EVALUATIONOFANTILEUKEMECAGEMPSE@4PLOYINGADVANCED...

EVALUATION OF ANTILEUKEMEC AGEMPS E@4PLOYINGADVANCEDLEUKEMIA L-l2lO IN MECE. V.

Abraham Goldin and John M. Venditti(Laboratory of Chemical Pharmacology, National Cancer Institute,

National Institutes of Health, Bethesda, ?â€˜@ryland.)

Ira Kline(MicrobiologicalAssociates, Inc., Bethesda, @ryland.)2i

INTRODUCTION

This report is our fifth of a series (4-7 ) presenting data obtained employing anassay procedure for the quantitative eva.luation of the relative effectiveness of chemical agents against systemic leukemia L-l2lO in mice. The assay procedure (1, 2 ) permitsthe compounds to be rated with respect to their antileukemic specificity employingAmethopterin as a standard for therapeutic effectiveness.

In the current study, twenty-eight compounds not previously evaluated in thisseries are rated according to their effectiveness in increasing the survival time ofmice with systemic leukemia L@-l2lOon daily subcutaneous treatment. In addition,thirty..four compounds previously reported in this series are re-evaluated in this assaysystem (4-7). The current report also includes data relative to the influence offactors such as the route of drug administration and the schedule of treatment on theeffectivenessof'selected compounds of interest.

MATERIALS AND METHODS

The materials and methods, with certain minor modifications, are essentially thesame as describedin previouspublicationsfran this laboratory (l..9).

The experiments were conducted in 20-30 gm., BDF1, CDBA, or D2BCW mice. Thestrain, sex, and weight range of the mice used in each experiment, are reported in theaccanpanying tables.

Mice were inoculated subcutaneously in the right hind leg with 0.2 ml. of asaline suspension of leukemia (L-l2lO) cells prepared from spleens of DBA/2 or CDRAstock tumor mice. The level of the experimantal leukemic inocu.lum, for each experiment,is reported in the tables. In addition to treated and control mice that received theexperimental inoculum, each experinent included groups of untreated mice that receivedserial dilutions of the experimental inocu.lum.

Treatment was initiated when the local tumor, at the site of inoculation, measured7 to 12 mm. in diameter. In the current group of experiments, this was seven to ninedays following tumor implantation. For the individual experiments, the time of treatment initiation, noted in the tables, ranged from two to four and one half days priorto the median day of death of the untreated controls. In each experiment, on the dayof treatment initiation, five or six mice selected at random from the population thathad received the experimental inoculumn were sacrificed, and. their spleens were implantedsubcutaneously into normal mice of the same strain. The consistent tumor death of therecipients of spleen indicated that the disease was systemic when treatment was started.The median survival tiu@s for the â€œretranspiant recipientsâ€• are measured from the day onwhich they were inoculated.@JThisstudy was supported by Contract No. SA-43-ph-2371 from the Cancer ChemotherapyNational Service Center, National Cancer Institute, National Institutes of Health,Public Health Service, U. S. Department of Health, Education, and Welfare.

.?JBDF1 = (C57 BL/6 x DBA/2)F1CDBA (BALD/c x DBA/2 )F1D2BC = ( ZBC x DBA/2)F1

157

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158 Cancer Research Goldin and Venditti

Treatments were administered in the constant volume of 0.01 mi/gin of bodyweight, and were generally continued, daily until death. In scene experiments, alternative schedules of treatzr@nt were esnployed. Such instances are specifically noted in thetables. Except where the intravenous or oral route is indicated, all drugs were injected subcutaneouslyin the scapulararea. Oral treatmentswere by gavage. The methodemployed for oral drug administration has been described previously in detail (9). Experiments involvingoral treatment includednormal mice which received the vehicle forthe test ccer@ourid by mouth.

Each compound studied, its source, its molecular formula, and the vehicle inwhich it was administered is listed, in the tables.

The vehicle employed 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 solutionF 5 per cent ethyl alcohol in n-salineG phosphate buffer (pH 7.2)

The source of each compound is coded as follows:

1 Chemical-Biological CoordinationCenter

Nationa]. Academy of ScienceNational Research Council210]. Constitution AvenueWashington 25, D. C.

