antioxidants in cancer therapy; their actions and...

Alternative Medicine Review ◆ Volume 4, Number 5 ◆ 1999

Copyright©1999 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

Antioxidants in Cancer Therapy;Their Actions and Interactions

With Oncologic Therapiesby Davis W. Lamson, MS, NDand Matthew S. Brignall, ND

Davis W. Lamson, MS, NDPrivate practice, Tahoma Clinic- Kent, WA. Coordinator of Oncology, Bastyr University- Kenmore, WA. Correspondence Address: 9803 17th Ave. NE,Seattle, WA. 98115.

Matthew S. Brignall, ND1999 graduate, Bastyr University. Currently doing a research fellowship at Tahoma Clinic in Kent, WA. e-mail: [email protected]

AbstractThere is a concern that antioxidants might reduce oxidizing free radicals created

by radiotherapy and some forms of chemotherapy, and thereby decrease theeffectiveness of the therapy. The question has arisen whether concurrent administrationof oral antioxidants is contraindicated during cancer therapeutics. Evidence reviewedhere demonstrates exogenous antioxidants alone produce beneficial effects in variouscancers, and except for a few specific cases, animal and human studies demonstrateno reduction of efficacy of chemotherapy or radiation when given with antioxidants. Infact, considerable data exists showing increased effectiveness of many cancertherapeutic agents, as well as a decrease in adverse effects, when given concurrentlywith antioxidants.Altern Med Rev 1999;4(5):304-329

IntroductionDietary and endogenous antioxidants prevent cellular damage by reacting with and elimi-

nating oxidizing free radicals. However, in cancer treatment, a mode of action of certain che-motherapeutic agents involves the generation of free radicals to cause cellular damage andnecrosis of malignant cells. So a concern has logically developed as to whether exogenousantioxidant compounds taken concurrently during chemotherapy could reduce the beneficialeffect of chemotherapy on malignant cells. The importance of this concern is underlined by arecent study which estimates 23 percent of cancer patients take antioxidants.1

The study of antioxidant use in cancer treatment is a rapidly evolving area. Antioxidantshave been extensively studied for their ability to prevent cancer in humans.2 This paper reviewsthe use of antioxidants as a therapeutic intervention in cancer patients, and their potential inter-actions with radiation and chemotherapy. There has been significant investigation of this area,with promising findings which indicate continuing investigation is warranted. For further dis-cussion of the use of antioxidants as sole cancer therapy, refer to the review article by Prasadpublished earlier this year.3 A number of reports show a reduction in adverse effects of chemo-therapy when given concurrently with antioxidants. These data are more completely summa-rized by Weijl et al.4


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Alternative Medicine Review ◆ Volume 4, Number 5 ◆ 1999 Page 305

Conflicting Views of AntioxidantUse in Cancer Therapy

It was suggested in a recent publica-tion that no supplementary antioxidants begiven concurrently with chemotherapy agentswhich employ a free radical mechanism.5 Thepaper must be commended for pointing out thatthe combination of antioxidants and chemo-therapy agents needs more investigation, andshould serve as a wake-up call regarding howmuch we need further definition of the actionsof specific antioxidants with chemotherapeu-tic agents. However, it should not serve as sci-entific closure on an adjunctive treatment ofpossible great promise in cancer therapy.

The present authors are by no meansrecommending any lack of caution about useof antioxidants. On the contrary, published re-search indicates the cautious and judicious useof a number of antioxidants can be helpful inthe treatment of cancer; as sole agents and asadjuncts to standard radiation and chemo-therapy protocols.

It was suggested that antioxidantsmight interfere with the oxidative mechanismsof alkylating agents.5 These drugs create sub-stantial DNA damage, resulting in cell necro-sis. However, recent evidence indicates a size-able amount of chemotherapy damage is byother mechanisms, which trigger apoptosis.6

Antioxidants have been shown to increase celldeath by this mechanism.7,8 Given this, anyargument that antioxidants are likely to inter-fere with most chemotherapy is too simplisticand probably untrue.

Numerous animal studies have beenpublished demonstrating decreased tumor sizeand/or increased longevity with thecombination of chemotherapy andantioxidants.7,9-16 A recent study was conductedon small-cell lung cancer in humans usingcombination chemotherapy ofcyclophosphamide, Adriamycin(doxorubicin), and vincristine with radiationand a combination of antioxidants, vitamins,

trace elements, and fatty acids. The conclusionwas “antioxidant treatment, in combinationwith chemotherapy and irradiation, prolongedthe survival time of patients” compared toexpected outcome without the composite oraltherapy.17 Two human studies found melatoninplus chemotherapy to induce greater tumorresponse than chemotherapy alone.18,19 Thetreatments producing these positive resultswould have been advised against by thoseadvocating no antioxidant use duringchemotherapy. These studies will be discussedin more detail below.

It is the opinion of the authors of thispaper that interactions between antioxidantsand chemotherapeutics cannot be predictedsolely on the basis of presumed mechanism ofaction. The fact remains that physicians mustbe aware of the available research to help theirpatients take advantage of positive interactionsexisting between antioxidants and chemo-therapy or radiation.

Additionally, physicians need to re-main aware of the large body of evidenceshowing a positive effect of antioxidants in theperiod following chemotherapy administra-tion. The general protocol with standard on-cologic therapies is to follow a watch-and-waitstrategy after therapeutic administration isconcluded. This is a period when supplemen-tal therapies are highly indicated and have beendemonstrated to result in a higher percentageof successful outcomes.20,21

Overview of Cancer TherapeuticAgents

Chemotherapy agents can be dividedinto several categories: alkylating agents (e.g.,cyclophosphamide, ifosfamide), antibioticswhich affect nucleic acids (e.g., doxorubicin,bleomycin), platinum compounds (e.g.,cisplatin), mitotic inhibitors (e.g., vincristine),antimetabolites (e.g., 5-fluorouracil),camptothecin derivatives (e.g., topotecan),

06 Alternative Medicine Review ◆ Volume 4, Number 5 ◆ 1999


biological responsemodifiers (e.g., inter-feron), and hormonetherapies (e.g.,tamoxifen). The agentsmost noted for creatingcellular damage by ini-tiating free radical oxi-dants are the alkylatingagents, the tumor anti-biotics, and the plati-num compounds. Theagents in these catego-ries demand definitionconcerning interactionswith antioxidants whichmight reduce effective-ness of chemotherapy. There is also the possi-bility of adverse interaction between antioxi-dant treatment and agents that do not act viaan oxidative mechanism (e.g., 5-fluorouracilor tamoxifen).

