inrats receiving identieal treatment with indo-methacin but kiled in week 31 (Narisawa et aL.,1983).

..162

Groups of 10-27 male weanling LobundSprague-Dawley rats received two intragastricadministrations of 30 mg/kg bw 1,2-dimethyl-hydrazine hydrochloride at seven-day intervalsor a single subcutaneous injection of 30 mg/kgbw methylazoxymethanol acetate. Treatmentwith 20 mg/l indomethacin in the drinking-water (estimated intake, 2.5 mgkg bw per day)was initiated 14 or 63 days after l,2-dimethyl-hydrazine treatment and 14 or 77 days aftermethylazoxymethanol acetate treatment. Thedevelopment of intestinal tumours was pre-vented or retarded significantly with indo-methacin in comparison with that of controlanimaIs. ln the rats treated with l,2-dimethyl-hydrazine, the incidence of colon tumours wasreduced from 20/25 to 4/27 (p -( 0.05) after14 days and from 12/12 to 10/13 (p -( 0.05) after63 days. ln those treated with methylazoxy-

methanol acetate, the incidence of colontumours was reduced from 16/17 to 3/15

(p -( 0.05) after 14 days and from 10/10 to 9/10after 77 days (Pollard & Luckert, 1983).

Two groups of 30 male Sprague-Dawley rats,with an average weight of 120 g, were given

subcutaneous injections of 20 mg;g bw1,2-dimethylhydrazine hydrochloride once a

week for 20 weeks. One group of rats was given20 mg/l (20 ppm) indomethacin in drinkingwater during the initiation and post-initiationphases. The rats were kiled 32 weeks after thestart of carcinogen treatment. Indomethacin

had no significant effect on food intake orwater consumption, and the average bodyweights of the two groups were similar. Theincidence of colonic tumours was reduced from88 to 56% (p -( 0.005). The numbers of metas-tases to lymph nodes were comparable

(Metzger et al., 1984).Male Sprague-Dawley rats, eight weeks old,

were given Altromin-1320 chow and anintrarectal instilation of 2 mg/kg bw N-nitroso-dimethyl(acetoxymethyl)amine once a week inweeks 1-10. Three groups of 50 rats were given0.001 % (10 ppm) indomethacin in the drink-ing-water in weeks 1-10, 11-20 and 1-20. Twocontrol groups were given 0.1% ethanol inwater or water only. Indomethacin given afterthe carcinogen treatment reduced themultiplicity of colon tumours from 4.7 to

Indomethacin

3.2 (p -( 0.05); when it was given during andafter the carcinogen it reduced the multiplicityfrom4.7t02.1 (p-(0.05) (Narisawaetal., 1984).

Six-week-old male ACI/N rats were fed a dietcontaining 1.5% 1-hydroxy-anthraquinone

(purity and diet consumption unspecified) for48 weeks. A second group was given I-hydroxy-

anthraquinone as above plus 16 ppm indo-methacin in the drinking-water for 48 weeks

(water intake unspecified). A control groupreceived basal diet and tap-water only.Treatment with I-hydroxyanthraquinonedecreased body weight by 7% (p -( 0.02) andincreased the relative liver weight by 15%(p -( 0.001). The number of rats with adenomasor adenocarcinomas in the colon (12/27) was

reduced to 0 by co-administration of indo-methacin (p -( 0.01), and the number of squa-mous-ce Il papilomas of the forestomach was

reduced from 14/27 to 2/14 (p -( 0.01) (Tanakaet al., 1991).

(b) OesophagusThese studies are summarized in Table 2. ln afirst experiment, groups of 24 and 45 three-month-old CS 7BL male mice were givenN-nitrosodiethylamine (purity unspecified) atconcentration of 0.04 ¡.l/ml (37.7 ppm) andindomethacin at a concentration of 16 mg/l (16ppm) in the drinking-water daily for two weeksand then three times a week for 18 weeks (water

intake not monitored). The number of

oesophageal tumours per centimetre wasreduced from 6.04 to 3.74 (p -( 0.001). ln a sec-ond experiment, groups of eight and 16 mice

were given the same treatments daily for 30days and then twice a week for 16 weeks. The

number of oesophageal tumours per centimetrewas reduced from 4.10 to 2.66 (p -( 0.01). ln athird experiment, 16 mice were given the car-cinogen daily for 30 days and then twice a weekfor four months, and 19 mice received indo-methacin in the drinking-water four months

after the beginning of carcinogen treatment.

Both groups were kiled eight months after thatdate. The number of tumours per centimetrewas reduced from 6.10 to 4.74 (p 0( 0.01) (Rubio,1984). (The Working Group noted that bodyweights and gastrointestinal toxicity were notdocumented.)

Groups of 18-61 female C57BL mice, threemonths of age, were given N-nitrosodiethy-lamine (purity unspecified) in the drinking-water at a concentration of 0.4 mg/l

(0.4 ppm) daily for three months. The firstgroup was kiled at the end of treatment and

the second group three months after theend of treatment; the third group was given

indomethacin at a concentration of1.6 mg/l (1.6 ppm) for three months from theend of carcinogen treatment. Indomethacin

treatment reduced the number of tumours percentimetre of oesophageal mucosa from 5.01 to2.85 (p 0( 0.01). ln a second experiment, two

Species, strain, sex No. of animais!

group

Mouse, C57BL, male 24 + 45

8 + 16

16 + 19

Mouse, C57BL, female 18-61

18 + 19

35 + 39

Rat, LLO, male 35 + 58

Carcinogen (dose)

Table 2. Prevention of oesophageal tumourigenesis by indomethacin

Preventive effcacy Reference

NDEA (0.4 ppm) 1.6 ppm Afer 43%; p 0( 0.01

( drinking-water) Afer 21%; p 0.05

32%; p 0( 0.01

Afer 32% p 0( 0.01

NSEE (50 mg mg bw) 25 ppm (diet) Afer 63%; p 0( 0.05

NDEA (37.7 ppm)

Indomethacin

Dose (route) Treatment

relative

to carcinogen

During 38%; p 0( 0.001During 35%; p 0( 0.01During and after 22%; p 0( 0.01

Rubio (1984)16 ppm

( drinking-water)

Rubio (1986)

Bespalov et al.

(1989)

NDEA, N-nitrosodiethylamine; NSEE, N-nitrososarcosine ethyl ester

163

IARC Handbooks of Cancer Prevention

groups of 19 and 18 mice were given the sameconcentration of N-nitrosodiethylamine in thedrinking-water for three months. The firstgroup was kiled six months after treatmentand the second was given indomethacin in the

drinking-water for six months starting at theend of carcinogen treatment, after which theywere kiled. lndomethacin treatment reduced

the tumour index from 4.79 to 3.78 (p -- 0.05).ln a third experiment, three groups of 39, 35

and 36 mice were given the carcinogen treat-ment for four months. The first group waskiled at the end of treatment and the secondthree months after treatment; the third groupwas given 1.6 mg/l (1.6 ppm) indomethacin forthree months after carcinogen treatment. Areduction in the tumour index from 5.23 to3.55 (p -- 0.01) was observed with indo-methacin treatment (Rubio, 1986). (TheWorking Group noted that body weights andgastrointestinal toxicity were not reported.)

A group of male outbred LlO rats, weighing120-130 g, received N-nitrososarcosine ethylester (purity unspecified) by gavage at a dose of50 mg/kg bw, five times per week for 16 weeks.After this treatment, a control group of 58 ratswas given basal diet, and a second group of 35rats received a diet containing 25 mg/kg(25 ppm) indomethacin (intake not document-ed). AlI rats were kiled 32 weeks after thebeginning of carcinogen treatment, andtumours of the oesophagus were examinedmacroscopicaIly and histologicaIly. Three ratsdied with a perforating gastric ulcer. lndo-methacin treatment reduced the incidence ofoesophageal tumours from 89.7 to 65.7%

(p -- 0.05), and their multiplicity from 4.3 :: 0.6to 1.6 :: 0.4. The incidence of forestomach

tumours was also decreased, from 41.4 to14.3% (p -- 0.05), and their multiplicity from0.9 :: 0.1 to 0.4:: 0.3 (Bespalov et al., 1989).

(c) Mammary glandThese studies are summarized in Table 3. FemaleSprague-Dawley rats, 50 days of age, received asingle intragastric administration of 5 mg7,12-dimethylbenz(a)anthracene (DMBA). Threedays later, 32 rats were given a low-fat di et (5%corn oil) and 34 rats a high-fat diet (18% cornoil), with or without indomethacin. lndo-

..164

methacin was added to the diet at a concentra-tion of 0.004% (w/w) (40 ppm) (food intakeunspecified). This treatment did not change thebody weights significantly. ln rats fed the low-fat diet, the reductions in the incidence, mult-plicity and size of mammary tumours were notsignificant. ln rats fed the high-fat diet,indomethacin had no significant effect on theincidence or multplicity of mammary tumours,but the mean tumour size was reduced from4.08 to 1.46 g (p -- 0.01) (Carter et aL., 1983).

Pemale Sprague-Dawley rats, 50 days old,received intragastric administrations of16 mg/rat DMBA in 1 ml sesame oil. Fourgroups of 25 rats were given indomethacin at25 or 50 mg/kg di et (25 or 50 ppm) from weeks-2 to +1 or from week +1 for 150 days. Whenadministered from weeks -2 to +1, indomethacindelayed the appearance of mammary tumoursby 10-20 days. After 150 days of indomethacintreatment, the total number of tumours per ratwas reduced from 8.66 to 5.79 with 50 ppm (p-- 0.01) and to 5.94 with 25 ppm (p -- 0.01).When administered at 50 ppm from weeks +1to the end, indomethacin reduced the mult-plicity of mammary carcinomas from 6.40 to3.71 (p -- 0.01), that of benign tumours from2.26 to 0.40 (p -- 0.01) and that of aIl tumoursfrom 8.66 to 4.11 (p -- 0.01). Administration ofthe lower dose of indomethacin during the sameperiod changed none of the three parameters.The experiment was repeated with a dose of 8 mgDMBA per rat. The results of the two experimentswere comparable (McCormick et aL., 1985).

Virgin female Sprague-Dawley rats, 36 daysold, received an intragastric administration of10 mg DMBA in 1 ml of sesame oil. lndo-methacin was mixed into the diet at a concen-tration of 50 mg/kg diet (50 ppm), which wasgiven either from weeks -2 to + 1 or weeks + 1 tothe end of the experiment at 27 weeks.Treatment had no effect on body weights.Administration of indomethacin from weeks

-2 to +1 did not reduce the multiplicity ofmammary cancers or of aIl tumours, butadministration from weeks + 1 to the end of

experiment reduced mammary carcinoma mul-tiplicity from 3.46 to 2.56 (p -- 0.05) and totaltumour multiplicity from 3.65 to 1.88 (p -- 0.01)(McCormick & Wilson, 1986).

