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EVALUATION OF ANTILEUKEMIC AGENTS EMPLOYING ADVANCEDLEUKEMiA L1210 IN MICE. VIII

John M. Vend.itti,' Ira Kline,2 Abraham @]@3J@1

Abstract

Fifteen compounds were evaluated for their ability to increase the lifespan of m.tcÃ©with advanced1euk@nia L1210. KLeven additional ccsr@ounds which had been evaluated previously in this assay system werestudied n@@reextensively. Of the ccsr@ounds assayed for the first time against advanced 1.1210, Benzanilide,4- (1, 4, 5, 6-tetmhydro-2-pyrimidinyl)-4' - ([i- (1, 4, 5, 6-tetrahydro-2-pyriinidinyl)phenyl)carbainoyl)- , hydrochloride (@SC-67, 734) and Cytosine, 1- @-D-arabinoftiranosy1- , hydrochloride (NSc- 63, 878 ) were 103 and 179per cent as effective as Ametbopterin (MIX) s@ihieh was employed as a standard for antileukemic activity.The antibiotics, [email protected]@ycin(53 per cent as effective as MEX) and Actinobolin (39 per cent as effective asMrx) were n@derate1y effective. ]@ta are presented on the influence of the treatment schedule includingthe time of treatment initiation, the site of tunxr inoculation, or the route of drug administration onthe antileukeinic effectiveness of selected compounds of interest including Cytoxan (NSc- 26, 271), methylglyoxalbisguanylhyth'azone , dihydroch.loride (NSC- 32, 946 ), 6-mercaptopurine (NSc- 755), prednisone (NSC10, 023.E), the pht@ia1e-nf1 ide derivatives (@c-5O, 469, NSC- 53, 212, and NSC- 60, 339 ), 1, 3-bis(2- chioroethyl)l-nitrosou.rea (NSC-409, 962), and two phenazinium derivatives (NSC-33, 419 and NSC-33, 426).

Introduction

This report is the eighth of a series (8-12,20,22) presenting data obtained using an assay procedure for the quantitative evaluation of the relative effectiveness of chemical agents against systemicleukemia 11210 in mice. The assay (5, 6 ) permits the evaluation of the compounds with respect to theirantileukem.ic activity in relation to LAmethopterin (MLX; NSC-740 ), which is used as a standard for therapeutic activity. In the 22 experin@nts included in the present study, 15 compounds not previously evaluated in this assay system are rated according to their relative effectiveness, when administered daily viathe subcutaneous (S. C. ) route, in increasing the n@dian survival time of mice with advanced leukemia L1210.Eleven compounds previously reported (8-12, 20, 22 ) were studied in more detail. In addition, data on theinfluence of the route of drug administration and the schedule of treatment on the antileukemic effectiveness of selected compounds are included.

Materials and Methods

The [email protected] and methods are essentially the same as described in previous reports from this laboratoiy (5, 7-12, 20, 22). Genemuy, in an experiment, a saline suspension of cells prepared from leukemiaL1210- infiltrated spleens of DBA/2 stock tumor mice was inoculated (0. 1 to 0. 2 in]. per mouse ) S. C. intothe right hind leg of BDF13 or ci@3 iiyirid mice. In some cases, noted specifically in the tables, thetumor was inoculated intraperitoneally (I. P. ) or DBA/2 mice were employed. The strain, sex, and weightrange of the mice and the level of leukemic inoculuxn used in each experiment are shown in the tables ofresults. In addition to treated and control mice that received the experin@ntal tumor inocu.lum each experiment included groups of untreated mice that received serial dilutions of the inoculum. Data from thelatter groups showed that, in the present experin@nts, the experimental tumor inoculum was 10 or 100 timesthat required to kill 100 per cent of untreated mice.

Treatment was begun when the local tun@r, at the site of S. C. leukemic inoculation, was estin@tedby manual palpation to be 7 to 12 mm in diameter. In the current series of experiments, this occurredtwo to four d2@ys prior to the median day of death of the untreated controls. In each experiment, on theday treatment was initiated (noted in the tables ), three to six mice selected at random from the population that had received the experimental leukemic inocu.lum were sacrificed and their spleens were implanted subcutaneously into [email protected] mice of the same strain. The consistent death from tumor of the recipient@s of such implants indicated that the disease @â€˜assystemic in the donor mice. The median survivaltimes for the recipients of the splenic tissue are reported in the tables relative to the day on @thichthey were inoculated.

I Dii@â‚¬Evaluation Branch, cancer chenx,therap.y National Service Center, National Cancer Institute, NationalInstitutes of Health, Bethesda, 1'@.ryland.

2 Microbiological Associates, Inc. , Bethesda, I4@ryland. This study was supporbed by Contract No. P11-43-62-182 from the @.ncer c@hen@theraw National Service Center, National Cancer Institute, National Institutes of Health, Public Health Service, U. S. Department of Health, Education, and Welfare.

3BD@ â€”(c57BL/6 female x DBA/2 [email protected] - (BALB/cAn [email protected] x DB@/2 [email protected] )F,@

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Each compound employed, its molecular fonnula and the vehicle in which it was administered aregiven in the tables.