In addition to the idea that chemo-therapy must create a lethal injury to DNA toproduce malignant cell death is the mechanismof apoptosis. A dose of chemotherapy whichdoes not produce necrosis can triggerapoptosis, either immediate or delayed. Addi-tionally, anti-apoptotic mutations can result indrug resistance in human tumors. At least oneantioxidant (quercetin) has been demonstratedto overcome such an anti-apoptotic blockage.22

Radiotherapy uses ionizing radiationto produce cell death through free radical for-mation. Two mechanisms are involved. Theapoptosis mechanism results in cell deathwithin a few hours of radiation. The secondmechanism is radiation-induced failure of mi-tosis and the inhibition of cellular prolifera-tion, which kills cancer cells. Currently, theprincipal target of radiation is considered tobe cellular DNA. However, studies show thesignal for apoptosis can be generated by theeffect of radiation on cell membranes, appar-ently through lipid peroxidation. This suggestsan alternate mechanism to the hypothesis that

DNA damage is re-quired for celldeath.23

Vitamin A andCarotenoids asCancerTreatment

Many researchreports on the anti-cancer properties ofvitamin A and therelated retinoidshave been pub-

lished over the last 20 years. Most of thesestudies examined all-trans retinoic acid (RA).RA is formed in human tissues from beta-caro-tene and retinol, does not accumulate in theliver, thus it is not associated with significanthepatotoxicity.24 Treatment with RA is asso-ciated with many side effects , including head-ache, lethargy, anorexia, vomiting, and visualdisturbance.24 Another retinoid used in cancertreatment is 13-Cis-retinoic acid (cRA), alsoknown as isotretinoin.25

RA in vitro demonstrates growth in-hibitory activity against at least 14 types ofhuman cancers.24 Acute promyelocytic leuke-mia (APL) has been shown to respond well toRA, but not to cRA.26 In one study, nine of 11patients with APL entered complete remissionafter treatment with 45 mg/m2 daily oral doseof RA.27 Similar results are reported else-where,28,29 and have been confirmed in vitro.30

Local application of an RA-containingcream demonstrated low toxicity and some his-tological improvement of cervicalintraepithelial neoplasia II (CIN II) in a phaseI study.31 In a phase III trial, RA led to com-plete regression of CIN II in 42 percent ofwomen compared with 27 percent in the pla-cebo group.32 No significant effect was notedin severe cervical dysplasia.32 After remissioninduced by conventional therapy, treatment

CATEGORIES OFCHEMOTHERAPEUTICS� Alkylating agents (e.g., cyclophospamide, ifosamide)� Antibiotics affecting nucleic acids (e.g., doxorubicin, bleomycin)�� Platinum compounds (e.g., cisplatin)� Mitotic inhibitors (e.g., vincristine)� Antimetabolites (e.g., 5-fluorouracil)� Camptothecin derivatives (e.g., topotecan, etoposide)� Biological response modifiers (e.g., interferon)� Hormone therapies (e.g., tamoxifen)

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with cRA is associated with fewer second pri-mary tumors in head and neck squamous-cellcarcinoma.33

Retinoic acid decreased the growth rateand increased differentiation of human smallcell lung cancer lines in vitro.34 Daily oraladministration of 300,000 IU vitamin A asretinol palmitate led to a significant reductionin second primary tumors and an increase indisease-free survival post-surgery in stage Ilung cancer.35 However, a small trial of cRAat 200 mg/day found no appreciable benefit inthe treatment of advanced non-small cell lungcancer. Of 23 patients evaluated in this trial,only one achieved a partial response totreatment.36

A trial of oral vitamin A at 100,000 IU/day in patients with resected malignant mela-noma found no survival benefit compared withthose taking placebo.37 In a trial of oral RA forhormone-refractory prostate cancer, dosed 45mg/m2 daily, only a 15-percent response ratewas seen.38 It is clear from these data that theeffects of the retinoids as sole therapeuticagents are limited, perhaps mainly to hemato-logic malignancies, which tend to develop RAresistance over time.28 For further informationon the use of retinoids in cancer therapy, referto the review by MA Smith, et al.24

In contrast to the retinoids,comparatively little is known about the use ofcarotenoids as anti-cancer agents in vivo. Theinterest in carotenoids mainly stems from theextensive epidemiological evidenceassociating dietary intake with lowerincidences of many cancer types.39 Alpha- andbeta-carotene have been examined for in vitrotumor inhibitory activity against humanneuroblastoma cell lines, and alpha-carotenewas found to have 10 times the anti-tumoractivity of beta-carotene.40 Currently there issome concern regarding supplementation withcarotenoids, as beta-carotene has beenassociated with higher risk of lung cancer insmokers,41 but not in the general population.42

Aside from this concern, high doses of beta-carotene, even over long periods of time, arenot associated with serious toxicity.39

There are also promising data show-ing chemopreventative activity of the caro-tenoid lycopene against prostate cancer.43 Invitro work suggests lycopene can induce dif-ferentiation, with vitamin D3, in human leu-kemia cells.44 One study showed lycopene tobe a stronger inhibitor of human cancer cellproliferation in vitro than alpha- or beta-caro-tene.45 As yet, human trials are lacking on theuse of lycopene.

Vitamin A and Carotenoids withRadiation

Evidence exists to support the use ofretinoids concomitantly with radiotherapy. Invitro studies have shown retinoic acid (RA)causes radiosensitization in human tumor celllines at concentrations which do not causecellular toxicity. This effect was reversiblewith removal of RA.46 In mice bearing humanbreast adenocarcinoma tumor lines, the effectof local radiation was enhanced bysupplemental vitamin A (150,000 IU) and beta-carotene (90 mg/kg) given during treatment.The beneficial effect of the supplementaltreatment was noted as decreased tumor sizeand increased survival time. Supplementalvitamin A and beta-carotene plus radiation hadsignificantly greater anti-tumor effect thanradiation or supplementation alone. The effectof vitamin A was not significantly differentfrom beta-carotene.9

In a randomized trial of oral vitamin A(1.5 million IU/day) plus radiotherapy foradvanced cervical cancer, vitamin A plusradiotherapy significantly increased T-cellresponse and non-significantly reduced relapserates compared with those undergoingradiotherapy only.46 A pilot human study of cis-retinoic acid (cRA) with radiotherapy andinterferon-a2a on locally advanced cervicalcancer noted a 47-percent tumor response and



33-percent complete remission rate, with nograde 3 or 4 toxicity noted. Historical controlswithout cRA treatment had a 42-percent tumorresponse rate and only 17-percent completeremissions.47 The ability of vitamin A toincrease tumor response to radiation whilereducing toxicity has been theorized to be dueto the stimulation of immune response to tumortissue.48

In a human study, beta-carotene at 75mg daily during radiation treatment for ad-vanced squamous cell carcinoma of the mouthsignificantly reduced the incidence of severemucositis reactions without causing noticeableside effects. The remission rate was unchangedby beta-carotene treatment.49 In vitro evidencesuggests synthetic beta-carotene does not havethe radioprotective effect noted with the natu-ral form.50 The meaning of this finding is asyet unclear.

Vitamin A and Carotenoids withChemotherapy

Perhaps more than any other antioxi-dant treatment, retinoids are increasingly be-ing pursued as adjunctive treatment to stan-dard chemotherapeutics. Most evidence sug-gests an increased cytotoxic effect with re-duced toxicity. In vitro studies using humansmall cell lung cancer lines demonstrated thatincubation with retinoic acid (RA) led to anincreased sensitivity to etoposide, but moreresistance to doxorubicin.51 Human synovialsarcoma cells exposed to RA in vitro werefound to have enhanced response to doxoru-bicin, vincristine, and especially cisplatin.52

Although the potential adverse interaction withdoxorubicin was not confirmed in the latterstudy, this is an area that merits further defini-tion.