Table 3. Prevention of mammary tumourigenesis by indomethacin

Species, strain, sex No. of animals/ Carcinogen Indomethacin Preventive efficacy Referencegroup (dose) Dose (route) Treatment

relative to

carcinogen

Rat, Sprague-Dawley, 32-34 DMBA (5 mg/rat) 40 ppm (diet) Afte r None Carter et al. (1983)female

Rat, Sprague-Dawley, 25 DMSA (16 mglrat) 25 or 50 ppm Sefore and Senign tumours, multiplicity, McCormick et al. (1985)female (diet) during 81% (p 0: 0.01)

After Carcinomas, multiplicity, 42% (p0: 0.01)

Rat, Sprague-Dawley, 25 DMSA (10 mg/rat) 50 ppm (diet) Sefore and None McCormick & Wilson (1986)female during Carcinoma multiplicity, 26% ; P

After 0: 0.05

Rat, Sprague-Dawley, 28-29 DMSA (10 mg/rat) 40 ppm (diet) After None Abou-El-Ela et al. (1989)female

Rat, Sprague-Dawley, 32-33 DMSA (5 mglrat) 50 ppm (diet) Afer High fat: tumour incidence, Noguchi et al. (1991)female 63% (p 0: 0.01)

Low fat: none

Rat, LLO, female 21 MNU (12 mg/rat) 25 ppm (diet) Afer Tumour incidence, 37%; p 0: Bespalov et al. (1992)0.05

DMBA, 7,12-dimethylbenz¡aJanthracene; MNU, N-methyl-N-nitrosourea

~I

S0.oSrD..::~nSi"

IARC Handbooks of Cancer Prevention

Virgin female Sprague-Dawley rats, 50 daysold, received a single intragastric administra-

tion of 10 mg DMBA. Three weeks later, groupsof 28-29 rats were placed on high-fat diets(20% corn oil) and 0.004% (w/w) (40 ppm)indomethacin until the end of the experimentat16 weeks. Indomethacin had no significanteffect on body weight or food intake and didnot reduce the incidence, latency or number ofmammary tumours per tumour-bearing rat(Abou-El-Ela et al., 1989).

Four groups of 32 or 33 virgin female

Sprague-Dawley rats received an intragastricadministration of 5 mg DM BA. Seven days later,two groups were given a high-fat di et (20%corn oil), and the two other groups received alow-fat diet (0.5% corn oil). One group on eachdiet was given 0.005% (w/w) (50 ppm) indo-methacin seven days after DMBA up to the endof the experiment, 20 weeks after DMBAadministration. Indomethacin treatmentreduced the number of rats with tumours from26/32 to 10/33 in the high-fat group (p .( 0.01)but increased the number of tumour-bearingrats from 9/33 to 11/32 in the group on thelow-fat diet. Indomethacin reduced the multi-plicity of mammary tumours in the high-fatgroups from 2.3 to 0.9 (p .( 0.001) but had nopreventive effect in rats fed the low-fat di et(Noguchi et al.i 1991).

Female LlO (outbred) albino rats, weighing200-230 g, were given one dose of 1 mgN-methyl-N-nitrosourea in 0.1 ml saline solu-tion into each of the 12 mammary glands (totaldose, 12 mg/rat). A control group of 25 ratsthen received basal diet, and 21 rats were givenindomethacin at 25 mg/kg in the diet (25 ppm)for six months, when aIl animaIs were kiled(feed intake unspecified). Most of the mammarytumours were adenocarcinomas. Indomethacinreduced the incidence of mammary tumoursfrom 19/25 to 10/21 (p .( 0.05) but did notaffect their multiplicity (1.36 and 1.14, respec-tively) (Bespalov et al., 1992).

(d) TongueTwo groups of 17 and 13 six-week-old maleACI/N ratsi weighing 120 g, were given4-nitroquinoline-l-oxide at 10 ppm in thedrinking-water for 12 weeks. One group was

166

switched to tap-water and the second to 10 ppmindomethacin for 24 weeks (water consumptionunspecified). No difference between the twogroups in body weight or relative liver weightwas seen. The incidence of aIl tumours (squa-mous-ceIl papiloma or carcinoma) was reducedfrom 12/17 to 3/13 (p .( 0.02) and the incidenceof carcinoma from 12/17 to 2/13 (p ~ 0.005)

(Tanaka et al., 1989); see also Table 4).

(e) Oral ca vit yTwo groups of five female and five male Syriangolden hamsters, eight weeks of age, receivedapplications of a 0.5% solution of DMBA inmineraI oil three times a week on the left buccalpouch. One of the groups simultaneouslyreceived a 0.5% solution of indomethacin

(1 mg/animal) in the mouth daily until kiling.A group of five male and five female animaIs

was left untreated. One female and one malefrom each treated group were kiled in weeks 8,

10, 12, 13 and 14. No morphological changeswere seen in untreated hamsters. Indomethacintreatment reduced the multiplicity of tumoursfrom 6.4 to 2.8 (p .( 0.05) (Perkins & Shklar,

1982). (The Working Group noted the smaIl

number of animaIs per group.)Three groups of 10-11 male Syrian golden

hamsters, three to four months old, were treat-ed with either mineraI oil, a 0.5% solution ofDM BA in mineraI oil, DMBA in mineraI oil plusan indomethacin suspension or mineraI oilplus the indomethacin suspension. DMBA wasapplied to the right buccal pouch three times aweek for 14.5 weeks; four drops of a suspensionof indomethacin (1 mg/animal) was adminis-

tered oraIly daily. AIl hamsters were kiled 16.5weeks after the beginning of treatment. Indo-methacin had no effect on the incidence of aIloral tumours or of carcinomas or on the latencyor multiplicity of tumours (Gould et al., 1985).

Two groups of six to 12 male Syrian ham-sters, four to six weeks old, received applica-

tions of a 0.5% solution of DMBA in liquidparaffin on both cheek pouches three times aweek for 10 weeks. During weeks 12-22 (time ofterminal kil), one group of hamsters received a

daily oral dose of 1 mg/animal (0.1 ml solution)sodium indomethacin trihydrate; the secondgroup was not treated. The total number of

Table 4. Prevention of tumorigenesis in other organs by indomethacinSex, species, No. of Carcinogen (dose) Organ Indomethacin Preventive efficacy Referencestrain animals/ Dose (route) Treatment

group relative to

carcinogen

Rat, ACI/N, male 13 4-NQO (10 ppm) Tongue 10 ppm (water) Afer Incidence: total tumour, 67% T anaka et al. (1989)

(p 0( 0.002); carcinoma, 78%(p 0( 0.005)

Hamster, Syrian 10 DMBA (unspecified) Oral cavity 1 mg (oral) During Multiplicity, 56% (p 0( 0.02) Perkins & Shklar (1992)

golden, male andfemale

Hamster, Syrian 10-11 DMBA (unspecified) Oral cavity 1 mg (oral) During 0 Gould et al. (1985)golden, male

Hamster, Syrian 6-12 DMBA (unspecified) Oral cavity 1 mg (oral) During 0 Franklin & Craig (1987)golden, male

Rat, ACI/N, male 10 MF (200 ppm) Liver 10 ppm (water) Before, during Incidence: adenoma, 86% Tanaka et al. (1993)and after (p 0( 0.01); carcinoma, 100%

(p 0( 0.001); multiplicity, 97%(p 0( 0.001)

Hamster, Syrian 20-30 BOP (10 mg/kg) Pancreas 20 ppm (water) Afer Multiplicity, 51 % (p 0( 0.05) Takahashi et al. (1990)golden, female

Mouse, BOF, 78-80 OH-BBN (8 doses of Urinary 7.5 ppm (diet) Before, during Incidence, 79% (p 0( 0.05) Grubbs et al. (1993)male 7.5 mg/mouse) bladder and after

78-84 15.0 mg/kg (diet) Before, during Incidence, 100% (p 0( 0.01)and after

Mouse, Swiss, 26 3-Methylcholanthrene Cervix 40 ppm (die!) Before, during Incidence, 71 % (p 0( 0.01) Rao & Hussain (1988)female and after

S0.0S(D..

~I 1 i

~I

Table 4. (contd)

Sex, species, No. of Carcinogen (dose) Organ Indomethacin Preventive effcacy Referencestrain animalsl Dose (route) Treatment

group relative to

carcinogenMouse, albino 30-61 DMBA (8 doses of 25 Vagina and 20 mg/l (water) After Carcinoma incidence, 40.5% Bespalov et al. (1992)outbred, female fl9) cervix

(p.: 0.05)

Mouse, Balb/c, 6 BaP (100 flg/rat) Skin 8.4 flg/mouse Before and Tumour weight reduced by 46% Andrews et al. (1991)male (topically) during

6 DMBA unspecified Skin None

Mouse, hrlhr, 20 UV radiation Skin 1.8 mg/kg (water) During a Haedersdal et al. (1995)female

Rat, LLO, male 25 ENU (75 mg/kg bw) Brain, kidney 20 mg/l (water) Afer Incidence: brain, 35% Alexandrov et al. (1996)and female postnatally (p .: 0.05); kidney, 29%

(p ;: 0.05)

4-NQO, 4-nitroquínoline-1-oxide; 2-AAF, 2-acetylaminofluorene; OH-BBN, N-nitrosobutyl(4-hydroxybutyl)amine; DMBA,7,12-dimethylbenz¡aJanthracene; BaP, benzo¡aJpyrene; BOP, N-nitrosobis(2-oxopropyl)amine; UV; ultraviolet; ENU, N-ethyl-N-nitrosourea

:i::n::$:::ei0"oo"'Vl

o..n$:::("ro..'"..ro..ro::,.õ'::

Indomethacin

smaIl and large tumours of the oral cavity in thetwo groups was similar (Franklin & Craig, 1987).

(f) LiverTwo groups of 10 five-week-old male inbredACI/N rats were fed a diet containing 200 ppm2-acetylaminofluorene in weeks 0-6 and basal

diet in weeks 17-36. One group was given

10 ppm indomethacin in the drinking-waterstarting one week before carcinogen treatmentto week 17. The experiment was terminated

in week 36. Treatment with 2-acetylaminofluo-rene increased the liver weight from 3.47 to4.75 g/100 g bw (p -( 0.001); and administrationof indomethacin reduced the weight to3.69 g/100 g bw (p -( 0.05). Indomethacin treat-ment also reduced the incidence of hepatic ade-nomas from 7/10 to 1/10 (p -( 0.01) and that ofhepatic carcinomas from 8/10 to 0/10 (p -(0.001). The number of aU hepatic neoplasms

per rat was reduced from 4.00 to 0.10 (p -( 0.001)(Tanaka et al., 1993; see also Table 4).