The vehicle used for each compound is coded as follows:

A distilled waterB 2 per cent sodium bicarbonate solutionC 0.5 per cent methylcelluloseD 0.85 per cent saline solutionE dilute sodium hydroxide solution

@bstof the compounds were supplied by the Cancer ChemotherapyNational Service Center (CCNSC),National Cancer Institute. The source of each ccmipoundis coded as follows:4

Chemical-Biological Coordination Center 43National Academy of ScienceNational Research Council2101 ConstitutionAvenueWashington, D. C.

4P Merck and CompanyContract No. SA-43-ph-1948 tocancer c@hemotherapy National

Service Center

20 Dr. John A. @ntgomeryHead, Organic Chemistry DivisionSouthern Research InstituteBirmin@hsin 5, Alaban@

211 Dr. M. J. ShearNational Cancer InstituteNational Institutes of HealthBethesda 14 , I,@ryland

27 Dr. John R. DiceResearch LaboratoriesParke, ]@vis and Company2800 Plymouth RoadAnn Arbor, Michigan

27C Dr. John EhrlichLaboratory Director in

Antibiotic ResearchParke, t@vis and CompanyDetroit, Michigan

35D Dr. Paul W. 0' ConnellBiological Screening OfficeThe Upjohn CompanyKalan@zoo, Michigan

37 Dr. George H. Hitchings37P Research Director

chemotherapy DivisionWellccme Research Laboratories1 Scarsdale RoadTuckahoe 7, New York

Endocrinology Sectioncancer Chemotherapy NationalService Center

National Institutes of HealthBethesda 14, ?@iyland

57A Dr. Benjamin PrescottNational Institute of Aller@r andInfectious Diseases

National Institutes of HealthBethesda 14, @iyland

74 Organic c@hemical S@ockroomNational Institutes of HealthBethesda l4,@ I'@ryland

229A Dr. J. M. RuegseggerClinical Research SectionLederle Laboratories DivisionAmerican Cyanamid CompanyPearl River, New York

243 Dr. Kenneth N. CampbellDirector Medicinal ChemistryMead Johnson and CompanyEvansville 21, Indiana

254A Dr. J. SchznutzResearch InstituteDr. A. Wander S. A.Borne, Switzerland

313 Professor A. Dil'@rcolaboratori Scientific e di [email protected] del Gracchi, 35Milano, Italia

339A Dr. Arnold M. SeligmanSinai Hospital of BaltimoreBaltimore, @ryland

365A Dr. Koert GerzonOrganic chemical DivisionThe Lilly Research laboratoriesEli Lilly and CompanyIndianapolis 6, Indiana

The compounds were administered generally Sâ€¢C. in the scapular region in the constant volume of0. 01 ml per g. of body weight and given daiJ@y until death. Instances in which an alternative schedule orroute of treatn@nt was used are noted in the tables.

q.@iedrugs were atiminfstered over a wide range of logarithmically- spaced dosage [email protected]. Typically,

4â€•oiThg@Ã¡@iÃ³Ã¼rÃ Ã©code number indicates that the compound was purchased by CCNSC.

Cancer Research Vol. 24, July 1964, Part 2



VENDITPI et al. Caiwer Chemotherapy Screening Data 829

for an active onmpound, as the dose level @.sincreased, there was an increase in the median survival timeof the mice. With further increase in dosage, the toxicity of the drug for the host became limiting andresulted in a diminution in median survival time. The relative effectiveness of the various therapieswas based on the increase in median survival time at the optimal dose of each dn@g (i. e. , the dose providing the naxinn.im increase in n@dian survival tiix@). Where the n@xiinum median survival time was observedat more than one dosage level, selection of the optimal dose is based on the entire individual survivalpattern. Instances in which the optinmi dose @ybe outside the range of doses employed are noted in thetables by the symbols * or t. Where all dose levels resulted in toxicity, as evidenced by body weightloss (denoted by the symbol*), the opting]. dose n@y be lower than any used. Where no clear evidence oftoxicity appeared at any dose level tested (indicatedby the symbol t), the optin@l dose may be higherthan any employed. In some cases, although the maximum median survival time occurred at one of the extreme dosage levels, the data indicated no advantage in testing at still more extren@ levels. Such instances are not noted specifically.

Amethopterin (MI!x)was used as a standard for antileukemic effectiveness in each experiment . Thecompounds are rated relative to the MPX standard for efficacy in increasing the survival time of theleukernic mice. The relative efficacy of each test compound was computed in per cent as : (Mi@@-M@)/(M@-M@)x 100 where Mt@is the median survival time at the optimal daily dose of the test compound, M@is themedian survival tiix@ at the optin@l daily dose of the MJ!Xstandard, M@is the median survival time of untreated controls.

Two ratings are shown in studies of the influence of the route of drug administration or the5 chedule of treatment on antileukemic effectiveness ; i â€¢e â€¢, the compounds are rated relat ive to (a ) the

daily S. C. administration of the Ml@ standard and (b ) the median survival time of the untreated controls.The latter rating is calculated as : (M,-M@)/(M@) x 100.