In studies of mice with transplantedhuman breast tumor tissue, concurrenttreatment of either vitamin A or beta-carotenewith cyclophosphamide led to a significantlygreater tumor response and survival time

compared to cyclophosphamide treatmentalone. The effect of beta-carotene was roughlyequivalent to that of vitamin A.9 Also in mice,co-administration of vitamin A withmethotrexate ameliorated intestinal damage,without inhibiting its in vivo anti-tumoractivity.53

In a phase I human trial of cisplatinwith 13-cis-retinoic acid (cRA), the two agentswere noted to have strong synergism againsthead and neck squamous cell carcinoma. Of10 evaluable patients, all had complete tumorresponse at the primary site. Dosages of 20mg/day cRA were well tolerated, but severetoxicities were seen at 40 mg/day.54 Extremelyhigh oral doses of RA (150 mg/m2 daily)showed no inhibitory effect on the activity ofcisplatin and etoposide on small cell lung car-cinoma in humans. This dose also was not as-sociated with any therapeutic benefit, andneeded to be discontinued in a majority ofpatients due to side effects .55 Vitamin A palmi-tate at an oral dose of 50,000 IU twice daily,plus b-interferon and combined chemotherapy(epirubicin, mitomycin C, and 5-fluorouracil)prolonged symptom palliation in 35 percentof pancreatic cancer patients. This treatmentwas associated with severe toxicities in sev-eral systems, but only hepatotoxicity wasthought to be associated with the addition ofretinoids.56 Sequential treatment of non-lym-phocytic leukemia patients with conventionalchemotherapy, followed by 16,000 IU/day ofretinol palmitate led to a further induction ofmaturation in blast cells than seen with che-motherapy alone. In three of four patients un-dergoing this sequential therapy, complete re-mission resulted.57 Addition of 400,000 IU/week vitamin A to a conventional chemo-therapy regimen (doxorubicin, bleomycin, 5-fluorouracil, and methotrexate) led to im-proved survival with less than the expectedseverity of side effects compared with histori-cal controls.10

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Althoughthe relative lack oftoxicity comparedto the retinoidsmakes it an attrac-tive option, beta-carotene in combi-nation with che-motherapy is alargely unex-plored area. Inmice, beta-caro-tene co-adminis-tration led to in-creased tumorgrowth delay withdoxorubicin andetoposide, and in-creased tumor cellkilling with cyclo-phosphamide insolid tumors. The co-administration of beta-carotene and 5-fluorouracil, however, reducedtumor growth delay in murine fibrosarcomas,but not in squamous cell carcinomas.58 Dataon other carotenoids is lacking.

Vitamin C as Cancer TreatmentThe use of vitamin C in the treatment

of cancer has been the source of many claimsand controversies over the last 25 years. Ini-tial reports from Drs. Pauling and Cameronwere promising, and gained much notoriety.They reported 100 cases of terminal cancer,independently assessed and refractory to con-ventional treatment, who lived on average fourtimes longer than 1000 age- and disease-matched controls.59 The protocol included in-travenous and oral administration, and is de-scribed in detail elsewhere.60 Prospective ran-domized trials held at the Mayo Clinic wereunable to replicate these results, finding neg-ligible difference between treated patients andcontrols in survival time.61,62 These results werecriticized on a number of grounds, including

the noticeable dif-ference betweenthe vitamin C andplacebo, lack ofintravenous ad-ministration, andtermination oftreatment with tu-mor progres-sion.60 Later invitro and in vivoresearch, and welldocumented casereports,63 suggesta vitamin C dosemuch higher thanthat used in thePauling/Cameronstudies can actu-ally be cytotoxicto tumors without

damaging normal cells. The required tissueconcentrations are thought to only be reach-able with intravenous doses over long periodsof time. This research, as well as the proposedmechanism of action, is examined elsewhere.64

Vitamin C is generally well-tolerated byhealthy people, even in doses as high as 200g/day IV.64,65 Dr. Cameron has noted that asmall percentage of cancer patients will re-spond to vitamin C with rapidly proliferatingand disseminating tumors.66 Other investiga-tors have not noted this effect.

Vitamin C with RadiationQuite surprisingly, no published stud-

ies have looked at the effect of doses over fivegrams of oral or intravenous vitamin C on ra-diotherapy in humans. It has been shown, how-ever, that cancer patients have a significantelevation in plasma and leukocyte ascorbatelevels after radiotherapy compared with pre-treatment levels without any change in dietaryintake.67

VITAMIN A SUMMARY� Retinoic acid has been shown to be apromising treatment for acute promyelocyticleukemia.� Vitamin A and beta-carotene increaseradiation’s effect in vivo, and vitamin A improvesresponse rate in humans.� Vitamin A and beta-carotene increase theeffect of cyclophosphamide in vivo.� Addition of vitamin A to combinedchemotherapy has led to increased responsein two human studies.� Vitamin A has been shown in vivo not tointerfere with methotrexate, cisplatin, andetoposide.� No in vivo evidence suggests that vitamin Areduces the effect of chemotherapy.� Beta-carotene has been shown in vivo notto interfere with doxorubicin or etoposide.� Beta-carotene has been shown to reduce theeffect of 5-fluorouracil on one tumor type in vivo.



In mice, vitamin C (1 g/kg), given in-traperitoneally with vitamin K3 (10 mg/kg),increased the therapeutic effect of radiation onsolid tumors without causing any signs of tox-icity due to the vitamins.68 In another mousestudy, a single intraperitoneal dose of 4.5 g/kgvitamin C was not cytotoxic to normal tissueand did not change the radiation effect on tu-mor tissue. The lethal dose of radiation in-creased and skin desquamation reaction wasreduced by ascorbate treatment. It should benoted that these vitamin C doses are muchgreater than have been used historically in hu-mans.69 The radioprotection of healthy tissueand radiosensitizing effect in tumors with useof ascorbate were confirmed in two othermouse tumor models.70,71

A randomized trial with 50 human sub-jects looked at the effect of concurrent vita-min C (five daily doses of 1 g each) and ra-diotherapy on different tumor types. Morecomplete responses to radiation were noted inthe vitamin C group at one month (87% to55%) and four months (63% to 45%) posttreatment. Side effects tended to be fewer inthe ascorbate-treated subjects as well. Plasmalevels of ascorbate in the treatment group weregreater than control subjects, but less than themean of 20 healthy subjects tested.72 It remainsto be investigated whether continuing treat-ment beyond the end of radiotherapy or use ofa higher dose would improve these results. Adouble-blind trial of topical vitamin C solu-tion for the prevention of radiation dermatitisfailed to find any beneficial effect. The trialdid not examine the absorption of the aqueouspreparation, although previous trials showedabout 12 percent of the vitamin C penetratedinto the epidermis.73