(g) PancreasOutbred female Syrian golden hamsters, fiveweeks old, received five weekly doses of10 mg/kg bw N-nitrosobis(2-oxopropyl)aminesubcutaneously. One group of 20 hamsters wasgiven 20 ppm indomethacin in weeks 6-32

(after which they were kiled) , and a control

group of 30 hamsters was given tap-water.Indomethacin treatment had no effect on body-weight gain but induced a nonsignificant reduc-tion in the incidence of pancreatic tumours,

from 20/28 to 10/19, and a significant reductionin the multiplicity of pancreatic adenocarcino-mas, from 1.29 to 0.63 (p -( 0.05) (Takahashi etal., 1990).

(h) Urinary bladderGroups of 78, 80 and 84 male C57BL x DBA/2Fimice, 49 days of age, received 7.5 mg N-nitroso-butyl( 4-hydroxybutyl)amine (purity unspecified)dissolved in 0.1 ml/l ethanol:water (20:80) by

intragastric administration once a week foreight weeks. The first group of mice was giventhe carcinogen alone, and the second and thirdgroups received diets containing indomethacinat 7.5 and 15 mg/kg diet (7.5 and 15 ppm) start-ing one week before cardnogen treatment and

continuing until the end of the experiment at

180 days; the higher concentration was deter-mined to be the maximal nontoxic dose.Indomethacin reduced the incidence of urinarybladder tumours from 14 to 4% (p -( 0.05) whengiven at 7.5 ppm and to 0 (p -( 0.01) when givenat 15 ppm. The incidence of aU bladdertumours, including papilomas, was reduced

from 24 to 5% (p -( 0.05) and 0 (p -( 0.01), respec-tively (Grubbs et al., 1993; see also Table 4).

(i) Cervix and vagina:These studies are summarized in Table 4.Random-bred, 10-12-week-old virgin Swiss

mice were treated with 3-methylcholanthrene

(purity unspecified) by the insertion of sterile,double cotton threads impregnated withbeeswax containing approximately 600 /lg3-methylcholanthrene Into the uterine cervixOevels of exposure unspecified). Four groups of25 mice were given 0, 10, 20 or 40 mg/kg of di et(0, 10,20 or 40 ppm) indomethacin starting twoweeks before carcinogen treatment up to16 weeks, when aU animaIs were kiled. Control

groups of 15 mice received beeswax-impreg-

nated threads and the same diets as describedabove (dietary intake not documented).Indomethacin treatment did not reduce body-

weight gain. No cervical tumours were observedin the mi ce treated with beeswax-impregnatedthread. ln 3-methylcholanthrene-treated mi ce,indomethacin at 40 ppm reduced the cervicaltumour incidence from 21/23 to 6/23 (p -( 0.01).The reduction at lower doses of indomethacinwas not significant (Rao & Hussain, 1988). (The

Working Group noted that the linearity of thepreventive efficacy in relation to the doses of

indomethacin was not documented.)

Groups of 30 outbred albino (SHR) virginfemale mice, 12 weeks old received polymer

sponge tampons impregnated with a 0.1 % tri-ethylene glycol solution of DMBA intravaginaUy.The average dose of DMBA was 25 /lg per appli-cation. The tampons were changed twice week-ly for eight weeks, for a total of 16 applications.Nine weeks after the start of DMBA treatment,61 mice received no further treatment and30 received indomethacin in the drinking-water at 20 mg/l (20 ppm; water consumptionunspecified) for a further 28 weeks. AIl surviving

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lARC Handbooks of Cancer Prevention

mice were kiled 36 weeks after the start of theexperiment, but 30-60% died with progressingtumours of the vagina and cervix before thattime. AIl tumours were examined histologicaIly.The total incidence of vaginal and cervical(papilomas plus carcinomas) was similar in thetwo groups (63-72%), but the ratio of carcinomasto papilomas was lower in mice given DMBAfoIlowed by indomethacin (12 carcinomas and7 papilomas) than in mice given DMBA al one(41 carcinomas and 3 papilomas; carcino-ma:papiloma ratio, 14). Significantly morecontrol than indomethacin-treated mice died

before the end of the experiment (61 % and 37%,respectively; p.( 0.05) (Bespalov et al., 1992).

(D SkinTwo groups of six male Balb/c mice,aged six to eight weeks, received two weeklyapplications of 20 III benzo(a)pyrene (purity

unspecified) dissolved in 0.5% acetone (totaldose, 100 l.g per rat). One group was given 8.4Ilg indomethacin dissolved in acetone at a con-centration of 0.42 mg/ml 20 min before thebenzo(a)pyrene application on the same area ofthe shaved dorsal trunk. Treatment lasted for sixmonths. Indomethacin pretreatment increasedthe time of tumour ons et from 19.8 to 24.8

weeks (p .( 0.05) but reduced the mean weight oftumours from 0.57 to 0.31 g. Two other groupsreceived weekly applications of DMBA dissolvedin lanolin plus liquid paraffin (dose of DMBAunspecified), and one group was treated weeklywith 16.8 Ilg indomethacin 20 min before

DMBA application, as described above. No dif-ference in tumour onset or weight was seenbetween the two groups (Andrews et al., 1991;see also Table 4).

Two groups of 20 female hr/hr C3H/Tifmice, 14-15 weeks of age, were exposed toultraviolet radiation at a daily dose of12.6 kJ/m2 for 8 min/day on four days perweek. Indomethacin was given in the drinking-water (concentration unspecified) at an intakeestimated to be 1.8 mg/kg bw per day. Micewere treated until they were kiled by tumours.Indomethacin delayed the time of appearanceof the first tumours (p .( 0.001) but increasedthe mortality rate (p .( 0.0005) (Haedersdal etaL., 1995).

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(k) Transplacental carcinogenesisGroups of 6-10 LlO outbred albino rats, three tofour months of age, were injected intravenouslyon day 21 of gestation with 75 mg/kg bwN-ethyl-N-nitrosourea in saline; there were

12-16 pregnant controls. Two groups of 42 and25 pups of each sex were treated with wateralone or with 20 mg/l (20 ppm) indomethacinin the drinking-water throughout postnatallife.The daily intake of indomethacin was estimatedto be 1.6 mg/kg bw. The incidence of braintumours was reduced from 36/42 to 14/25

(p .( 0.05) and their multiplicity was decreased from1.95 to 0.92 (p .( 0.05). The multiplicity of kidneytumours was reduced from 0.45 to 0.32 (p .( 0.05).There was no significant difference in body weightsbetween the groups (exact data not provided)(Alexandrov et aL., 1996; see also Table 4).

(1) Multi-organ c8rcinogenesisGroups of 19-20 male Fischer 344 rats, sixweeks of age, were treated sequentially with fivecarcinogens, as foIlows: a single intraperitonealinjection of 100 mg/kg bw N-nitrosodiethyl-amine on day 1; intraperitoneal injections of20 mg/kg bw N-methyl-N-nitrosourea on days3, 9 and 12; administration of N-nitrosobutyl(4-hydroxybutyl) amine in the drinking-water

(0.05%) (500 ppm) during weeks 1 and 2;subcutaneous injections of 40 mg/kg bw1,2-dimethylhydrazine on days 17, 20, 23

and 26; administration of N-nitrosobis-2-

hydroxypropylamine in the drinking-water(0.1%) (1000 ppm) during weeks 3 and 4.Groups of rats were given indomethacin in thedrinking-water (20 ppm) and basal diet in weeks6-28. Indomethacin did not reduce body-weight gain or food or water consumption. Theincidences and multplicities of lung adenomaswere significantly decreased in indomethacin-treated rats. Indomethacin treatment did notreduce the incidence or multiplicity of urinarybladder papilomas but did decrease the develop-ment of preneoplastic lesions. The incidence ofadenomas of the large intestine and the numberof rats bearing tumours were decreased in theindomethacin-treated. group in comparisonwith control. Only the decrease in tumour inci-dence was statistically significant (p .( 0.05)controls (Shibata et aL., 1995; see also Table 1).

Indomethacin

4.2.2 ln-vitro models

(a) Cultured mammalian cellsNon-regressing, premalignant, nodule-like alve-olar lesions can be induced in cultured mou semammary organs by DMBA. Female Balb/cmice were pretreated with oestradiol and prog-esterone for nine days to stimulate hormones,and then their mammary glands were excisedand cultured for 10 days with insulin, prolactin,aldosterone and hydrocortisone to promote

growth. During this period, the cultures wereexposed to 2 ¡.g/ml DMBA for 72-96 h. After thepromotion period, aIl of the hormones exceptinsulin were withdrawn to induce regression ofthe lobular alveolar structures. HaIt of the mam-mary glands were also treated with indo-methacin at doses of (10-9 to 10-5 mol/l duringthe first 10 days of culture. The average inci-

dence of mammary gland lesions in the DMBA-treated group was 63%; indomethacin inhibitedthe formation of DMBA-induced lesions, themost effective dose of 10-6 mol/l causing 77%inhibition (Mehta et al.i 1991).

Inhibition of TPA-induced early antigen ofEpstein-Barr virus in lymphoblastoid Raji ceIlshas been used to screen for anti-tumour pro-moters. Indomethacin inhibited the inductionin a dose-related manner; the effective concen-tration resulting in 50% inhibition was13 ¡.g/ml (Saito et aL., 1986).

Indomethacin was a competitive inhibitor ofdihydrodiol dehydrogenase in isolated hepato-cytes from uninduced Sprague-Dawley rats.Preincubation of ceIls with 30 ¡.mol/l indo-

methacin before addition of (:t)-trans-7,8-dihy-droxy-7,8-dihydrobenzo(a)pyrene prevented theformation of benzo(a (pyrene-7,8-dione, whichmay be an activated metabolite of the carcino-gen benzo(a)pyrene. (Flowers-Geary et aL., 1995).

(b) Antimutagenicity in short-term testsThe antimutagenicity effects of indomethacinare summarized in Table 5 and are displayedgraphicaIly as an activity profie in Figure 2.