Results

Table A lists the ccsi@ounds tested, the source of eacti, and the tables in which the results appear.The results of the current experin@nts are shown in Th.bles I through VIII.

In Table I the test compounds, on daily S. C. administration, are rated relative to the IWC standard. Table I also shows, fbr each cczz@oundtested in each experiment, the molecular fornnila, the optimaldaily dose level, and the median survival time observed at this level.

Tables II and III summarize data on the influence of the route of administration on the antileukemic activity of NSC-740, 26,271, 32,946, 755, lO,O23E, 60,339, 53,212, and 50,469. Tables IV and Vsummarize data on the influence of treatment schedule on the antileukemic activity of NSC-74O, 26, 271,32,946, 755, 10,023E, and 409,962. Table VI summarizes the antileukeinicactivity of NSC-4O9,962 onvarious treatment schedules in CDBAand DBA/2 mice. Table VII summarizes data on the influence of thesite of tumor inoculation, route of drug administration, and day of treatment initiation on the antileukeniic effectiveness of NSC-33, 419 Ã©.ndNSC-33, 426. Table VIII presents the detailed results of the 22experiments in the current study and shows, for each experiment, the compounds tested, the vehicle foreach, the dose levels employed, the route of drug administration, and schedule of treatment. In addition,Table VIII s1@ws, for each experin@ntal group, data on n@dian and individual survival times and the numberof survivors, if any.

A. [email protected]@2IESSOF COMPOUNDSON DAILYSUBCTJTA@EOUSTREaT1'@NT,AGAfl@TADVANCII@IEUI@NIA L1210

1. Phth@@.lani1ide Derivatives and Belated Compounds (Table I Section 1 Table VIII &perin@r@tsDL-385 388 389 390 and 391): The antileukemic activity of NSC-53, 212, which was previously reportedby our laboratory (22) to exceed that of )fIYX,was confirmed in these studies. The activity of NBC67, 734 (previously unreported in this series ) approximated that of Z'fIX. NBC-50, 469 and NBC-60, 339 alsoexhibited considerable antileukemic activity in agreement with previous experiments (22 ). NSC-57 , 142 andNSC-57,l55, at the doses studied in these experiments, were essentially ineffectiveagainst advancedleukemia L121O.

2. Urea Derivative (@.b1e I, Section 2 Â¶I@b].eVIII Experiments DL-335@, 346 348. and 379-379A).Urea, 1, 3-bis(2-ch.loroethyl)-1-nitroso- (BCMJ), NSC-4O9, 962, has been shown by Schabel@ et al. , (16) tohave marked activity in the treatment of mice with early I.P. or intracerebra].ly (I. C. )-inocu.iatedleukemia 11210. In the four experiments included in the present study, NSC-409, 962, when given daily tomice with advanced S. C. -inoculated L121O, provided increases in median survival time which ranged from150 to 375 per cent of the M1@ effect.



830 Caiwer Research Vol. 24, July 1964, Part 2

3. Antibiotics (Table I Section 3 Table VIII @bcperiments DL-385 392 and 395): A new antibiotic, t@unon@rcin (NSC-82,l5l@ (2) at its optimal daily dose (14 mgJkg was 53 per cent as active asMI!X. Actinobolin (NBC-31, 083), which has displayed activity against a spectrum of transplantable tumors(1,17), was 39 per cent as effective as MIX against advanced 11210. However, Actinobolin elicited thiseffect at the highest daily dose tested (833 mgJkg), and the possibility remains that Actinobolin might bemore effective against advanced L1210 at higher daily doses or if the interval between treatments wasdiminished. The relative effectiveness of Azaserine (NSC-742) in the current experiments was somewhatless than that observed in previous experiments conducted in this laboratory (9, 22).

4. Pyriinidine Derivative (Table I, Section 4. Â¶L@bleVIII@ @bcÃ§perimentDLâ€”385): The marked activity of Cytosine, [email protected] , hydrochloride, NSC-63, 878, against a number of experimentaltumors has been shown by EvaÂ±is,et al. (3). The current experiment (Table VIII, experiment DL.-385) showsthat NSC-63,878 was more effective than M[@Xin the advanced L121O assay system and that this Cytosinearabinoside retained its antileukemic effectiveness when given daily, every second day, and every fourthday.

5. Other Ccinpound.s (@ble I Section 5 @bleVIII &periments DL-351 353 355 362 365 366369 385 391 392 394 395 and 396 ): The antileukemic effectiveness of Cytoxan (NBC-26, 271), 6-mercaptopurine (NSC-755), and methylglyoxa.lbisguanylhydrazone, dihydrochioride (NSc-32, 946) observed in thecurrent experiments agrees with the results of previous experiments conducted in this laboratory (8, 9, ll,12,22). In two experiments(DL-362and 369), prednisoneprovided increases in median survival time of 28and 43 per cent relative to MDC. In previous experiments, NSC-1O,O23E was less effective against advanced L1210 (9). A tribenzoic acid analog of 6-thioguanine riboside (NSC-3O, 688), at the highest dailydose tested (180 mgJkg), was 33 per cent as effective as MIX and produced no evidence of toxicity to thehost. It is possible t1@t NSC-30, 688 might display greater effectiveness against advanced leukemia L12.1Oat higher daily doses. None of the remainingtest compoundswere more than 20 per cent as effective asMDCin this assay system.