Vitamin C with ChemotherapyVitamin C has been extensively tested

in vitro and in vivo for its ability to preventthe adverse effects of, decrease resistance to,and increase the effects of chemotherapeutic

agents. Co-treatment with doxorubicin andvitamin C (2 mg/kg) led to a reduction in thetoxicity seen with doxorubicin alone in miceand guinea pigs. The prevention ofcardiomyopathy was confirmed by electronmicroscopy. Treatment with ascorbic acid wasnot associated with decreased effect ofdoxorubicin, and was associated with anincreased life span compared with doxorubicintreatment alone.11 In vitro experiments dosuggest, however, that vitamin C does enhancedoxorubicin resistance in human breast cancercell lines already known to be resistant. It didnot lead to resistance in cells which weredoxorubicin-sensitive.74 Vitamin C at non-cytotoxic concentrations (1 mM) increased theactivity of doxorubicin, cisplatin, andpaclitaxel in human breast carcinoma cells invitro. This effect was particularly marked andsynergistic with doxorubicin. The authors notethat since vitamin C has already shown anability to reduce the cardiotoxicity ofdoxorubicin, ascorbic acid and doxorubicin are

VITAMIN C SUMMARY� Vitamin C increases the effect ofradiotherapy in humans and in mice.� Vitamin C increases the effect ofcyclophosphamide, vinblastine,doxorubicin, 5-fluorouracil, procarbazine,and asparaginase in vivo.� Co-administration of vitamin K mayincrease both of the above activities ofvitamin C.� Vitamin C has been shown toincrease the effect of cisplatin andpaclitaxel in vitro.� No in vivo evidence suggests thatvitamin C decreases the effect ofchemotherapy.� Vitamin C may increase theresistance to doxorubicin in resistantbreast cancer cells.

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Cancer



an attractive future treatment for breastcancer.75

Vitamin C has been shown to increasethe drug accumulation and decrease resistanceto vincristine in human non-small-cell lungcancer cells in vitro. An ascorbic acid-sensi-tive uptake mechanism was theorized to ex-plain these results.76

Combined intraperitoneal administra-tion of vitamin C (1g/kg) and vitamin K (10mg/kg) given prior to chemotherapy increasedsurvival and the effect of several chemothera-peutic agents (cyclophosphamide, vinblastine,doxorubicin, 5-fluorouracil, procarbazine, andasparaginase) in a murine ascitic liver tumormodel. The vitamin combination did not in-crease the toxicity of these agents to healthytissue. Splenic and thymic weights of the vi-tamin-treated animals were higher than thosereceiving cytotoxic treatment alone, suggest-ing an immune-stimulating action of the vita-mins.12 These results have yet to be confirmedin humans.

Vitamin E as Cancer TreatmentVitamin E succinate (VES, alpha to-

copherol succinate),has generated some inter-est as an adjunctive cancer therapy recently.VES demonstrated growth inhibition of hu-man B-cell lymphoma77 and estrogen recep-tor-negative breast cancer78 cell lines in vitro.Vitamin E at 3 mM concentration arrested tu-mor cells in the G

1 phase of the cell cycle, lead-

ing to apoptosis.7 Recent research on humanoral squamous carcinoma cells suggests theVES effect is biphasic; growth stimulatory atphysiological concentrations, while pharma-cological concentrations are inhibitory.79 Aphase I trial of intravenous vitamin E in treat-ment refractory neuroblastoma found mild tox-icity (tendency toward increased bleeding timewas noted) at doses below 2,300 mg/m2. Fiveof 13 patients experienced pain relief and/ortumor regression with treatment. No completeremissions resulted from treatment.80 Vitamin

E, 200 mg daily, given together with 18 g/dayomega-3 fatty acids from fish oil, prolongedsurvival in patients with generalized malig-nancy in a randomized controlled trial. Im-provement in T-helper/suppressor ratio wasalso noted with treatment.81 Phase I clinicaltrials are being planned or are underway inpatients with breast and prostate cancers.82

Vitamin E and its derivatives are particularlyattractive therapeutic agents due to their re-markable lack of toxicity in vivo.83

Vitamin E with RadiationThe picture here is unfortunately far

from clear. An initial report showed micetreated with 1 g/kg of vitamin E had an in-creased in the lethal radiation dose (LD50).Unfortunately, squamous cell carcinoma celllines treated in this study were less radiosen-sitive, with 35-percent cell survival versus 13percent in controls.84 A later experiment wasable to replicate this finding in vitro in cellsincubated for several weeks with vitamin E,but not those in which it was added immedi-ately before irradiation.85 The latest experimentto look at this issue actually found that somedoses of vitamin E enhanced mouse sarcomatumor cell kill. Intraperitoneal pretreatmentwith 50, 250, and 500 mg/kg, but not 1000mg/kg, led to better tumor response than ra-diation alone. The authors also noted that in-tramuscular and oral tocopherol administra-tion had a similar effect.86 From these resultsit would appear vitamin E doses used in hu-mans increase the effect of radiotherapy, andsuper-human doses (above 35,000 IU) mayblunt the therapeutic efficacy of radiotherapy.

Radiation-induced fibrosis is a sequelato irradiation therapy which does not sponta-neously regress. A combination of vitamin E(1000 IU/day) and pentoxifylline (800 mg/day) completely reversed a case of radiation-induced cervicothoracic fibrosis in a 67-year-old woman after an 18-month course of treat-ment. The findings were confirmed with CT



scan. A phase IItrial is currentlyunderway to con-firm these re-sults.87

Vitamin EwithChemotherapy

There area few interestingrecent reports onthe concurrent useof vitamin E withchemotherapy.Vitamin E, 750 mg/kg intraperitoneally, givenwith 5-fluorouracil had a greater anti-tumoreffect in mice bearing human colon cancerlines than either agent alone; treatment led tocomplete cessation of tumor growth. The sameinvestigators found in vitro addition of vitaminE to either 5-fluorouracil or doxorubicinenhances the effect of these agents on humancolon cancer cells.7 Another report showed pre-treatment with 85 mg (approximately 4000mg/kg) alpha-tocopherol reduced the lethalityof a single 15 mg/kg dose of doxorubicin from85 percent to 10 percent in mice. This dose oftocopherol did not alter the suppression oftumor cell DNA synthesis by doxorubicin. Thetumor-bearing mice pretreated with vitamin Elived longer on average than those treated withdoxorubicin alone. The authors theorized thevitamin E blocked lipid peroxidation-mediatedtoxicity, while not impairing the anti-tumorproperty of doxorubicin.14 Both the toxicityprevention effect and the lack of inhibition ofvitamin E toward doxorubicin were confirmedin a later experiment.88 In vitro experimentsshowed VES can enhance the cytotoxic effectof doxorubicin on human prostate cancer cellsat concentrations easily attained in humanplasma (5 mg/ml). This inhibition was foundto be dose-dependent.89 Oral and

intraper i tonealadministration ofvitamin E (20 mg/kg/day) enhancedthe anti-tumoractivity ofcisplatin onneuroblastoma inmice.90

Selenium asCancerTreatment

The use ofs e l e n i u m

compounds as a cancer treatment predatesmost conventional treatments currently inuse.91 In spite of this, comparatively little isknown regarding the use of selenium as acancer therapy in living systems.Subcutaneous injection of 2 mcg/g seleniuminto tumor-bearing mice led to a 75-percentreduction in tumor mass compared tocontrols.92 This inhibitory effect of seleniumwas confirmed in human breast cancer cellsin vitro.93 In an open trial of 32 patients withtreatment refractory brain tumors, intravenousinfusion of selenium (1000 mcg/day for 4-8weeks) was associated with a slight to definiteimprovement in all participants. Symptomaticdecrease was seen in nausea, emesis, headache,vertigo, and seizure activity. Although theresults are largely credited to the seleniumtreatment, it should be noted these patientswere concurrently receiving chemotherapy,oxygen therapy, vitamins E and A, dietarychanges, and psychotherapy.94 Unpublishedresearch from the 1950s outlines the treatmentof over 1000 malignancies with seleniumcompounds, reportedly with beneficialresults.95 Unfortunately, a study of thismagnitude has yet to appear in the peer-reviewed literature.