Indomethacin reduced aflatoxin-inducedmutagenicity in Saccharomyces cerevisiae (Niggliet al., 1986) and clastogenicity in human lym-phocytes (Amstad et aL., 1984). It inhibitedarachidonic acid-induced sister chromatid

exchange in Chine se hamster ovary cells co-cultured with human leukocytes (Weitberg,1988). Indomethacin inhibited the inductionof sister chromatid exchange by arachidonicacid in combination with benzo(a)pyrene or

DMBA in a human tumour-derived cellline andinhibited sister chromatid exchange inductionby the last two compounds in a rat tumour-derived ceIl line (Abe, 1986). Indomethacin

completely inhibited the mutagenicity of 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene in V79

ceIls pretreated with arachidonic acid (Sevaniaii& Peterson, 1989). ln Salmonella typhimurium

strain TA98, indomethacin reduced the muta-genicity of N-acetylbenzidine, but it enhancedbenzidine-induced mutagenicity. It inhibitedDNA binding induced by benzidine orbenzidine analogues in a microsomal activationsystem initiated by arachidonic acid but had noeffect when the activation system was initiatedby hydrogen peroxide (Petry et aL., 1988). Itpartially inhibited benzidine- or diethylstilboe-strol-induced sister chromatid exchange in celllines derived from rat and human hepatomas(Buenaventura et aL., 1984; Grady et al., 1986),and it inhibited sister chromatid exchange

induced by diethylstiboestrol in mouse cells(Hilbertz-Nilsson & Forsberg, 1989). It alsoreduced the frequency of chromium chIo ride-induced chromosomal aberrations in humaiilymphocytes (Friedman et aL., 1987). It inhibit-ed DNA single-strand breaks induced by thetumour promoter, fecapentane-12, but it didnot inhibit hydrogen peroxide-induced breaks

(Plummer et al., 1995). Pretreatment of ratswith indomethacin prevented hydralazinehydrochloride-induced unscheduled DNAsynthesis in hepatocytes in vitro (Martell et aL.,1995). Indomethacin did not inhibit mito-mycin C-induced sister chromatid exchange inhuman lymphocytes (Ekmekci et al., 1995). Itinhibited DNA binding induced by phenylhy-droquinone in vitro (Pathak & Roy, 1993), and itinhibited the effects of the tumour promoter,TPA, including chromosomal aberrations inhuman lymphocytes and sister chromatidexchange in Chinese hamster ovary ceIls co-cultured with human leukocytes (Emerit &Cerutti, 1982; Weitberg, 1988). Indomethacinenhanced the frequency of styrene- and styrene

..171

Table 5. Antimutagenic effects of indomethacinMutagen Dose of muta- Test code8 % Inhibitionb Dose range (¡.g/ml) Reference

gen (¡.g/ml) (% enhancement) Low High

Aflatoxin B1 0.09 CHL 38 10.0 10.0 Amstad et al. (1984)

Aflatoxin B1 78.0 SCG 55 0.1 0.7 Niggli et al. (1986)

Arachidonic acid 24.3 SiC 86 10.7 10.7 Weitberg (1988)

Benzolalpyrene + arachidonic acid 25.2 SHT (9) 18.0 36.0 Abe (1986)

Benzol alpyrene 25.2 SHT 40 36.0 36.0 Abe (1986)

Benzol alpyrene 126 SiC 0 18.0 36.0 Abe (1986)

Benzolalpyrene 50.4 SIT 0 18.0 36.0 Abe (1986)

Benzolajpyrene 75.6 SIT 69 36.0 36.0 Abe (1986)

B(ajP-diol 0.5 G9H 100 7.2 7.2 Sevanian & Peterson (1989)

B¡ajP-diol 1.0 G9H 100 7.2 7.2 Sevanian & Peterson (1989)

BlalP-diol 1.5 G9H 100 7.2 7.2 Sevanian & Peterson (1989)

Benzidine + arachidonic acid 4.6 BIO 99 7.2 7.2 Petry et al. (1988)Benzidine 0.028 SA9 (42) 3.6 36.0 Petry et al. (1988)Benzidine 5.0 SHT 80 3.6 3.6 Grady et al. (1986)

Benzidine 7.5 SHT 75 3.6 3.6 Grady et al. (1986)

Benzidine 10.0 SHT 56 3.6 3.6 Grady et al. (1986)

Benzidine 1.0 SIT 25 3.6 3.6 Grady et al. (1986)Benzidine 5.0 SIT 100 3.6 3.6 Grady et al. (1986)

Benzidine 7.5 SIT 100 3.6 3.6 Grady et al. (1986)

Benzidine 10.0 SIT 80 3.6 3.6 Grady et al. (1986)

Dichlorobenzidine 6.3 BIO 55 7.2 7.2 Petry et al. (1988)N-Acetylbenzidine 5.6 BIO 76 7.2 7.2 Petry et al. (1988)N-Acetylbenzidine 0.034 SA9 37 3.6 36.0 Petry et al. (1988)T etramethylbenzidine 6.0 BIO 93 7.2 7.2 Petry et al. (1988)Chromium chloride 2.5 CHL 57 10.7 21.0 Friedman et al. (1987)

Dianisidine 6.1 BIO 99 7.2 7.2 Petry et al. (1988)Diethylstilboestrol 0.027 SHT 100 3.6 3.7 Buenaventura et al. (1984)

Diethylstiboestrol 0.27 SIM 65 0.4 3.6 Hillbertz-Nilsson & Forsberg

(1989)Diethylstilboestrol 2.7 SIT 100 3.6 3.6 Buenaventura et al. (1984);

Shamon et al. (1994)

DMBA 5.1 SHT 5 17.9 36.0 Abe (1986)

DMBA + arachidonic acid 5.1 SHT 54 35.8 36.0 Abe (1986)DMBA 128 SiC 5 17.9 36.0 Abe 1986)DMBA 51 SIT 4 17.9 36. Abe (1986)

51 SIT 64 35.8 36.0 Abe (1986)Fecapentane-12 12.5 DIH 100 35.8 36.0 Plummer et al. (1995)

Fecapentane-12 25.0 DIH 100 35.8 36.0 Plummer et al. (1995)

Hydrogen peroxide 3.4 DIH (17) 35.80 36.0 Plummer et al. (1995)

Hydrogen peroxide 6.8 DIH 10 35.80 36.0 Plummeret al. (1995)

Hydralazine 110 URP 73 5.0 5.0 Martell et al. (1995)

Hydralazine 200 URP 55 5.0 5.0 Martelli et al. (1995)

Mitomycin C 0.03 SHL 21 0.0 0.0 Ekmekci et al. (1995)

Phenyl hydroquinone 186 BIO 92 179 179 Pathak & Roy (1993)

TPA 0.1 CHL 79 10.0 10.0 Emerit & Cerutti (1982)

TPA 0.1 SIC 88 10.7 10.7 Weitberg (1988)

Styrene 52.0 SHL (52) 26.9 53.7 Lee & Norppa (1995)

Styrene 104 SHL (63) 26.9 53.7 Lee & Norppa (1995)

Styrene oxide 6 SHL (181) 26.9 53.7 Lee & Norppa (1995)

Styrene oxide 12.0 SHL (51) 26.9 53.7 Lee & Norppa (1995)B(ajP-diol, 7,8-dihydroxy-7,8-dihydrobenz(ajpyrene; DMBA, 7, 12-dimethylbenz(ajanthracene; TPA, 12-0-tetradecanoylphorboI13-acetate8 The test codes are defined in Appendix 2

b A positive value is the percentage inhibition of the effect induced by the mutagen in the test; a negative value (in parentheses) is the percentage enhancement of the effect.-172

Indomethacin -

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rARC Handbooks of Cancer Prevention

oxide-induced sister chromatid exchange inhuman lymphocytes (Lee & Norppa, 1995).

Indomethacin at 100 ¡.mol/l inhibitedDMBAinduced forward mutation to 8-azagua-nine resistance in S. typhimurium strain TM677by 69% (Shamon et al., 1994). Transformed focican be induced in Balbc3T3 cells in a two-stageassay, with initiation by 3-methylcholanthrene(0.5 ¡.g/ml) and promotion by TPA 0.1 ¡.g/ml).Indomethacin inhibited the induction of trans-formed foci in a dose-dependent manner, causing81 % inhibition at a concentration of20 ¡.g/ml (Semba & Inui, 1990).

Indomethacin reversed the inhibition ofgap-junction interceIlular communication inliver cells from male Wistar rats induced by thehepatic tumour promo ter phenobarbital,

1,1) I-trichloro-2,2-(p-chlorophenyl)ethane(DDT) or y-hexachlorocyclohexane (lindane).Treatment with 2 mmol/l phenobarbital inhib-ited interceIlular communication by 30%, asmeasured by microinjection of fluorescentLucifer YeIlow dye after a 5-h incubation.

Indomethacin did not reverse the inhibition ofcommunication induced by DDT or lindane(Leibold & Schwartz, 1993)

4.3 Mechanisms of chemoprevention4.3.1 Inhibiton of carcinogen activation

ln 1971, Vane reported that indomethacin

inhibits prostaglandin production by interferingwith the cyclooxygenase(COX)l-catalysed oxy-

genation of arachidonic acid. For a fuIl descriptionof this mechanism, see the General Remarks.

An additional important mechanism by whichindomethacin may prevent cancer is inhibitionof carcinogen activation (Szarka et al., 1994).

There is indirect evidence that COX cataly-ses conversion of the benzene metabolite,hydroquinone, into reactive oxygen productsthat accumulate in bone marrow and damageDNA. Indomethacin inhibits activation ofhydroquinone,. thereby preventing DNA dam-age and further myelotoxicity (Schlosser et al.,1990). Another mutagen similarly activated andformed during protein pyrolysis is 3-methyl-imidazo(4)5-fJquinoline (IQ). Once forme d, IQand its methylated derivatives are potent muta-gens (Wild & Degen, 1987; Petry et al., 1989).

1 Used as a synonym for prostaglandin endoperoxide synthase (PGH synthase)

174

Indomethacin and other NSAIDs which prevent

bioactivation of these molecules may preventcancer through this mechanism (Earnest et al.,1992).

4.3.2 Effects on cell prolieration and

apoptosisEarly investigations demonstrated that indo-methacin and other NSAIDs interfere with adiverse range of biological processes related toceIl growth including reductions in glycolysis

(Cooney & Dawson, 1977)) uncoupling of oxida-tive phosphorylation (Whitehouse, 1964),

decreased mucopolysaccharide formation (Kalbhenet al.) 1967) and interference with calcium ionuptake and other calcium-mediated. processes

(Northover, 1977). Enzye pathways found sub-sequently to be inhibited by indomethacin

include phospholipase Az (Kaplan et al., 1978;Lobo & Hoult) 1994), 15-lipoxygenase (Siegel et aL.,1980), myeloperoxidase (Shacter et aL., 1991) andglutathione S-transferase (Wu & Mathews, 1983).

A direct inhibitory effect of indomethacinon cellular proliferation is indicated by theresults of studies of cell cultures, showing thatindomethacin inhibits cell multplication andprogression of the ceIl cycle from G i to S phase

(Bayer & Beaven, 1979; Bayer et aL., 1979).Several recent reports support the concept thatindomethacin prevents tumour cell growththrough alterations in the ceIl cycle and induc-tion of apoptosis leading to cell death (Lu et al.)1995; Shiff et al, 1996). ln one study, indo-methacin reduced the levels of two keycyclin-dependent kinases, p33 and p34, in HT-29

colon ceIls, both of which are crucial to cellcycle progression. Indomethacin induced apop-tosis in these cells and increased the proportionof cells in the GolGi phases, which correlated withits abilty to suppress cell prolieration (Shiff et

al.) 1996). A similar mechanism has not yetbeen demonstrated in human colon tissue.