B. INFLIJENGEOF THE @Ui@EOF DR1X@ALt4INISTRATIONON TEE ANTILEIJKEMICEFF@TIVENESS OF SEI@CTED COMPOU@IDS

(@@es II III and VIII &periments DL-90@ 355 362 366 388 389 and 390)

The previously reported (21) diminution in the effectiveness of ME!X NSC-740) against advancedL1210 when treatment is given orally was observed in the current experiments Table II ). MIX displayedapproximately eqjial effectiveness when given S. C. , I.P. , or intravenously (I. V. â€¢ The current experiment(@ble II, experiment DL-355) and previous observations (15,18,19) show that Cytoxan, when given daily,S. C. , to mice with advanced L1210, was as effective or more effective than MIX. The currant experiment(DL-3@s) also shows that the naxted effectiveness of Cytoxan s@s retained when the compound was given I. P.or orally and is consistent with the previous observations of Lane (15). NBC-32, 946, 755, and 10, O23Ealso retained their maximum antileukemic effectiveness when given S. C. , I. P. , or orally (Table II@. Theoptimal oral d.aily dose of MIT (5. 0 mgJkg) was approximately three to five times the optimal S. C. dailydose. With Cytoxan (NSC-26, 271), NSC-32, 946, and NSC-lO,023E, the optimal oral daily dose was approximately two, three, and five times respectively the optimal S.C. daily dose whereas with NSC-755 theoptimal daily dose was the same by either route (Table II).

@rprevious experiments (9, 22) showed that terephthalanilide, 2- chloro-4' , 4' â€˜-di-2-imidazolin- 2-yl- , (NBC-60, 339) and its dilzydrochloride (NBC-38, 280), were markedly effective against advanced leukemiaL121O when administered daily by the S. C. or I.P. route. In addition, NSC-60, 339 was more toxic to normalmice when aÃ±minfstered as a single injection I.V. or I.P. than when given S. C. (22). The current experimerits (Tai@le III, experiments DL-388, 389, and 390), show that NSC-6O,339, 53, 212, and 50,469 were moreeffectivea@inst advancedL121O on daily S.C. treatmentthan on daily I.V. treatment. Kensler (14) hasreported that the activity of many phth@Thnilide derivatives against early leukemia L1210 was reduced ifthey were given orally when food was available ad libitum to the mice.

â€˜@. INFLUENCE OF TEE SCEEDULE OF TREP@T@NT ON A1ITILEtJKEMEC EFFECTIVKNNBS

(Tables IV V@VI and VIII Experiments DL-335 346 351 352 353 365 369 and 379-379A)

In continuation of detailed studies of agents of current clinical interest, NBC- 740, 755, 10, 023E,26,271, and 32,946 were investigatedfurther with respect to the influence of the treatment schedule ontheir effectiveness against advanced leukemia L1210 (Table IV). The current stud.ies confirmed our previous findings (5, 6, ll, 18) that against advanced 11210, ML@Xwas more effective when administered dailyor every two days than wt@n given twice daily, every third, or fourth day, and that treatment every sevendays was the optima]. schedule for Cytoxan therapy.

In agreement with our previous experiments (12, 22 ), NSC-32, 946 was more effective when given twoor four times daily than when given daily, every two days , every four days , or weekly.



VENDITTI et al. Cancer Chemotherapy Screening Data 831

In a previous study conducted in our laboratory (22 ), NBC-755 was slightly more effective whengiven twice daily than when given on a more or a less frequent schedule â€¢ In the current experiment , DL365, NSC- 755 was somewhat more active when given every two days than on the other treatment schedules.NSC-l0,023E was more effective when injected every two days than when given daily (experiment DL-369).

The effectiveness of NBC-4O9,962 (BCIIU) was retained over a wide range of treatment schedules, ofwhich trea1@nt every four days or every seven days appeared to be most effective (Tables V, VI, and VIII,experiments DL-335, 346, 379, 379A). In one experiment (DL-335), a single BcNIJ treatment of 96 mgJkg resulted in five tumor- free survivors out of eight CDBAmice (see Table V and Table VIII, experiment DL335). Ã¸nday 106, the five tumor- free survivors. and the group of 10 untreated and previously uninoculatedmice from experiment DL-335 (@bls VIII) were inoculated with L12l0 leukemia. No drug treatment was given.The five mice which had been previously inoculated with L12l0 and had survived after a single treatment of96 mg/kg BCNUdisplayed a median survival time of 20 days from day 106. The group of 10 mice which hadnot been inoculated previously exhibited a median survival time of 10 days from day 106. In two subsequent experiments (DL-346, 379-379A) a single dose of 96 mgJkg resulted in early lethal toxicity in mostof the mice and. lower single dosage levels failed to produce survivors although a few individual animalsexperienced extensive increases in lifetime (see the individual survival times in Table VIII ). The datasunmmrized in Table VI (Experiment DL-379-379A) suggest that the CDBAhybrid mice with advanced leukemiaL1210 responded more favorably to BCNUtreatment than leukemic DBA/2 mice. The mice used in experimentDL-379-379A were inoculated from the same leukemic cell suspension. In experiment DL-379, CDBAmice weretreated from day 7 (three days prior to the median day of death of the untreated controls ), and in oxperiment DL-379A, DM12 mice were treated from day 6 (four days prior to the median day of death of theuntreated controls). Despite the later time of treatment initiation, the CDBAmice displayed greater increases in lifespan than DM/2 mice with each of the treatment schedules employed. Glynn, et al. , (4) hadsuggested that the differential therapeutic response of inbred and hybrid leukemic mice to 3' , 5'-dichloroamethopterin (DCM) therapy may be attributable to the greater role of host defense mechanisms in thehybrids. The current data emphasize further the need for considering host factors such as an immune respouse to the tumor in the eva.luat ion of drug effectiveness.