VITAMIN E SUMMARY� Vitamin E induces apoptosis inexperimental tumor lines.� Vitamin E with omega-3 fatty acidsincreased survival time in terminal cancerpatients.� Vitamin E in doses below 500 mg/kg(approximately 35,000 IU human dose)may increase the effect of radiotherapy inmice.� Vitamin E increases the activity of 5-fluorouracil, doxorubicin, and cisplatin invivo.� No evidence exists that vitamin Ereduces the effect of chemotherapy invivo.

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Selenium withRadiation

Little is knownabout the interactionbetween seleniumsupplementation andradiotherapy. In the onehuman trial available,patients with advancedrectal cancer weregiven daily supplemen-tation with 400 mcg of selenium after treat-ment. The selenium was well-tolerated, but theresearchers presented no data regarding inter-action between the two treatments.96 An ani-mal study suggests that selenium depletionreduces the lethal dose of radiation.97 Untilmore is known regarding the effect of sele-nium on radiotherapy, pharmacological doses(above 400 mcg/day) cannot be advised.

Selenium with ChemotherapyInteractions between selenium and

platinum-containing chemotherapy agentshave been extensively studied. In a mousestudy, selenium decreased nephrotoxicity ofcisplatin, while simultaneously increasing itsanti-tumor activity.15 Other animal studies con-firmed these findings.16,98 A randomized cross-over trial in humans looked at the effect ofselenium (4000 mcg/day from four days be-fore until four days post-chemotherapy) on thetoxicity of cisplatin. Selenium consumptionwas associated with a higher WBC count, evenwith less consumption of granulocyte stimu-lating factor. Nephrotoxicity, measured byurine enzymes, was also significantly less inpatients taking selenium. No mention is madein this study of any effect of selenium intakeon the therapeutic activity of cisplatin.99

One in vitro study suggests a selenium-containing antioxidant compound calledEbselen (2-phenyl-1,3-benzisoselenazol-3(2H)one) has a mild inhibitory effect on the

anti-tumor effect ofbleomycin. Theauthors did notspeculate on whetherdietary selenium wouldhave an adverse effecton therapeutic use ofbleomycin.100 Perhapsuntil these results arefollowed up, it would bebest to avoid thiscombination.

Coenzyme Q10 as CancerTreatment

A series of case reports from theInstitute for Biomedical Research at theUniversity of Texas at Austin describe thetherapeutic benefit of coenzyme Q10 (CoQ10)in cancer patients. These investigators havenoted tumor regressions and long-termsurvival associated with oral CoQ10, at dosesfrom 90 to 390 mg/day.101,102 This same groupused 90 mg CoQ10/day, combined with otherantioxidants (vitamin C 2850 mg, vitamin E2500 IU, b-carotene 32.5 IU, selenium 387mcg) and 3.5 g omega-3 fatty acids, in an opentrial in node-positive breast cancer patients.Patients also underwent conventionaltreatment. The investigators observed nodistant metastasis in any patient, and partialremission in six of 32 patients. No patients diedduring the 18-month study period. The lackof a control group makes these data hard tointerpret.103

CoQ10 with RadiationA 1998 study warns that CoQ10 re-

duces the effect of radiotherapy on small-celllung cancer in mice. This trial did indeed showa significant inhibition of radiation-inducedcell growth delay at 40 mg/kg oral dose, and aborderline inhibition at 20 mg/kg. However,no inhibitory effect on radiotherapy was noted

SELENIUM SUMMARY� Data are incomplete regardinginteraction between selenium andradiotherapy.� Selenium increased the activityof cisplatin in mice, and decreasedits toxicity in humans.� No in vivo evidence exists tosuggest that selenium reduces theeffect of chemotherapy.



at 10 mg/kg CoQ10, adose roughly equivalentto 700 mg in an adult hu-man.104 Based on this,the normal human doseof CoQ10 of 100-400mg/day probably haslittle inhibitory effect onconcurrent radiotherapy.

CoQ10 with ChemotherapyA number of studies have looked at the

capacity of CoQ10 to prevent the cardiactoxicity associated with doxorubicin. A smallstudy in humans showed CoQ10administration at 1 mg/kg led to an over 20-percent reduction in episodes of ECG changepost-treatment compared with doxorubicinalone. Diarrhea and stomatitis were alsosignificantly reduced.105 A mouse studyconfirms the protective effect of CoQ10treatment on the toxicity of doxorubicin. Inthis study, it was noted that CoQ10 did notreduce the anti-tumor effect of doxorubicin.Instead, a trend toward better tumor controlwas seen.106 In a study of 20 leukemia patientsundergoing treatment with the similar agentdaunorubicin, 100 mg CoQ10 twice daily wasable to significantly reduce adverse cardiacevents as measured by echocardiography. Nomention was made of the effect of CoQ10treatment on the therapeutic benefit ofdaunorubicin chemotherapy.107

Melatonin as Cancer TreatmentAlthough it is not usually considered

a standard antioxidant, melatonin, the hormonesecreted by the pineal gland in response tocycles of light and dark, has exhibited potentfree radical-scavenging properties against hy-droxyl and peroxyl radicals.108

Melatonin has also been found to havesome interesting anti-tumor properties in vitro.It increases p53 expression in breast cancercells, and therefore significantly reduces cell

proliferation.8 Im-paired p53 expres-sion is associatedwith many humancancers.109 Melato-nin is also known tomodify manycytokines, includingTNF, IL1, IL-2, IL-6, and gamma-inter-

feron, in ways consistent with increased hostdefense against cancers.110 Melatonin, perhapsthrough reduction of TNF secretion, has beenshown to reduce cachexia in patients withmetastatic solid tumors. Patients taking mela-tonin (20 mg/day) were found to have signifi-cantly less weight loss (3 kg vs. 16 kg) anddisease progression (53% vs. 90%) than thosetreated with supportive care alone.111

In another study, 63 patients with non-small cell lung cancer refractory to cisplatintherapy were randomized to receive either 10mg/day of melatonin or supportive care alone.Patients receiving melatonin lived longer onaverage than those receiving supportive carealone (6 vs. 3 months) and were more likelyto survive for one year (8/31 survivors vs. 2/32). No drug-related toxicity was noted by theauthors.112 Treatment with melatonin (20 mg/day) was also associated with greater one-yearsurvival than supportive care alone in patientswith brain metastases.113 Other studies havenoted increased survival in malignantmelanoma114 and patients with metastaticdisease.115 The latter study stressed that basedin its effects on the immune system, melatonincould be tested in association with other anti-tumor treatments.115 The DiBella multitherapyof cancer, of which melatonin is a part (alongwith many other agents), was found not to havesufficient efficacy against advanced cancer towarrant further investigation.116 Animalexperiments suggest doses as high as 250 mg/kg are non-toxic.117

CoQ10 SUMMARY� Doses of CoQ10 commonly usedin humans do not appear to inhibitthe effect of radiotherapy in vivo.� CoQ10 has been shown not toinhibit the effect of doxorubicin invivo.� No in vivo evidence suggestsCoQ10 inhibits the effect ofchemotherapy.