Indomethacin may also protect againstcancer by altering the activity of enzymes otherthan cyclooxygenase. These effects includeinhibition of enzymes such as cyclic AMP

protein kinase and phosphodiesterase, both

of which may be critical to cancer initiationand promotion (Kantor & Hampton, 1978;

Indomethacin

Abramson & Weissmann, 1989). Likewise,indomethacin may exert cancer preventiveeffects in the colon by preventing inductionof ornithine decarboxylase, the first and rate-limiting enzyme in polyamine biosynthesis(Narisawa et al., 1985, 1987). Data showingan association between ornithine decarboxy-

lase activity, tumour promotion and cellproliferation in various organs including thecolon and skin have been reported (Pegg

& McCann, 1982; Slaga, 1983). Moreimportantly, in patients with adenomatouspolyps, ornithine decarboxylase activity ismarkedly elevated (Luk & Baylin, 1984).Suppression of ornithine decarboxylaseby indomethacin in mouse skin with concomi-tant prevention of skin carcinogenesis by

the tumour promoter TPA (Furstenberger& Marks, 1978, 1980; Verma et al., 1980) furthersupports the theory that this enzyme isinvolved in carcinogenesis.

Although not direct chemopreventivemechanisms, other growth regulatory effectsexerted by indomethacin, such as inhibition ofangiogenesis (Gullno, 1981; Ziche et al., 1982;Peterson, 1986), may be relevant. The results ofa recent study conducted in murine 3T3fibroblasts suggest that the abilty ofindomethacin to block angiogenesis may be

related to its inhibitory effect on hyaluronicacid production (August et al., 1994).Hyaluronic acid has been recovered from thestroma of several malignant tumours (Knudsonet al., 1984), including human breast tumours(Bertrand et al., 1992; Shuster et al., 1993),and is believed to play a role in cell migration.Interruption of hyaluronic acid synthesis,therefore, may be yet another potential targetof the action of indomethacin.

Nitric oxide stimulates COX-2 activity in aconcentration-dependent manner (Salvemini etal., 1993). At pharmacological, micromolar

doses, indomethacin had no effect on nitricoxide synthase activity or mRNA expression, incontrast to aspirin, which inhibited the enzymethrough a post-translational modificationmechanism at milimolar concentrations(Amin et al., 1995).

4.3.3 Immune surveilance

Another mechanism that may be relevant tothe chemopreventive action of indomethacin isimmunomodulation (Honn et aL., 1981; Plescia,1982; Goodwin & Ceuppens, 1985; Hwang,1989). Of the arachidonic acid metabolites,

only prostaglandin E2 has a defined function inregulating both humoral and ceIlular immuneresponses (Goodwin, 1981, 1984). Elevatedtissue levels of prostaglandin E2 have beenshown to suppress immune surveilance byinhibiting T-cell proliferation, natural kiler ceIl

cytotoxicity and lymphokine production(Taffet & Russell, 1981; Goodwin & Ceuppens,1983). Apparently, prostaglandin E2 exertsits activity by interfering with the productionand activity of interleukin 2, a potentlymphokine needed for T-cell proliferation.Drugs such as indomethacin, which blockcyclooxygenase activityand prostaglandin pro-

duction, stimulate the immune response bothin vitro and in vivo (Han et al., 1983; Goodwin,1984).

An alternative mechanism implicating theimmune system involves the abilty of indo-methacin to restore expression of majorhistocompatabilty antigens (HLA) in humancolon cancer ce lis (Arvind et aL.1 1996). ln

human colon tumours and in histologically nor-mal mucosa distant from colon adenomas,expression of class 1 and Il HLA antigens iseither reduced or lost. Loss of HLA antigenexpression allows cancer cells to escape

immune surveilance (McDougaIl et al., 1990;Tsioulias et al., 1992, 1993). Indomethacininduced expression of the class Il antigen, HLA-DR, in a time- and dose-dependent manner andincreased the steady-state levels of HLA-DRmRNA (Arvind et al., 1996).

The capacity of indomethacin to stimulatethe lipoxygenase pathway, particularly 15-lipoxy-genase (Vanderhoek et al., 1984), and influencethe immune system through productionof leukotrienes and other metabolites is

an alternative mechanism worthy of furtherstudy. Additional experiments conductedwith specific COX-2 inhibitors wiIl assist indelineating the role of this enzyme in chemo-prevention.

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IARC Handbooks of Cancer Prevention

5. Other Beneficiai Effects

Rogers et aL. (1993) randomized 44 patientswith a clinical diagnosis of Alzeimer's disease to

indomethacin (100-150 mg/day) or a matchingplacebo in a double-blind study of six months'duration. Gnly 14 of 24 (58%) of those ran-domized to indomethacin and 14 of 20 (70%)of those randomized to placebo completed thetrial and were available for measurements.

More subjects on indomethacin stopped theirtreatment, primarily because of gastrointestinalside-effects. Patients on indomethacin who com-pleted the study showed a 1.3% improvementin standardized tests, whereas those on placeboshowed a 8.4% decline; at least a 4% declinewas seen in only 2 of 14 patients onindomethacin and 12 of 14 patients on placebo.

The remainder of the studies on Alzheimerdisease (McGeer et aL., 1996), which were obser-vational in nature, were based on a variety ofconditions used as surrogates for NSAID use,including history of arthritis and analgesic use.

These are summarized in the chapter onaspirin.

6. Carcinogenicity

6.1 HumansNo data were available to the Working Group.

6. 2 Experimental animais

Groups of six-week-old female Sprague-Dawleyrats received indomethacin in the drinking-water at a concentration of 10 mg/l

(10 ppm) for 92 weeks. The cumulative dose ofindomethacin was estimated to be 200 mg perrat. Control rats were given drinking-water

only. A significant increase in moderate (10/48;p -( 0.05) and severe (5/48; p -( 0.05) hyperplasiaof the urinary tract was observed in comparisonwith the control group (5/49 and 1/49, respec-tively). The number of rats with mammaryadenocarcinomas was higher in those given

indomethacin (5/48) th an in the untreated

control group (1/49; p -( 0.01). The authorsreported a higher incidence of benign mammarygland tumours in the treated (19/48) than inuntreated rats (11/49; p -( 0.01) (Holmäng et al.,1995).

176

Groups of 50 28-day-old (adolescent) and97 -day-old (adult) male Sprague-Dawley ratsreceived a single application of 25 mg/kg bwindomethacin dissolved in 1 ml acetone on theshaved dorsal skin. A second group received thesame dose of indomethacin and acetone plus21.3 mg/animal of a carrier substance(Amuno(ß). Control groups received either 1 mlacetone or the carrier only. The animaIs wereobserved until natural death. Adolescent rats

treated with indomethacin with or withoutcarrier had a lower average body weight thancontrol rats (p -( 0.05). More malignant tumourswere observed in the indomethacin-treated

adolescent rats with or without carrier than intheir respective controls (p -( 0.02). ln contrast,treatment of adult rats with indomethacin withor without carrier had no effect of the inci-dence of malignant tumours. Leydig-celltumours of the testis (distinguished fromhyperplasia) were more frequent in indo-methacin-treated rats than in either adolescent(p = 0.005) or adult (p = 0.03) controls. Malignantintestinal tumours were observed in 3/50 ado-lescent rats treated with indomethacin and in8/50 also given the carrier but not in control

rats (0/50). The increase was not significant. Nodifference was seen in the adult treated rats(Goerttler et al., 1992). (The Working Groupnoted that a single dose of indomethacin wasused and that the route of administration was

inappropriate for carcinogen evaluation.)Two groups of six-week-old female Sprague-

Dawley rats were fed a semisynthetic peIleteddiet containing 0.2% N-(4-(5-nitro-2-furyl)-2-thiazolyl)formamide for seven weeks. They

were then fed the basal diet up to week 92. Onegroup was given indomethacin in the drinking-water at a concentration of 1 mg/l for 92 weeks

starting one week before the carcinogen treat-ment, for an estimated cumulative dose of 200mg per rat. The controls were fed synthetic dietfor 92 weeks. There was no significantdifference in body weight between treated anduntreated rats. lndomethacin treatment increasedthe incidence of urothelial tumours from 4/50 to10/48 (p -( 0.05) (Holmäng et al., 1995).

Weanling female Fischer 344 rats were fedstandard diet and water ad libitum (type of dietand consumption not specified) and given

Indomethacin

subcutaneous injections of 1,2-dimethyl-hydrazine (purity unspecified) at 40 mg/ratonce a week for 10 weeks. After laparotomy, 42rats were found to be free of visible metastasesand 16 rats had grossly apparent metastases inregional nodes, the peritoneum, the omentumand the liver. One-haIt of the animaIs with nometastases were given indomethacin in drink-ing-water at a concentration of 20 ¡.g/ml

(20 ppm) until they died or became moribund;the remaining 21 rats were given drug-free

water. lndomethacin treatment reduced themedian survival from 69 to 29 days (p .: 0.01)and increased the number of rats with grosslyevident metastases from three to nine

(p = 0.035). When eight rats with metastaseswere treated with indomethacin as described

above, there was no significant effect on meansurvival (Danzi et al.i 1984). (The WorkingGroup noted that assignment of rats with andwithout metastases on the basis of staging lapa-rotomy could be subject to considerable variation.)

7. Other Toxic Effects

7.1 Adverse effects

7.1.1 HumansSee also General Remarks and the chapter on

sulindac.

(a) Gastrointestinal tract taxicity

ln the meta-analysis of Henry et aL. (1996),described in the chapter on aspirin, the risks forserious upper gastrointestinal complications afteruse of indomethacin were statistically indistin-guishable fram those of most other NSAIDs.

Within individual studies, however, indome-thacin was consistently associated with a higherrisk for such complications, and in a rankinganalysis it ranked 5 (with 1 the most and 12 theleast toxic) of 12 NSAIDs analysed. The pooledrelative risk estimate from a meta-analysis offive studies that included indomethacin was 3.0(95% Ci, 2.2-4.2) for low-dose indomethacinusers and 7.0 (95% CI, 4.4-11) for high-dose

users in comparison with non-users. Given base-line risks for ulcer disease of 0.5 per 1000 per yearin younger adults (Garcia Rodriguez et al., 1992)and 4 per 1000 in older adults (SmaIley et al.,1996), the rates of serious ulcer complications

among indomethacin users can be estiated to be2 per 1000 in younger adults and 10-20 per 1000

in those 65 years and older.

(b) Reproductive and develapmental effectsln non-randomized trials of short courses (oneto three days) of indomethacin at doses of

100-400 mg/day for the prevention of pre-termlabour, no increase in the risk for congenital

anomalies, premature closure of the ductus

arteriosus or pulmonary hypertension wasobserved (Ostensen, 1994). Of 57 infantsdelivered at or before 30 weeks who had beenexposed to indomethacin prenataIly, 62% hadpersistent ductus arteriosus, compared with44% of unexposed infants matched withexposed infants on gestational age andsex (Norton et aL., 1993). This difference wasstatisticaIly significant. More of the indo-methacin-exposed infants with persistent ductusarteriosus required surgicalligation th an affectedinfants who had not been exposed.