Kelly, et al. , (13 ) had reported the activity of a number of phenazinium aerivatives against earcoma 37. The response of mice with L1210 leukemia to two of these agents under various experimental conditions with respect to the site of tumor inoculation, the route of treatment, and the time in the courseof the disease when daily treatment is initiatedis summarizedin Table VII and shown in detail in TableVIII (experiments DL-394 and 396 ). With both NBC-33, 419 and NBC-33, 426 the most extensive increase@ inlifespan occurred when mice with I.P. -inoculated L1210 were treated I.P. from day 1. The effectiveness oftreatment with either compound was M-inThlshed if (a) the tumor was inoculated S. C. , (b ) the treatment wasgiven S.C., or (c) the initiation of treatment was delayed. In general, NBC-33,426 was the more effectiveof the two agents in the treatment of L1210. ]@ta presented previously by this laboratory (8, 9 ) showedthat [email protected] (NBc-9, 369) when given I. P. was effective against early leukemiaL1210 but that the drug was relatively ineffective when given S. C. or when the tumor had been inoculatedS.C. These observationsemphasizethe influence of the treatment route, the site of tumor inoculation,and the time of treatment initiation on the effectiveness of therapy.

References

1. @irchorial, J. H. ; Holmberg, E. A. D. ; Reilly, H. C. ; Hemphill, S. ; and Reppert, J. A. The Effects ofActinobolin on Transplanted I'buseLeukemias. In: Antibiotics Annual 1958-1959, New York, ?@dicalEncyclopedia, Inc., 1959, pp. 528-32.

2. Di@rco, A. ; Soldati, N. ; Fioretti, A. ; and r@sdia, T. R@serche sull'Attivita della Daunomicina suCellula Normali e Neoplastiche Coltivate in Vitro. Tumori, 49:235-51, 1963.

3. Evans, J. S. ; Misser, E. A. ; I4ngel, G. D. ; lbrsblad, K. R. ; and Hunter, J. H. Antitumor Activity ofl-@-D-Arabinofuranosy1cytosine Hydrochloride. Proc. Soc. Exper. Biol. & Med. , 106: 350-53, 1961.

4. Glynn, J. P.3 Humphreys, S. R.; Trivers, G.; Bianco, A. R.; and Goldin, A. Studies on Immunity toleukemia L1210 in Mice. Cancer Res., 23:1008-15, 1963.

5. Goldin, A. ; Venditti, J. M.; Thimphreys, S. R. ; and 1.@nte1, N. I'bdification of Treatment Schedules inthe @.nagement of Advanced Ibuse Leukemia with Am.ethopterin. J. Nat â€¢Cancer I@ist. , 17: 203-12, 1956.

6. . Comparison of the Relative Effectiveness of Folic Acid Congeners Against Advanced Leukemia in Mice. J. Nat. Cancer Inst. , 19:ll33.-35, 1957.

7. . Quantitative Evaluation of Chemotherapeutic Agents against Advanced Leukemia in Mice.J. Nat. Cancer Inst., 21:495-511, 1958.



832 Cancer Research Vol. 24, July 1964, Part 2

8. Goldin, A. ; Venlitti, J. M.; and KLine, I. Evaluation of Antileukemic Agents @nploying Advanced I.eukemia L-1210 in Mice. V. In: Cancer Chemotherapy Screening Data. XIV. (J. Leiter, ed. ). CancerRes., 22:157-220, 1962.

9. â€¢ Evaluation of Antileukemic Agents @nploying Advanced Leukemia L-l210 in Mice. VI. In:Cancer Chemotherapy Screening l@ta. XVII. (j. Leiter, ed. ). Cancer Res. , 22: 749-835, 1962.

10. Goldin, A. ; Venditti, J. M.; Kline, I. ; and I@ntel, N. Evaluation of Antileukemic Agents @knp1oyingAdvanced Leukemia L1210 in Mice. In: Cancer Chemotherapy Screening 1@ta. IV. (J. Loiter, ed.).Cancer Res., 19:429-66, 1959.

ll. â€¢Evaluation of Antileukemic Agents @knp1oyingAdvanced Leukemia 11210 in Nice. II. In:Cancer chemotherapy Screening Data. VI. (J. Leiter, ed. ). Cancer Res. , 20:382-448, 1960.