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Melatoninwith Radiation

In a ran-domized trial in-cluding 30 patientswith glioblastoma,the effect of radio-therapy plus 20mg/day of melato-nin was comparedto that of radio-therapy alone. Atthe end of one year,six of the 14 pa-tients receivingmelatonin were still living, compared to oneof the 16 undergoing radiotherapy alone. Theauthors also noted fewer side effects from ra-diotherapy in patients taking melatonin.118

Melatonin with ChemotherapyMelatonin has been studied a number

of times as an adjunct to standard chemo-therapy in humans. A phase II study usedtamoxifen plus melatonin (20 mg/day) in thetreatment of metastatic breast cancer whichhad progressed under treatment withtamoxifen alone. Four of the 14 patients testedhad partial response to this combination, witha median of eight months before disease pro-gression. Treatment was well-tolerated andrelief of anxiety or depression was noted bymany patients.19 A similar study was conductedusing the same combination of treatments inpatients with metastatic solid tumors other thanbreast cancer which had not responded to pre-vious chemotherapies. Partial response orstable disease was seen in 16/25 patients. Oneyear survival was seen in 7/25 patients.119

In another phase II study, melatonin(20 mg/day) led to a normalization of plateletcounts in nine of twelve breast cancer patientswho acquired thrombocytopenia duringepirubicin therapy. Objective tumor regression

was noted in fiveof the 12 pa-tients.120 A ran-domized trial in-vestigated the dif-ference betweenmelatonin (20 mg/day), cisplatin, andetoposide, andtreatment withcisplatin andetoposide alone inadvanced non-small cell lungcancer. One-yearsurvival was sig-

nificantly higher in patients receiving adjunc-tive melatonin compared to standard chemo-therapy alone (15 of 34 vs. 7 of 36). Therewas a non-significant trend toward greater tu-mor response in melatonin-treated patients aswell (11 of 34 vs. 6 of 36). Myelosuppression,neuropathy, and cachexia were noted less fre-quently in patients receiving melatonin thanin those that were receiving only chemo-therapy.121 A double-blind trial was unable toreplicate this protective effect of melatonin onthe myelosuppression mediated by carboplatinand etoposide. This may reflect the effecthigher doses of chemotherapeutic agents givenin the second trial. The authors concluded thatpotentiation of the effect of chemotherapy bymelatonin was unlikely.122 Concomitanttherapy with melatonin (40 mg/day) has beenfound to increase the effect of interleukin-2against a variety of solid cancers.123 The com-bination of melatonin (40 mg/day) andinterleukin-2 has been found to be a more ef-fective treatment than cisplatin and etoposidein non-small cell lung cancer.124

MELATONIN SUMMARY� Melatonin increases tumor cellapoptosis.� Melatonin decreases cachexiasymptoms in humans.� Melatonin improves survival time assole agent in terminal cancer patients.� Melatonin increases radiation effectin humans.� Melatonin increases survival time andtumor response in patients treated withtamoxifen, cisplatin, and etoposide.� No in vivo evidence suggests thatmelatonin decreases chemotherapyeffect.



N-acetylcysteine as CancerTreatment

We were unable to locate researchdemonstrating N-acetylcysteine (NAC) as ananti-tumor agent. NAC is known to be safe indoses well above that used in most human tri-als. Diarrhea is the most commonly reportedside effect of higher doses.125

N-acetylcysteine with RadiationThe effect of NAC on radiotherapy was

observed in 10 patients with non-small celllung cancer. NAC was administered by IV(100 mg/kg over 30 minutes) before the firstradiation session, followed by 30 mg/kg IVover the next seven hours. They then inhaleda nebulized solution containing 600 mg NAC30 minutes prior to and after each subsequentradiation treatment. Patients receiving NAChad tissue reactions and tumor responses fromradiotherapy judged to be similar to a controlgroup. Average survival time was similar be-tween patients receiving NAC treatment andthose who underwent radiation only. The au-thors concluded the treatment outcome did notjustify the expense.126 An in vitro experimentshowed that NAC is not likely to block thetumor cell killing effect of radiation.127

Application of gauze soaked in 10-per-cent NAC solution to the skin 15 min-utes before radiotherapy was tested inan unblinded trial. Topical NAC ap-peared to be associated with more rapidhealing and less use of analgesics com-pared with those in the control group.128

N-acetylcysteine withChemotherapy

NAC has been employed witha number of chemotherapy agents as ameans of reducing toxicity. It hasgained such recognition in this regardthat it is often used in clinical trials asan adjunct to the therapy being tested.

Animal studies have shown NAC protectsagainst hematuria resulting from cyclophos-phamide therapy without reducing itstumoricidal effect.129-131 A phase I human trialfound 6 g/day NAC completely protectedagainst hematuria, which is a dose-limitingside effect of ifosfamide (an analogue of cy-clophosphamide).132 Another human studyfound similar results.133

Human trials with dosages as high as140 mg/kg NAC were unable to show anyprevention of cardiomyopathy due to treatmentwith doxorubicin. One of these trials also notedthat NAC treatment was not associated with areduction of the anti-tumor action ofdoxorubicin,134,135 and a mouse studyconcurred. This study also noted preventionof cardiotoxicity, which as noted above, wasnot replicated in human studies.136 Anotheranimal study raises the possibility of areduction of the anti-neoplastic action ofdoxorubicin by NAC. NAC did, however, leadto a significant reduction in cardiac toxicity.137

As data on the subject of doxorubicin withNAC are currently conflicting, thiscombination might best be avoided at this time.

N-ACETYLCYSTEINE SUMMARY� NAC does not appear to block the therapeuticeffect of radiation in humans or in vitro.� NAC does not block the therapeutic effect ofcyclophosphamide in vivo.� NAC appears to be associated with limitedbenefit in cancer therapy.� One of two animal studies shows NAC toreduce the efficacy of doxorubicin. This finding wasnot replicated in human studies.� NAC has been shown in vitro to reduce theefficacy of cisplatin.

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It has been shown in two separate invitro studies that NAC inhibits the cytotoxicactivity of cisplatin.138,139 NAC may have a role,however, in the reversal of renal toxicity dueto cisplatin.140 Other than use in salvagetherapy, the combination of cisplatin and NACshould also probably be avoided at this time.