There have been case reports of perinataldeath associated with severe oligohydramniosin the infants of mothers who used indo-

methacin (Itskovitz et al., 1980; Veersema et aL.,1983). Of 37 fetuses exposed to indomethacinfor treatment of pre-term labour, 70% werediagnosed with oligohydramnios, in compari-

son with 3% of fetuses whose mothers had

been treated with agents other th an NSAIDs(Hendricks et al., 1990).

ln two studies, indomethacin treatment ofmothers for pre-term labour was associatedwith necrotizing enterocolitis in the neonate(Norton et al., 1993; Major et al., 1994).

An unspecified defect was identified fromhospital dis charge records in one infant amongthe offspring of 50 women who were membersof a health care cooperative in Seattle

(USA) and who filed a prescription forindomethacin during the first trimester(Aselton et al., 1985).

(c) Other taxie manifestationsIndomethacin users report a variety of signsand symptoms more frequently than users ofother NSAIDs These include veTtigo andheadache (Fries et al., 1991).

""

IARC Handbooks of Cancer Prevention

7.1.2 Experimental animaIs

Many of the toxic effects of indomethacin innon-hum an species may result from its actionas a prostaglandin synthesis inhibitor. As in

humans, the primary site of acute toxicity invarious species is the gastrointestinal tract.Drug-induced adverse effects have also beenreported in the tissues of the kidney, liver, heartand bone, and significant adverse reproductiveand developmental effects have been found.

(a) Acute and short-term toxicityIndomethacin was toxic to several species whenadministered at low levels. The LDso values were

as foIlows: mou se, 5.7 mg/kg bw day oraIly forfive days Oulou et al., 1969); and rat, 2.4 mg/kgbw per day oraIly for 14 days (Awouters et al.,1975) and 13 mg/kg bw intraperitoneaIly forseven days (Klaassen, 1976). No defined symp-toms of toxicity were reported (Klaas sen, 1976).When slightly higher levels of 5-10 mg/kg bwper day oraIly were administered to male andfemale rats for up to 21 days, 77-100% of theanimaIs died within four to 10 days. Surviving

female rats had a lower weight gain (Gaetani etal., 1972).

Marked growth inhibition, measured asdecreased body-weight gain, and decreased

food and water consumption were seen in ratstreated with indomethacin at 2.5-5 mg/kg perday oralIy on five days per week for up to26 weeks. AlI female and 40% of male ratstreated at 5 mg/kg bw per day died within24 weeks. Overt signs of toxicity includedbloody faeces, emaciation, hypoactivity, pilo-erection, urinary incontinence, loss of groom-ing activity and anorexia. None of the surviv-ing rats exhibited any abnormal appearance orbehaviour, and no significant changes were seenon haematology, blood chemistry, urinalysis,organ weight analysis or pathology (Nomma et al.,1978).

AlI male and female rats given indo-methacin 1-3 mg/kg bw per day oraIly onsix days per week for 30 days or 3 mg/kg bwper day oraIly for six to 12 weeks survived

and remained in good health. Two of sixrats at 6 mg/kg bw per day died after 10 and 13days (Nomura et aL., 1978; Anthony et al.,1994).

178

(b) Gastrointestinal tract toxicity

Instilation of indomethacin at 12 mg/kg perday directly into the stomach of male andfemale marmosets resulted in the death of aIlanimaIs within 20 days. Diarrhoea was observedin animaIs of each sex treated with the drug atthis level of 6 mg/kg per day oraIly for up tofour weeks (Oberto et aL., 1990).

Gastrointestinal damage induced by indo-methacin has been reported in rats, mice,rabbits, guinea-pigs, dogs and marmosets.Typical lesions include gastric inflammation,mucosal and submucosal haemorrhages,ulceration, perforations and adhesions of thesmalI bowel and peritonitis. The extent oftoxicity appears to vary with the excretion ofintact drug into the bile and the length

of its contact in the smalI intestine, due to

enterohepatic circulation of the drug (Hucker et

al., 1966; Yesair et al., 1970a; Duggan et al.,1973, 1975; Klaassen, 1976; Cronen et al.,1982).

ln rats, a species considered to be highlysusceptible to the ulcerogenic effect of indo-

methacin (Wilhelmi, 1974), low oral doses

rapidly induced marked gastric and duodenaldamage when administered as either a singleacute dose or over several weeks. Unspecified

gastrointestinal lesions were observed within24-48 h of a single oral dose of 16 mg/kg bwin female rats (Fracasso et al., 1987), while oraldoses as low as 6-10 mg/kg bw producedsmaIl haemorrhages, smaIl to large (:: 2 mm)ulcers and slight to marked hyperaemia

(30-100% incidence) within two to five days oftreatment (Shriver et aL., 1977; Laufer et al.,1994). Multiple oral doses of 6-9 mg/kg bw perday for up to four days or 3 mg/kg per day forup to II days resulted in similar lesions, smaIl

bowel perforation and adhesions in male rats(Shriver et al., 1977; Laufer et aL., 1994). Oraldoses of 5 mg/kg bw per day on five days perweek for up to 26 weeks produced fibrinousperitonitis, due to perforated ulcers, in theileum in 40% of male and 100% of female ratsthat died during the experimental period

(Nomura et aL., 1978). Few les ions were report-ed in rats after single or multiple daily oraldoses of 1-3 mg/kg for up to four days (Shriveret al., 1977).

Indomethacin

Non-ulcerated lesions in the rat caecum,

consisting of prominent mucosal folds showingsubmucosal fibrosis with fibrous obliterationand thickening of the muscularis mucosae, wereinduced by indomethacin administered in aregimen designed to mimic a course of hum antreatment. Anthony et al. (1994) treated rats for30 weeks with consecutive doses of 3 mg/kg bwper day for 12 weeks, 4.5 mg/kg bw per day forone week, 6 mg/kg bw per day for one week, nodrug for six weeks, 4.5 mg/kg bw per day fortwo weeks and control diet for eight weeks.These diaphragm-like caecal lesions, similar toles ions observed in the ileum of some patientstreated for long periods with NSAIDs (Lang etal., 1988), appear to arise from healed caecalulcers.

Gastrointestinal ulceration was also report-ed in mice and guinea-pigs treated twice withindomethacin at doses of 2.5-10 mg/kg bw and50-100 mg/kg bw orally, respectively(Wilhelmi, 1974). Regions of focal necrosis andsubepithelial oedema were noted in rabbitstreated intraluminaIly into the stomach with asolution delivering 100 mg/kg bw of drug for15 min (Wallace et al., 1991). ln dogs, ulcera-tion and inflammation were reported in thesmall and large intestines after treatment with2.5 mg/kg bw per day indomethacin oraIly forup to three years (Stewart et aL., 1980). Subacutediffuse inflammation of the gastrointestinalsubmucosa and serosa with peritoneal involve-ment, necrosis or ulceration of the mucosa andhaemorrhages were also reported in male andfemale marmosets (Callthrix jacchus) treatedwith indomethacin at 6-12 mg/kg bw per dayfor up to four weeks (Oberto et al., 1990).

Gastrointestinal damage seems to stem fromthe abilty of indomethacin to suppress prosta-glandin synthesis. ln this region, prosta-

glandins are involved in modulation of gastricacid and mucus production, intestinalbicarbonate secretion, regulation of mucosalblood flow and the inflammatory process.

Thus, development of indomethacin-induced

gastrointestinallesions may be prevented untiweaning in suckling rat pups by prostaglandins,which are known to be present in milk (Bedrick& Holtzapple, 1986). Lesions may develop as aresult of drug-induced ischaemia in the

mesenteric tissues, an effect demonstrated indogs, in regions corresponding to drug-inducedulceration (Cronen et aL., 1982).

Exacerbation of indomethacin-induced gas-trointestinal damage was reported in rats anddogs by an experimentally induced increase ingastric acid production or a decrease in duode-nal alkaline secretion. Duodenallesions (up toa 100% incidence), some penetrating to themuscularis mucosae, and a few lesions in thestomach were precipitated in dogs subsequent-ly injected with gastric acid-inducing histamine(40-80 /lg/kg bw intramuscularly, four timesper hour for 6 h) beginning 12 h after a singleoral dose of 70 mg indomethacin. Alone, thisdose produced no ulcers in either the stomachor duodenum within 18 h (Takeuchi et aL.,1988). A similar increase in gastric damage wasproduced in rats (Ellot et aL., 1996).

ln 630 Wistar rats receiving 12-14 mg/kg bwindomethacin by gavage, there was significantlymore intestinal ulceration (two- to fourfold) inthose receiving a regular diet th an in thoseon fat-free diets, independent of feeding schedule,sex or castration. Pasting also reduced the intesti-nal toxicity observed in animaIs fed a regular dietby two- to fivefold (Del Soldato & Meli, 1977).

(c) NephrotoxicityThe primary renal lesions induced by indo-methacin in animaIs and frequently in humanpatients are papilary necrosis and interstitialinflammation Oackson & Lawrence, 1978).Drug-induced alterations in renal functionand architecture were observed in rats, dogs

and marmosets, which may be the result ofeither tissue phospholipid accumulation, inhi-bition of prostaglandin synthesis or a combina-tion of the two. Renal damage induced by otheragents may also be enhanced by indomethacin.

Papilary necrosis was observed in rats aftera single dose of 75 mg/kg bw (Arnold et al.,1974). Renal papilary necrosis associated witheither short- or long-term treatment with

indomethacin may be the result of selectivephospholipid accumulation in renal tissue, thepapilae being the most sensitive. ln rats treat-ed subcutaneously with 10 or 50 mg/kg bw perday for three days, indomethacin caused a

marked increase in aIl papilary phospholipids

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IARC Handbooks of Cancer Prevention

(sphingomyelin, phosphatidylcholine, phos-phatidylinositol, phosphatidylserine and phos-phatidylethanolamine), with an increase in sphin-gomyelin and phosphatidylethanolamine inthe cortex and no observed effect in the meduIla.Alterations in renal papilary phospholipid

concentrations were observed even at doses aslow as 1 mg/kg per day for up to four weeks, butno significant changes were observed in themeduIla or cortex (Pernández- Tomé & SterinSpeziale, 1994). This result agrees with otherreports of phospholipid accumulation precedingceIlular necrosis (Mingeot-Leclercq et aL., 1988).

Other renal effects of indomethacininclude degenerative changes in the renal

parenchyma after oral administration of5-10 mg/kg bw per day to male and femalerats for up to 21 consecutive days (Gaetani etaL., 1972), and dose-related subacute intersti-tial inflammation of the renal cortex in femaleand male marmosets treated with 2~12 mg/kgbw per day for up to four weeks (Oberto et aL.,1990). Although no renallesions were seen onhistological examination of rats treated orallywith 2 mg/kg bw for up to four months

(Kleinknecht et aL., 1983), indomethacinaccelerated the destruction of renal glomeruli

in puromycin aminonucleoside-inducednephrosis.