12. . Evaluation of Antileukemic Agents @knp1oyingAdvanced Leukemia L121O in Nice. IV. In:Cancer Chemotherapy Screening Data. IX. (.@. Loiter, ed. ). Cancer Res. , 21: 27-92, 1961.

13. Kelly, N. G. 3 &iith, N. H. ; and Leiter, J. Relation of Chemical Structure to Development of Â¶Thimor]@mage and Body Tremors in a Series of Phenazinesand Related Compounds. J. Nat. Cancer Inst., 20:1113-22, 1958.

14. Kensler, C. J. Chemotherapetthic Activity of Phthalanilide Derivatives : An Approach to AnticodicTherapy? Cancer Res., 23:1353-63, 1963.

15. Lane, M. Sane Effects of CyClOphoSIhBmIde (Cytoxan) on Nox@nal Mice and Mice with 11210 Leukemia. J.I@t. CancerInst., 23:1347-59,1959.

16. Schabel, F. M., Jr.; Johnston, T. P.; McCaleb, G. S.; I@bntgomery, 3. A.; Laster, W. R.; and Skipper,H. E. Experimental Evaluation of Potential Anticancer Agents. VIII. Effects of Certain Nitrosoureas on Intracerebral L12l0 Leukemia. Cancer Resâ€¢, 23:725-33, 1963.

17. Sugiu.ra, K. , and Reilly, H. C. The Effect of Actinobolin on a Spectnun of Tumors. In: AntibioticsAnnual 1958-1959,New York @dicalEncyclopedia,Inc., 1959, pp. 522-27.

18. Venditti, J. M. ; Goldin, A. ; and Kline, I. The Influence of Treatment Schedule on the Chemotherapyof Advanced leukemia L1210 in Mice. Cancer Chemother. Rep. , 6 : 55- 7 , 1960.

19. Venditti, J. M.; Humphreys, S. R. ; and Goldin, A. The Effectiveness of Cytoxan Against l.buse Leukemia L1210 and Resistant Sublines. Cancer Chemother. Rep. , 3: 6-8, 1959.

20. Venditti, J. 14.; Thmrphreys, S. R. ; @.nte1, N. ; Kline, I. ; and Goldin, A. Evaluation of AntileukemicAgents @np1cyingAdvanced Leukemia L1210 in Mice. III. Congeners of Folic Acid. In: Cancer ChemotherapyScreening]@ta. VIII. (J. Leiter, ed.). Cancer Resâ€¢, 20:698-733, 1960.

21. Venditti, J. N. ; Schrecker, A. W.; I'@ad, J. A. R. ; Kline, I. ; and Goldin, A. Influence of the Routeof Administration on the Relative Effectiveness of 3' 5'-Dich.loroamethopterin and Amethopterina@inst Advanced Leukemia (L121O) in Mice. Cancer Res. , 20:145.1-56, 1960.

22. Venditti, J. N. ; Sheldcn, D. R. ; and Gold.in, A. Evaluation of Antileukemic Agents @nploying AdvancedIeuk@nia L1210 in Mice. VII. In: Cancer thenotherapy Screening Data. XXVII. (J. Leiter, ad. ). Cancer Res., 24:145-96,1964.

Acknowledgement

The authorsare gratefulto Dr. Denis D. Tyrer, @.omiT. RitzGibbon, Miriam Gang, and James J. Morsefor their suggestionsand help in the preparation of the manuscript.

It is a pleasure to acknowled.ge the valuable assistance of Mr. E. Waynn Artis and the following inthe execnrtion of these experiments:

Barrington Butts Georgianria ThibodoCarlyle Cochran Wilma ToddLawrence Crawford Ernest TurnerSidney Green Carl VonDerPool

@xmaHarrison Melissa WashingtonRoland Koward Robert WheelerLenwood Keys Lafayette Whittle



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Caneer Chemotherapy Screening DataVENDITTI et al. 835

11

S

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837VEi@mrrriet al. Cancer Chemotherapy Screening Data

a,a,Co

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VENDnâ€•rI et al Cancer Chemotherapy Screening Data 839

10

a,4)

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VENDIrFI et at. Cancer Chemotherapy Screening Data 841

I

I

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A

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VENDITTI et at. Caiwer Chemotherapy Screening Data 843

â€˜0

In

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Vol. 24, July 1964, Part 2844

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VENDIrrI et at. Cancer Chemotherapy Screening Data 845

Hâ€˜.0

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VENDrrrI et at. Cancer Chemotherapy Screening Data 847

Hâ€˜.0

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VENDITTI et at. Cancer Chenwtherapy Screening Data 849

â€˜.0Cu

HCu

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4- CuCuCuHCu4-H

Vol. 24, July 1964, Part 2Cancer Research850

CuC@

HC'@

0Cr

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VENDIrrI et at. Cancer Chenwtherapy Screening Data 851

C 1@@.C'

@)

In10

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Cu _________________â€˜.0 â€˜.0

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VENDrrrI et at. Cancer Chemotherapy Screening Data 853

I

SIII

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VEiwIi'rI et at. C@ncerChemotherapy Screening Data 855

â€˜-0U'

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857VENDrrrI et at. Cancer Chemotherapy Screening Data

H

Cr) v-I v-I Cu

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a'

I

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VENDIrFI et at. Cancer Chemotherapy Screening Data 863

H

H

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VENDITTI et at. Cancer Chemotherapy Screening Data 865

4-4-CV4-â€˜-0CV

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867Cancer Chemotherapy Screening DataVENDIrrI et at.