Glutathione as Cancer TreatmentGlutathione is a tri-peptide thiol (sulf-

hydryl-containing) compound which is themajor intracellular antioxidant in the body. Ahuman study suggests oral glutathione ispoorly absorbed, with negligible plasma con-centrations found after administration of asingle 3 g oral dose.141 This conclusion is con-tradicted by a rat study which found dietaryglutathione was absorbed in a dose-dependentmanner, and remained elevated in the plasmafor three hours after administration.142 Aero-sol administration of glutathione is an effec-tive means of delivery to the plasma143, as isintravenous administration.144 Glutathione isthought to be non-toxic to humans,144 althoughone study found a 5 g oral daily dose was as-sociated with GI irritation and sulfur odor.145

A case report from Japan in 1984 raisedthe possibility that glutathione might be aneffective treatment for hepatocellularcarcinoma. A trial of six hepatocarcinomapatients on 5 g oral glutathione daily foundregression or stagnation of tumor growth inthree patients. One patient also had a reductionin alpha-fetoprotein (a tumor marker) from 496to 5. Two patients of the six survived for oneyear. These patients were both women, raisingthe possibility of a sex-dependent effect.145 Ina rat study, oral administration of glutathionecaused regression of liver tumors, andincreased survival of tumor-bearing animals.146

The usefulness of glutathione as an anti-tumoragent may be limited to the liver, kidney, andperipheral neurons, as these are the only tissuesbelieved to have sufficient transport enzymesfor cellular uptake.144 For further discussion

of glutathione as an antioxidant, refer to thereview article by Kidd.147

Glutathione with RadiationA randomized pilot trial with 45 par-

ticipants investigated the radioprotective ef-fect of glutathione. Patients were administered1200 mg glutathione or saline placebo intra-venously 15 minutes prior to pelvic radio-therapy. Patients receiving glutathione sufferedless from post-therapy diarrhea (28%, com-pared to 52% of controls) and were more likelyto complete the treatment cycle (71% to 52%).Although the sample size was too small toshow significance, the authors concluded glu-tathione was unlikely to interfere with the ef-fect of radiation on neoplasms.148 The argu-ment was not based on patient outcome.

Glutathione with ChemotherapyIncreased cellular concentrations of

glutathione have been associated with resis-tance to both anthracyclines and platinumagents.149 Given the suggestion of the inabil-ity of most cell types to take up exogenousglutathione,144 decreased chemotherapy effi-cacy due to glutathione administration may belimited to liver, kidney, and neurological tu-mors.

The use of cisplatin and glutathioneconcurrently has been studied in several smallhuman trials. One human trial found 3 g/m2

intravenous glutathione given 20 minutes priorto cisplatin (100 mg/m2) led to a significantreduction in nephrotoxicity in patients withovarian cancer compared with those receivingcisplatin alone. There was a trend towardgreater tumor response in the glutathionegroup—73 percent, compared to 62 percentin the control group.150 A similar trial usingsmaller doses of glutathione (2500 mg/m2) andcisplatin (50 - 75 mg/m2) did not find thereduction in nephrotoxicity reported above.However, the trend toward greater tumorresponse with glutathione treatment (72%



r e s p o n s e ,compared to 52%in controls) wascomparable.151

A double-blind trial studiedthe neuroprotectiveeffect of intrave-nous glutathione (1500 mg/m2) duringcisplatin treatment for gastric cancer. Afternine weeks, no patient of the 24 receiving glu-tathione, but 16 of 18 patients receiving pla-cebo, had developed neuropathy symptoms.Again, a trend toward greater tumor response(76%, compared to 52% in controls) was seenwith glutathione treatment.152

An open trial with 79 ovarian cancerpatients found i.v. administration of 2500 mgglutathione prior to treatment with a cisplatin/ cyclophosphamide combination led to greatertumor response and reduced toxicity comparedto that found in other trials using these che-motherapeutic agents.153 Another trial using thesame glutathione dose with the same combi-nation chemotherapy found no cases of neph-rotoxicity in 20 patients. The authors reported,based on their experience, that the effect ofthe chemotherapy was not interfered with, andmay have been enhanced.154 These results havenot been followed up in controlled trials, how-ever. The interactions between glutathione andchemotherapy agents other than cisplatin andcyclophosphamide have not been explored inhuman trials.

Flavonoids as Cancer TreatmentFlavonoids are plant compounds

known to have antioxidant properties in vitroand in vivo. Many of the thousands of fla-vonoids in nature have been studied for anti-cancer properties. Space does not permit adetailed discussion of this work. The most wellcharacterized anti-tumor flavonoids areepigallocatechin gallate (from green tea),155

genistein (from soy and red clover),156,157

curcumin (fromt u r m e r i c ) , 1 5 8

silibinin (frommilk thistle),159

and quercetin(from many yel-low vegetables).The authors are

presently preparing a review of the use of quer-cetin as cancer therapy.

Flavonoids with RadiationLittle is known about the effects of fla-

vonoids on radiotherapy. An in vitro experi-ment showed post-treatment application ofquercetin caused greater cell death in radia-tion-treated hepatoma cells than radiationalone. In the same experiment, genistein wasshowed to be associated with increased celldeath from radiation when applied during orafter treatment.160 Many different rutosides(flavonoids with similar structures to querce-tin) were found to have neither a protectivenor sensitizing effect on radiotherapy in ex-perimental mouse tumors.161 There is notenough evidence currently to support or ar-gue against the use of therapeutic doses of fla-vonoids together with radiation.

Flavonoids with ChemotherapyRecent research has focused on the

ability of flavonoids to increase the concen-tration of chemotherapeutics in tumor cells.Resistance to many chemotherapy agents isthought to be due to reduced accumulation intumor cells.162 Oral administration of green teain mice to increased the concentration of doxo-rubicin in two tumor types, but not in normaltissue. The anti-tumor activity of doxorubicinwas enhanced 2.5 times.163 Another report con-firmed this action of green tea, finding the tu-mor inhibition of doxorubicin increased fromnegligible to 62 percent. This report, however,determined the activity of green tea to be due

GLUTATHIONE SUMMARY� Glutathione is not thought to interfere withradiotherapy.� Glutathione decreases toxicity, and appearsto increase the anti-tumor effect, of cisplatin inhumans.� Glutathione/chemotherapy interactions arepoorly explored.

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to an amino acid, theanine, rather than its fla-vonoid content.164

Quercetin has been shown in vitro toincrease the concentration of doxorubicin inmultidrug-resistant human breast cancercells.165 Conversely, quercetin decreased theconcentration of doxorubicin in a resistanthuman colon cancer cell line.166 Quercetin andgenistein both increased the concentration ofdaunorubicin in some multidrug-resistant celllines, but had no effect in others.167 Genisteinin vitro increased the concentration of cisplatinin resistant cell lines.168 Other than the greentea studies, none of these studies analyzed celldeath due to flavonoid administration.

In mice with transplanted human tu-mors, quercetin (20 mg/kg) given withcisplatin reduced tumor growth to a greaterdegree than cisplatin alone.169 In a separate ex-periment, quercetin enhanced the effect ofcisplatin and busulfan in vitro and in vivo. Noenhancement or reduction of the anti-tumoractivity of doxorubicin or etoposide wasseen.170 An in vitro study found quercetin in-creased the effect of doxorubicin against re-sistant breast cancer cells.165

It should be cautioned, however, thata recent study showed a potential adverseinteraction. Tangeretin, a flavonoid found incitrus fruits, completely blocked the inhibitoryeffect of tamoxifen on mammary cancer inmice.171 One in vitro study suggests attenuation

of tamoxifen may be a concern with genisteinas well.172 Another in vitro study, however,shows tamoxifen and genistein synergisticallyinhibit the growth of estrogen receptor-negative breast cancer cells.173 Until theflavonoid-tamoxifen interactions areinvestigated more completely, it may be bestto avoid using therapeutic doses of flavonoidcompounds in breast cancer treated withtamoxifen.