Intravenous administration of 4 mg/kg bwindomethacin to anaesthetized dogs produceda very rapid, sharp decrease in renal blood flowand a decrease in water and sodium excretion(Tost et al., 1995). These effects may be relatedto inhibition of prostaglandin synthesis, as

prostaglandins are involved in the regulation ofrenal blood pressure (Plower et aL., 1985); how-ever, this effect was not observed in alert dogsor rats, suggesting an interaction with anaes-thesia (Swain et al., 1975).

(d) Cardiovascular toxicityIndomethacin caused premature con striction ofthe ductus arteriosus in the offspring of rats(Momma & Takao, 1989), rabbits (Sharpe et al.,1975) and sheep (Levin et al., 1979) wh en givennear the end of gestation. ln pregnant ratstreated oraIly with 2.5~ 10 mg/kg bw on gesta-tional day 21 or 22, fetal ductal constrictionappeared within 6 h of maternaI treatment and

180

lasted for up to 36 h. Hampering of fetal cardiacfunction by retardation of significant blood

flow through the ductus arteriosus can result infetal acidaemia, hypoxaemia, pulmonary arter-ial hypertension, altered morphological devel-

opment of the pulmonary vascular bed, rightventricular hypertrophy, diminished ventricularcavity, left ventricular dilatation, degenerativechanges in the papilary muscles of the tricuspidvalve, fetal death within 24 h of maternaI treat-ment and respiratory difficulties in the neonate(Momma & Takao, 1989).

Intraventricular injection of 4 mg/kg bwindomethacin to cats di mini shed the coronary

circulation and, to a lesser degree, reduced

myocardial oxygen consumption (Stepaniuk &Stoliarchuk, 1985).

Indomethacin impairs scar formation afterexperimental myocardial infarct in dogs andenhances murine myocarditis due to coxsackievirus B4 (Hammerman et al., 1983; Khatib et al.,1992).

(e) HepatotoxicityDegenerative changes in the liver, includingvacuolar changes and fatty liver, were reportedin male and female rats treated with 5-10 mg/kgbw per day for up to 21 days (Gaetani et al.,1972). Alterations in a variety of hepatic micro-somal drug~metabolizing enzymes were ob-served in rats dosed with indomethacin (Burkeet al., 1983), as noted above.

(f) Effects on bone formationBone formation du ring the healing of fractures

or induction of heterotopic bone is retarded

or completely inhibited by indomethacin. Thiseffect, observed experimentally in rats and rab-bits, may be elicited in the early phase of boneinduction by a reduction in the inflammatory

response, causing less favourable circumstances

for bone formation (Rö et al., 1976; Sudmann &Bang, 1979; AIlen et al., 1980).

(g) Haematological effectsIndomethacin induced changes in blood and

blood chemistr, including iron-deficiency (micro-cytic) anaemia, hypoalbuminaemia, leukocytosis,thrombocytosis and decreased total serum

proteins, in rats treated with 3-6 mg/kg bw per

Indomethacin

day in the di et for up to 12 weeks or 5 mg/kg bwper day oraIly for up to 21 days (Gaetani et al.,1972; Anthony et al., 1994). No drug-inducedalterations in haematological or blood chemicalparameters were observed after treatment ofmale and female rats oraIly with 1-3 mg/kg bwper day on six days per week for 30 days

(Nomura et al., 1978).Slight hypotrophy of the bone marrow, thy-

mus and testis and slight thyroid hypertrophywere seen afer oral administration of 5-10 mg/kgbw per day indomethacin to male and female ratsfor up to 21 days (Gaetani et aL., 1972).

(h) Reproductive and development effectsIndomethacin induced reductions in fetal anddecidual tissue weights, fetal malformations,fetal death and prolonged gestation and partu-rition. The developmental toxicity of indomethacinwas recently reviewed (Lione & Sciall, 1995).

Effects on fertility. Indomethacin reduced fertiltyin male mice treated with 146 ¡.g/day for seven

days and rats treated with 0.8 mg/kg bw orallydaily for 28 days or 2 mg/kg bw intraperito-neaIly for seven days. It had anti-mating effectsin female rats treated with 0.8-4 mg/kg bworaIly, daily from pro-estrous for a period of sixcycles before mating (Marley & Smith, 1974;Yegnanarayan & Joglekar, 1978; Löscher &Blazaki, 1986). Significant increases in the num-ber of abnormal sperm were observed in micetreated with 12-36 mg/kg bw per day oraIly or12-24 mg/kg bw per day intraperitoneaIly for2-30 days (Shobha Devi & Polasa, 1987).

Effects on ovulation. Indomethacin has beenreported to suppress ovulation in rats, mi ce,rabbits, cows, and two species of monkey. Thedoses sufficient to completely block inducedovulation were reported to be 7 mg/kg bw sub-cutaneously or 7.5-8 mg per animal intraperi-toneally in rats, (Armstrong & Grinwich, 1972;Orczyk & Behrman, 1972; Yegnanarayan &

Joglekar, 1978), 200 ¡.g subcutaneously in mice(Saksena et al., 1974), 3 mg/kg bw orallyfor two days before induction of ovulation inrabbits (O'Grady et al., 1972; Yegnanarayan &Joglekar, 1978) or two injections of 15 mg/kgbw intramuscularly in cynomolgus monkeys

(Macaca fascicularis) Oaszczak, 1975). Inducedovulation was also suppressed in rhesusmonkeys (Macaca mulatta) (Wallach et al.,1975). ln cows, injection of 20 mg of the drugdirectly into the preovulatory ovarian follclecompletely blocked ovulation; however, itwas ineffective when given as 5 g intramuscu-larly five times over 24 h or by intrauterineinfusion of 1440 mg total dose per uterine horn(De Silva & Reeves, 1985).

Effects on gestation. Pregnancy disruption result-ing from indomethacin treatment, reported inmany species may result from reductions inimplantation, suppressed placental develop-

ment or adverse fetal effects. Prostaglandininhibition may prevent implantation, resultingin lowered ova retention due to tubal distur-bances or reduced uterine vascular permeabilty.Inhibition or delay of implantation wasreported after treatment early in gestation in

mi ce (150 ¡.g/day subcutaneously on gestationdays 1-4 or a single injection of 225 ¡.g on

day 2; Lau et aL., 1973), in rats (4 mg/kg bworaIly daily on days 1-7, 3 mg/kg subcuta-

neously on days 3 and 4, or 400 ¡.g into the uter-ine horns on day 4; Yegnanarayan & Joglekar,

1978; Gupta et al., 1981; Philips & Poyser,

1981), in rabbits (8-20 mg/kg bw intravenouslyevery 12 h fram 2 days before mating to nine

days after mating, and similar doses adminis-

tered on gestation days 4-7; EI-Banna et aL.,1976; Hoffman, 1978), and in hamsters

(0.1 mg/kg bw subcutaneously to pregnantfemales on gestation day 4; Evans & Kennedy,1978). Other implantation-related effectsinclude reductions in litter size in hamsters andmarked reductions in the number of decidualimplantation sites, fetal, placental and decidualtissue weights, and fetal viabilty. Increased fetalresorptions in rabbits (an apparent anti-implan-tation effect if it occurs early in gestation) werealso observed (Hoos & Hoffman, 1983).

Inhibition of placental development wassuggested to be the basis of pregnancy failure inmature gilts given 10 mg/kg bw per day indo-methacin in the diet on days 10-25 of gestation(Kraeling et al., 1985).

Post-implantation effects. MaternaI treatmentwith indomethacin in the post-implantation

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IARC Handbooks of Cancer Prevention

period (mid-gestation) resulted in increased

numbers of intrauterine deaths and fetalresorptions in mice (5 mg/kg subcutaneouslyon gestation days 8-15 or 15 mg/kg bw subcu-taneously on days 8-10 or 13-15, Persaud &

Moore, 1974); apparent abortion and no suc-cessful deliveries at term in rats (4 mg/kg bworally daily on days 10-16 of pregnancy;

Yegnanarayan & Joglekar, 1978) and a reduc-tion in the vi ab ilt y of implanted fetuses in rab-bits (8 mg/kg bw subcutaneously twice daily ongestation days 9-12; Hoffman, 1978).

MaternaI treatment near term resulted inincreased numbers of fetal deaths in rats(0.1 and 1.0 mg/kg bw twice daily on days18-21 of gestation; Aiken, 1972), in rabbits(2.5-10 mg/kg bw per day subcutaneously ongestation days 26-29; Harris, 1980) and in ewes(0.5-1 mg/kg bw intravenously or 75 mg orallythree times daily for four days on gestation

days 123-139; Levin et al., 1979). Some of thestilbirths in rats were attributed to placentalseparation (Aiken, 1972).

Teratogenicity. Indomethacin appears to be terato-genic in mice but not rats. Mouse fetuses wereborn with eventration of the abdominal viscera,meromelia and defective limb posture whenpregnant mice were treated subcutaneously

with either 5 mg/kg bw on days 8-15 or15 mg/kg bw on gestation days 13-15 (Persaud& Moore, 1974). Evidence that indomethacininduces cleft palate in mice was provided bothin vitro and in vivo (Montenegro & Palomino,1989, 1990). Indomethacin was not teratogenicin rats when administered to dams on gestationdays 10-11 at 4 mg/kg bw orally three times(Klein et aL., 1981).

Prolongation of gestation. Delay in the onset of par-

turition, previously a therapeutic indication for useof indomethacin in humans, has also been

reported in laboratory animaIs, including ham-sters, rabbits and rhesus monkeys. Parturitiononset was delayed in pregnant and pseudopreg-nant hamsters (300 or 600 iig twice daily ondays 14-16 of pregnancy or 1 mg daily from day5 of pseudopregnancy), although the treatmentdid not affect the duration of parturition (Lau etal., 1975). ln rabbits, prolongation of the

""182

gestation period was route- and time-depen-

dent: 8-10 mg/kg per day in the drinking waterfrom day 20 until delivery prolonged gestation,while subcutaneous administration of similarlevels near the end of gestation (days 29-31) didnot suppress plasma prostaglandin levels anddid not prolong gestation (Challs et al., 1975).

With doses similar to those used in human ther-apy, Novy et aL. (1974) reported up to 20 days'prolongation of gestation in rhesus monkeys

treated with 100 mg/day on days 150-165 ofgestation and 200 mg/day on days 166-187 ofgestation. These results were confirmed at lowerdoses (10-15 mg/kg bw per day on days150-165 of gestation and 21-28 mg/kg bw perday from day 166 of gestation unti delivery)(Manaugh & Novy, 1976).