Cu

Cu

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VENDITTI et at. Carwer ChenwtFwrapy&reening Data 871

H

H

Cu

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ii IH H(v_I

HG)

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â€˜0 Co

873VENDIrrI et at. Canz@erChemotherapy Screening Data

HaDCu

C.Cuâ€˜.0Cu-CCu

4-Cu

CfCu

HCu

0Cu

a-)13 H0

di@10

Co

C.

â€˜.0

It

4-

Cf@

Cu

@ LI

@ H

II@

H

U' U'U'U.' U' U'U'U' U.'U'@â€˜@@g;'Cu'.0@a'@a'4-@a'a'a'

@@@@288oooo28@@@o28@oo288Cf_I

H H 0Cf_I H H 0a' In 4- Co U' Cf_ICf_ICu H(CU

a' In@ Coâ€˜.0Cr)Cu HU'It'

a' Cf_I4- Co U' a' Cr) 4- Co U' Cr)â€˜.0Cr)Cu H Cf_ICuHLLLL@Cfl@Cf)pppppp@;C;P;5dCOCoHCOCOHC;@:lCOHHHtOtOU'

@:Co

2j@j-@0@C)CuII

Cr) H

r-@ r@f4' C)@1 @-â€˜@

@@C)v-S2

C-z. .03-Cr,

(Y)



: @Co@ITH:HH H

(r)H H HHHHH

HH

Cu'0

Cf_IHH

HH In

Cu

HC

In 4- H H In 4- Hv-I

4- Cu C- â€˜.0C- Cr)U.'4- â€˜0â€˜-0

Cf_I H Cu H

C-Cu

HH

U.'U' Cu Cr) U' Cu H (â€˜aCUOJ

H Cr) Co â€˜-0U' H â€˜.0C- â€˜.0â€˜.0â€˜-0

CUH

U'H HLi.'

Cu Cu

4- Co

HH

H C-

C- Co H

Cu;:i

(;1

CoCu

C.Cuâ€˜.0Cu

U'Cu

4-CuCvCu

CuCu

HCu

0Cu

0

@ @:jL-@â€˜@

@ :1

0

Co

C-

â€˜.0

It

4-

Cv

Cu

fl!@@ LI

@:H

8

874 Catwer Research Vol. 24, July 1964, Part 2

Â§q4@iU'

U'U'U'a'

:1@ a' a' a'C- CQ a' a' a' a'C-@@ a' (7'a'a' a' a' a' a'a' a'1 @Â°â€˜a'a'Co1oooo2Sooo-288a'

Cr)4- Co U' Cf_IIn Cu HU'

a' In 4- Co U'â€˜-0Cr)Cu HU'

a' In 4- Co U'â€˜.0Cr)Cu Ha'

Cr)4- Co U' Cr)Cr) Cu HS

II SI

SI SI II

II IS

S II S ISIS

II II

SS II SS

SI II

I IS S IIIS

II II

IS IS IS

SS IS

S SI I SSI00

000; â€¢0H0

0 0I5I

:!@@@ @1:@@

@ â€˜@ C)â€¢

I@0

F.@0

80

00CO

0) â€¢

Fâ€˜@Ii@@ -@0

@8CO

.c;-@0 a,

@i10014

L RU.'p

Lp

Lp

PIH

C)CO

C)Co

Of

H

p4H

04

H

C)Co

C)Co

C)Co

-03-Cr_ICr)



Hv-IHCuHHCuCuCuHHâ€˜.0Cf_I

CoHH 4- 4- Cr)In4-HHHCoH

H 4- â€˜.0CoU'U' a' CoU' 4-CuInHCu Cf_IU' Cr)Cua'

CuU.'e@H C')U' LAC.- 4-U' Coa'H â€˜.0Cr)U'CoIn4-HCuHCuH

VENDITTI et at. Carwer Chenwtherapy Screening Data 875

H

H

Cu

H

H InH H

In In H

H In H

CUH

Cu H

H

H H

It@ U'U' si;. U'U' U' U'

@11@8c2I@@'g;

CV;r@r@dd@@288@c000000.@

dâ€•@

@rnCo

@J1:@

@C)0Jj

@ -03- â€˜:1

@ Cr)

a, 0

@z

c@@

,@ Si.'I@I@â€”C)S

ii@CoCu

V.@ U@ C)

@Z@')

I@ â€˜.0

8r@1i1,?r.@ CoC,@C)V.

@1HS

;@-@b M

A@Cu-@:@1@ .