Combinations of AntioxidantsGiven that many antioxidants have

been shown to have anti-tumor properties, itis worth exploring their use in combination. Astudy in mice found co-administration of beta-carotene and alpha-tocopherol led to muchgreater tumor regression than either agentalone. The effect was synergistic, being muchgreater than the sum of the mild tumor inhibi-tion of beta-carotene and alpha-tocopherol.174

Other studies have shown multivitaminsupplements were associated with fewer re-currences of solid tumors after remission fol-lowing standard oncologic therapies.20,21

A small double-blind trial of a mixtureof antioxidants, including 600 mg vitamin E,1 g vitamin C, and 200 mg NAC taken onlyduring treatment, looked at the potential of thismixture to prevent cardiotoxicity duringchemo- and radiotherapy. No patient taking theantioxidant mixture had a fall in ejection frac-tion greater than 10 percent. In patients takingplacebo, four of six patients undergoing ra-diotherapy and two of seven patients treatedwith chemotherapy had an ejection fraction re-duction of 10 percent or more. Treatment out-comes in patients taking antioxidants versusplacebo were not discussed.175

An open trial of combination antioxi-dant treatment along with chemotherapy andradiation in patients with small-cell lung can-cer had encouraging results. Patients taking thesupplement, which contained at least 15,000IU vitamin A, 10,000 IU beta-carotene, 300

FLAVONOID SUMMARY� Several flavonoids increaseradiosensitivity of tumor cells in vitro.� Green tea, quercetin, and genisteinincrease the concentration ofchemotherapy agents in some resistantcell lines.� Quercetin increases the anti-tumoractivity of cisplatin and busulfan in vivo,and does not interfere with the activity ofdoxorubicin or etoposide.� Tamoxifen activity has been reducedin vivo by tangeretin and in vitro bygenistein.



IU alpha-tocopherol, 2 gvitamin C, and 800 mcgselenium, were able totolerate chemotherapyand radiation well. Theirtwo-year survival ratewas greater than that ofhistorical controls(>33% to <15%), with44 percent still alive atthe end of the study(mean survival time forsurvivors = 32 months). No side effects fromnutritional treatment were noted.17 Hopefullythese promising results will be followed upwith larger and more well-controlled studies.

Current Attitudes and NewApproaches to Treatment

Cancer therapy has been remarkablyconsistent for the last 50 years. Surgery, ra-diation, and chemotherapy have been the cor-nerstones of conventional treatment. Not sur-prisingly, the clinical success of these treat-ments has reached a plateau.176 Some authorshave even questioned the validity of chemo-therapy as a treatment for most cancers.177

Clearly, there is a need for new therapies whichcan increase the efficacy of cancer treatment.Careful application of antioxidants may be ameans helping to raise cancer therapy to a newlevel of success.4

The attitude of many conventionalpractitioners toward antioxidant therapy forcancer has been hostile.178 Others have raisedthe argument that antioxidants could blunt theeffect of standard therapies, particularly alky-lating, platinum, and tumor antibiotic agents,which are oxidative in nature.5 While this ap-pears a theoretical concern, the evidence re-viewed here shows that this proposed interac-tion of anti- and pro-oxidant therapies is notgenerally of primary importance in vivo. It istime to put this argument in perspective.

PotentialMechanisms ofAntioxidants inCancer Therapy

How couldantioxidant therapyprotect normal cellsagainst damage fromcancer therapies, whileoften increasing theircytotoxic effect against

malignant cells? While the answer to thisquestion is not entirely mapped out, there areconcepts which might help us understand. Oneis the recent evidence that radiation andchemotherapy often harm DNA to a relativelyminor extent, which causes the cells to undergoapoptosis, rather than necrosis.6 Since manyantioxidant treatments stimulate apoptoticpathways,7,8 the potential exists for asynergistic effect with radiation orchemotherapy with antioxidants.

A second concept is that the defensivemechanisms of many cancer cells are knownto be impaired. This presumably makes tumorcells unable to use the extra antioxidants in arepair capacity; this has been illustrated invitro. An experimental murine ascites tumorcell line was found to have 10 -100 times lesscatalase than comparable normal cells. Thisled to a build-up of hydrogen peroxide in thecells upon treatment with vitamin C, in turnleading to cell death. The cytotoxic effects ofvitamin C were completely eliminated by ad-dition of catalase to the cell culture.179 Sincepublication of these findings, most human tu-mor cell lines studied have proved to be simi-larly low in catalase.180

COMBINATIONANTIOXIDANT SUMMARY� Combinations of antioxidantshave been shown to havesynergistic anti-tumor effects invivo.� Combinations of antioxidantswith chemotherapy and radiationhave been shown to increasesurvival time and reduce toxicity inhumans.

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Caveats When Considering UsingAntioxidants in Cancer Treatment

We wish to emphasize three concernsregarding the use of antioxidants raised in thispaper. One is the routine use of N-acetylcysteine with certain chemotherapeuticagents, namely cisplatinum and doxorubicin.Given the limited therapeutic benefits associ-ated with NAC in cancer treatment, and thenumber of other antioxidants shown above tohelp reduce the toxicities of these two chemo-therapeutic agents, there appears little reasonto consider NAC a first-line adjunct with ei-ther agent. Since the potential for adverse in-teraction with chemotherapy appears to begreater with NAC, perhaps it should be usedonly in situations where it has clearly beenshown to not interfere with other therapies.

The second concern we wish toreiterate is the interaction between tangeretinand tamoxifen. Except in cases whereinteractions with specific flavonoids areclearly defined, it seems prudent to avoidtreatment with flavonoids in therapeutic dosesconcurrently with tamoxifen. It is unknowncurrently if there is any reduction in tamoxifenactivity associated with dietary flavonoids,which are ubiquitous in the plant kingdom.

The third area of concern is the poten-tial reduction of 5-fluorouracil (5-FU) activ-ity by beta-carotene.58 The nature of this in-teraction is not clear. Until this is clarified, thecombination would best be avoided.

ConclusionFrequently, the effects of using anti-

oxidants concurrent with chemotherapy andradiation are synergistic. Except for three spe-cific interactions outlined above (flavonoidswith tamoxifen, NAC with doxorubicin, andbeta-carotene with 5-fluorouracil), there is noevidence to date showing that natural antioxi-dants interfere with conventional cancer thera-peutics in vivo. Studies have shown patients

treated with antioxidants, with or without che-motherapy and radiation, have many benefits.Patients have been noted to tolerate standardtreatment better, experience less weight loss,have a better quality of life, and most impor-tantly, live longer than patients receiving nosupplements. It is time to research the role ofthese agents in conventional oncologic treat-ment, rather than dismiss them as a class basedon theoretical concerns.

The authors wish to thank the SmilingDog Foundation for financial support of thisproject and to Bastyr University for its admin-istration.

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NOTICE OF INTENTThe American Academy ofOphthalmology’s Committee onOphthalmic Procedures AssessmentComplementary Therapies Task Forcewill develop a ComplementaryTherapies Assessment (CTA) onAntioxidant Vitamin and MineralSupplements for AMD. CTAs evaluatecomplementary therapies in eye careand develop an opinion on theirsafety and effectiveness, based onthe best available evidence andscientific data.

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