Administration of indomethacin at the endof gestation appeared to provoke both maternaIand fetal adverse events at parturition in rats,rabbits and rhesus monkeys. The maternaI

events included protracted parturition, haem-

orrhage and gastric ulcers in rats treated with0.1 or 1.0 mg/kg bw twice daily on days 18-21of gestation (Aiken, 1972). Fetal events includ-

ing signs of prolonged intrauterine stress (stain-ing of the fetal skin, umbilcal cord and placen-tal membranes with meconium and a virtualabsence of amniotic fluid) were noted in rhesusmonkey fetuses at delivery. Four of eight fetus-es died, two probably from prolonged labour-induced stress or hypoxia. No gross morpho-logical abnormalities were seen in either the

fetuses or the placentas (Manaugh & Novy,1976). Fetallung maturation was inhibited atbirth after treatment of pregnant rabbits at10 mg/kg bw per day intramuscularly for threedays before delivery (Bustos et aL., 1978).

Persistent fetal circulation syndrome was reportedin neonatal rats in a study in which pregnantrats were treated with 2-4 mg/kg bw per dayorally from gestation day 17 to delivery (Harker

et al., 1981). The appearance of me di al hyper-

trophy and newly muscularized arterioles,combined with immature, thick saccularwalls, produced a decreased surface for oxygenexchange and increased pulmonary vascularresistance.

Prolongation of the length of the oestrus

cycle was reportedly induced by indomethacin

Indomethacin

in guinea-pigs injected subcutaneously with

10 mg/kg bw twice daily for 12 days beginningon day 7 of the cycle or implanted with 33 mgper uterine horn, providing a slow-release

dose of 0.2-0.6 mg/day. Oestrus cycles were

lengthened by three days in the animaIs treat-ed with 20 mg/kg bw per daYJ while cycles of upto 75 days were observed in the implanted

animaIs. Two animaIs treated with 20 mg/kgbw per day died with gastrointestinal perfora-tions after II days of treatment. The authorssuggested that the drug blocked the formationof luteolysin in the uterus, prolonging the lifeof the corpus lutea (Horton & Poyser, 1973).

No effect on the length of the oestrus cycle wasnoted in female rats treated with 0.8-4 mg/kgbw per day oraIly from pro-oestrus for six cyclesbefore mating (Yegnanarayan & Joglekar, 1978).The au th ors suggested that the doses used in

the studies could not result in the high

intrauterine concentrations required to inhibitcorpus luteum regression.

Table 6. Genetic and related effects of indomethacin

7.2 Genetic and related eftects

7.2.1 HumansNo data were available to the Working Group.

7.2.2 Experimental models

The genetic and related effects of indomethacinare listed in Table 6.

Indomethacin induced DNA damage inBacillus subtils (Kuboyama & Fujii, 1992). Itdid not indu ce mutation in Escherichia coli

or Drosophila melanogaster (King et aL., 1979),but it induced mutation in Salmonella typhimuri-

um tester strain TAI00 in the presence of exoge-nous metabolic activation (Kuboyama & Fujii,1992). It did not induce chromos omal aberra-tions or aneuploidy (Ishidate et aL., 1988)in hamster ceIls in vitro. Indomethacin inducedchromos omal aberrations and sperm abnor-malities in mice in vivo (Shobha Devi & Polasa,1987). Conflcting results were reported formicronucleus induction in mice (ShobhaDevi & Polasa, 1987; King et al., 1979). It didnot induce sister chromatid ex change in humanlymphocytes in vivo (Kullich & Klein, 1986).

End-point Test system

+

Doseb

(LED or HID)100

1790

1790

1790

1790

27

1790

27

10740

895

Kuboyama & Fujii (1992)

King et al. (1979)

King et al. (1979)

King et al. (1979)

King et al. (1979)

Kuboyama & Fujíí (1992)

King et al. (1979)

Kuboyama & Fujíí (1992)

King et al. (1979)

King et al. (1979)

B. subtils rec, differential toxicity

S. typhimurium TA1535, reverse mutation

S. typhimurium TA 1537, reverse mutation

S. typhimurium TA 1538, reverse mutation

S. typhimurium TA 98, reverse mutation

S. typhimurium TA98, reverse mutation

S. typhimurium TA100, reverse mutation

S. typhimurium TA100, reverse mutation

E. coli K12, forward or reverse mutation

D. melanogaster, sex-Iinked receessive recessive

lethal mutation

ehromosomal aberration, ehinese hamste r

ceUs in vitroe SLH Sister chromatid exchange, human lymphocytes in vitro-A AIA Aneuploidy, human ceUs in vitroe eVA ehromosomal aberation, mouse spermatocytes in vivo +M MVM Micronucleus formation, mice in vivo (+)M MVM Micronucleus formation, mice in vivo +P SPM Sperm morphology, mice in vivo +Definitions of the abbreviations and terms used are given in Appendix 1.a ln the absenæ (-) and presence (+) of an exogenous metabolic activation system; + positive, (+) weakly positive; - negative; 0, not determined

b Lowest effective dose (LED) or highest ineffective dose (HID) expressed as ¡.g/ml for in-vitro studies and as mg/kg body weight per day for in-vivo studies

D

G

G

G

G

G

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codeBSD

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179

12

Kullich & Klein (1986)

Ishidate et al. (1988)

Shobha Devi & Polasa (1987)

Shobha Devi & Polasa (1987)

King et al. (1979)

Shobha Devi & Pola sa (1987)

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IARC Handbooks of Cancer Prevention

8. Summary of Data

8.1 Chemistry, occurrence and human

exposureIndomethacin has been used for over 30 yearsas an analgesic and anti-inflammatory agent. Itis used in the treatment of a variety of muscu-loskeletal conditions, notably rheumatoid andosteoarthritis. It is conventionaIly prescribed atdoses of 25-100 mg three or four times daily.

8.2 Metabolism and kinetic properties

Convention al oral administration results in ahigh level of bioavailabilty, aIthough foodstaken concomitantly may delay and/or reduceabsorption. Indomethacin is strongly bound toserum albumin. After its distribution,indomethacin undergoes glucuronide conjuga-tion, O-demethylation and N-deacylation. Lessthan 10% of an oral dose is recovered as theunchanged parent compound in urine; indo-methacin is also eliminated in bile and under-goes extensive enterohepatic recirculation.

8.3 Cancer-preventive effects

8.3.1 HumansNo studies have been reported that specificallyaddress protection by indomethacin againstcancer. Case reports of the use of indomethacinin patients with familal adenomatous polypo-sis showed regression of polyps in about one-haIt of the patients.

8.3.2 Experimental animaIs

The chemopreventive efficacy of indomethacinwas assessed in mou se, rat and hamster models.ln seven studies in mice, the effects ofindomethacin were studied on carcinogenesisin the oesophagus, urinary bladder, cervix andskin. lndomethacin was effective in aIl of thestudies, but appeared to be less effective duringlate stages of carcinogenesis and in the skin.

The cancer-preventive efficacy of indo-methacin was investigated in 20 studies in ratsin models of cancers of the oesophagus, colon,urinary bladder, tongue, liver, mammary gland,nervous system and kidney. It was effective inaIl 12 studies in which the colon was the targetorgan, but inconsistent resuIts were obtained inmodels of mammary gland carcinogenesis: it

..184

was effective in three studies and ineffective inanother three. ln single studies in rats,indomethacin had chemopreventive effects inmodels of cancers of the urinary bladder, liverand tongue.

The efficacy of indomethacin in inhibitingoral cavity tumorigenesis in hamsters remainscontroversial. No conclusive reduction wasseen in pancreatic tumorigenesis in hamsters.

lndomethacin had antimutagenic activityin a variety of test systems.

8.3.3 Mechanism of actionWhile the anti-inflammatory action of indo-methacin is directly linked to its abilty toinhibit the cyclooxygenases, the precise molec-

ular mechanism(s) whereby indomethacin andother non-steroidal anti-inflammatory drugs

exert their chemopreventive effects remain

unclear. Mechanisms secondary to prosta-glandin reduction, such as enhanced immunesurveilance and stimulation of T-ceIl prolifera-tion, may be involved. Furthermore, indo-

methacin may exert a protective effect againstcancer by influencing receptors or affectingenzymes other than cyclooxygenases.

8.4 Other beneficial effects

One smaIl clinical trial in which many patientscould not be followed up suggests thatindomethacin slows the progression ofAlzheimer's disease.

8.5 Carcinogenicity

8.5.1 HumansNo data were available to the Working Group.

8.5.2 Experimental animaIs

Indomethacin given to rats in the drinking-water for lie induced hyperplasia of the urinarytract. ln a further study in rats, the incidence ofurinary bladder tumours induced by N-(4-(5-nitro-2-furyl)-2-thiazolyl)formamide was

enhanced by concomitant treatment withindomethacin.

8.6 Toxic effects

8.6.1 HumansIndomethacin has a wide variety of adverseeffects, the most clinicaIly important of which

Indomethacin

are ulcers and bleeding in the upper gastroin-testinal tract. lndomethacin increases the riskfor these complications in a dose-dependent

manner. lndomethacin decreases renal func-tion and increases blood pressure, sometimes

causes rash and headache and rarely results inhepatotoxicity and aseptie meningitis.

8.6.2 Experimental animaIs

Many of the toxic effects of indomethacin inexperimental animaIs may be due to inhibitionof prostaglandin synthesis. As in humans, theprimary site of acute toxieity is the gastroin-testinal tract, although adverse effects have alsobeen reported in kidney, liver, heart and bone.

Toxie effects on male fertilty, female mat-ing behaviour, ovulation and gestation, terato-genicity and effects on fetal circula tory devel-

opme nt have been reported in isolated studiesin experimental animaIs.

ln one study in miee treated in vivo,indomethacin induced chromosomal aberra-tions in spermatocytes and micronuclei in bonemarrow.

9. Recommendations for Research

Toxicity would be a major drawback todeveloping indomethacin as a chemopreven-

tive agent in humans. The preventive effieacyof indomethacin has been assessed extensivelyin animal models, and no further experimentalinvestigation is needed, unless specifie mecha-nisms of action are addressed.

10. Evaluation 1

10.1 Cancer-preventive activity

10.1.1 HumansThere is inadequate evidence that indomethacinhas cancer-preventive activity in humans.

10.1.2 Experimental modelsThere is suffcient evidence that indomethacinhas cancer-preventive activity in experimentalanimaIs. This evaluation is based on models ofcancers of the colon and oesophagus.

1 For definitions of the italicized terms, see the Preamble, pp. 12-13

10.2 Overall evaluationEpidemiological studies in humans provideinadequate evidence for the cancer-preventive

activity of indomethacin, although sorne datasuggest that it prevents the progression of ade-

nomatous polyps in patients with familal ade-nomatous polyposis. ln experimental animaIs,there is suffcient evidence that indomethacinprevents colon cancer. The adverse effects ofindomethacin include dose-dependent bleedingand ulceration in the upper gastrointestinaltract and hepatic and renal toxicity.

Despite the availabilty of extensive data

from studies of experimental models, indo-

methacin cannot be regarded as a chemopre-

ventive agent in humans, because of inade-

quate epidemiological data.

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