V.@Z

@H0 a'

@ C)@J..@C)vi@

oC_

@2@z@â€•

â€¢@@LV.1z&

â€˜.@J,@.0In@â€˜

-4'01@â€¢: C')0' In

C-Cu

â€˜.0Cu

U'Cu

4-Cu

InCu

HCu

0

@ H

:1

a'

Co

C-



H 4- In


HH

â€˜.0130

r H CuCu Cu

H

Cu

H

H H

H

Cr) Cu H H Cu In H H

H

4- Cu

C- a' 0 â€˜.0'0 C- C- a' a' C- C- a' Co U' aD

H H H

U' U'

I.43

USSISI

SII

-I-

4-0 Co U.'a' InCo 0 â€˜0In Cu

HH000

.@i-@CO

-I- 00004-8

@g:@g@@jCo U'

C)

UL@1

â€¢@r!Sr@'a,I H

C-

HCf_I

Cr)

rnH

(â€˜aC)

C')rn

H

â€œto(â€˜a

C)

Co

0 C)

z4-

C)

8

10 14. -P.0 13

. 0 01g= g@

@ H -.1H â€¢ 0

43: 0@@@ 4343

C)



CUH

0)0) HCu

InH InH

HHH CUH

4- HO)(â€˜a

H H

HH H4-

H Cu

HH H

CUH H HH

H H

Cr) H

HHHH

HCuHHCu

H Cu HCu

H HH 4- H H

HH H H

H H

In Cu4-InH

CuH Cu

H HH Cu

H H

H CuIn H CuCu4-CUHCu

H

HHH Cu H

Cu Cf_ICu InH

HCuH HCY_ICu

H H InCuHHIn

H-

4- 4-CuH 4- 4- v-I v-fHH

VENDITFI et at. Cancer Chemotherapy Scresning Data 877

UC'

CV@C'

0C'

CU

CoCUC-CUâ€˜.0(Li

U'In H

f-I

Z@H

H

H

HHâ€˜-5

UCU4-CUC'CU

HCU

0CU

â€˜.0H

UH

C'H

:1

Co

C-

CuCuCuHHHHHHInH

f-I

U'U'1â€”i-H

H

-I-U'U' U.'U' U' U'U' U' LI.'U' U' U'U'U' U'U'g1@@g;

In H H 0 0g1@@g:;Cf_IH H 0 0Cf_I H H 0 0Cf_I H H 0 0@. a\ Cr)@ Co0000IIILI

â€˜@

@ U

@:

Of

H

C)

Co

04H

04

H

C)

Co

Al

H

C)

Co

04

H

0

z@@

H

04

H

I a,C.- @dCV_II@

\0-@-

Cr)Cr)

U'0

rnCÂ°

C)

Co

C)Co

.@

IILl



4-U'


U'

H

fi! U;. -I-@1@a@0 @@a'a'a'Co It%a'In-*Co0 â€˜.0Cr)Cu v-f

oc@c@c@Co U' a' Cr14- aD0 â€˜-0 Cf_I (â€ã H

I-0 Co U' a' Cr)

@â€˜0InCu

4- 0000

0 Co U' a' Cf_II@ @\0 (v-_ICu

IF

0

Co

04

H04

H

C)Co

04

HC)CO

C)Co

04

H

HC)

+(â€ã

0

z@@

0)

â€œI-I(â€ã(â€ã

C)

I@-@

(Y_II@

:@-@

â€˜.0

-@

Cr)(v-_I

8

11

8



U':@-1---U'U.'

InHH

H

HCu

n-f

InIn4-H InCuH

In

H HH

H H

CuIn HH

H H

In

4-

H

VENDITTI et at. Cancer Chemotherapy Screening Data 879

U

w

In U' In â€˜0U' 4- In In 4- Cu 4- H

H H In In Cu In In â€˜0In C.-

H

U' 4-

In H

ItCV

CvCv

0Cf

0Cu

CoCu

C.Cuâ€˜.0CuItCu

4-Cu

Cv

@1

@ 4@

@k@ â€˜.0

@03

CrH

:1

0

Co

C-

V.

I

U' U'-I- â€¢ -I-@ @@a'a'a'

0 0 0 0 2-I-Co U' a' In 4- Co

@ â€˜.0In Cu H

04

H

C)Co

0000-I- . . â€¢0 aD U' a' In 4-I@ g â€˜-0 Cf_I C') H

I

C)

Co

C)Co

H In

N- C-

HH :@a'a'@ Co

S I I S II S S I I

I S I S IS S S I I

I I I I IS S I S S

â€¢0 0 0 0H CO

.43.0 g

FF

F@@

+0)0

z@ I@

I.U'U.'U' I@@ Co

S I I I IS I S S I

S I I S II I S S S

S S I I SI S I S I

C)â€¢0 0 : aCo CO

.43.@

I@0@

II: ?@j

i=@i

-@

ij

I a,

Cr) I 14U'

â€˜.0

(v_ICr)



1964;24:827-879. Cancer Res John M. Venditti, Ira Kline and Abraham Goldin Leukemia L1210 in Mice. VIIIEvaluation of Antileukemic Agents Employing Advanced

Updated version

http://cancerres.aacrjournals.org/content/24/6_Part_2/827

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