4 Dr. A. H. LandTechnical Information Dept.Merck, Sharp and Dobme Research

LaboratoriesRahway, New Jersey

4P Merck and CompanyContract No. SA-43-ph-1948to Cancer Chemotherapy NationalService Center

5 Dr. John A. CarbonOrganic Research DivisionAbbott LaboratoriesNorth Chicago, Illinois

20 Southern Research InstituteBirmingliern 5, Alabama

21F Dr. Anthony SchreckerNational Cancer InstituteNatlona]. Institutes of HealthBethesda 14, Me.ryland

25 U. S. Army Chemical Warfarelaboratories

Army Chemical Center, Me.ryland

27 Dr. John R. DiceResearch laboratoriesParke, Davis and Company2800 Plymouth RoadAnn Arbor, Michigan

35 Dr. Douglas A. ShepherdHead, Biological Screening OfficesThe Upjohn CompanyKalamazoo, Michigan

37 Burroughs Wellcome and Company1 Scarsdale RoadTuckahoe 7, New York

43 Endocrinolo@r SectionCancer Chemotherapy NationalService CenterNational Institutes of HealthBethesda 14, Me.ryland

49 Distillation Products IndustriesEastman Kodak CompanyRochester, New York

58A Professor Robert C. ElderfieldDepartment of ChemistryUniversity of MichiganAnn Arbor, Michigan

59E Dr. Charles HeidelbergerMcArd.le Memorial laboratoryMedical SchoolUniversity of Wisconsin

@dison 6, Wisconsin



Goldin and Venditti Cancer Chemotherapy Screening Data 159

62A Professor Roland K. RobinsDepartment of ChemistryArizona State UniversityTempe, Arizona

67A The Givaudan CorporationDelawanna, New Jersey

74S Dr. Michael B. ShimkinNational Institutes of HealthBethesda 14, Maryland

99 The Minnesota Mining and Mfg.Company

2301 Hudson RoadSt. Paul 6, Minnesota

l4OF Dr. Jonathan L HartwellCancer Chemotherapy National

Service CenterNational Institutes of HealthBethesda 14, Maryland

201 Professor A. D. WelchYale UniversityNew Haven, Connecticut

210 Dr. BirthAbteilung WME 3Farbenfarbriken Bayer, A. G.Bayer LeverkusenVerkauf Pharm C.Leverkusen, Germany

2l3A Dr. W. C. J. RossChester Beatty Research InstituteThe Royal Cancer HospitalFulham RoadLondon, S. W. 3, England

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

233B Dr. S. S. BarkulisDirector of Microbiolo@r DivisionCiba Pharmaceutical, Inc.Summit, New Jersey

253 Mr. Frederic A. FrenchMt. Zion HospitalSan Francisco 15, California

285A Professor C. T. BabnerDepartment of ChemistryCarson- Newman CollegeJefferson City, Tennessee

365 The Lilly Research LaboratoriesEli Lilly and CompanyIndianapolis 6, Indiana

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

In each experiment, the drugs were administered over a wide range of logarithmical.l,yspaced dosage levels. For an active compound, as the dose level was increased,there was an increase in the survival time of the mice. With further increase indosage, the toxicity of the drug for the host became limiting and this resulted in adiminution of the survival time.

The optimal daily dose for a compound is defined as the dose level providing themaximum median survival time. Where the maximum median survival time was observed atmore than one dose level, selection of the ciptimal dose is based on the entire individual survival time pattern. Instances in which the optimal dose may be outside the rangeemployed are noted in the tables by * or f. Where all dose levels produced toxicity,denoted by *, the optimal dose may be lower than any used. Where no clear toxicityappeared at any dose level employed, denoted by -f@,the optimal level may be higher thanany employed. In some cases, although the maxiimim median survival time occurred at oneof the extreme dose levels tested, the data indicated no advantage in testing at stillmore extreme levels. Such instances are not noted specifica]..ly.

In each experiment, Amethopterin was employed as a standard. The compounds arerated relative to the Amethopterin standard for efficacy in increasing the survival timeof the leukemic mice. The relative efficacy of a compound is computed in per cent as:

Mt Mc

x 100M M

5 c




Where Mt the median survival time at the optimal daily dose of the test compound,

M5 = the median survival time at the optimal daily dose of the Amethopterinstandard,

M the median survival time of untreated controls.

In studies of the influence of the route of drug administration or the scheduleof treatment on antileukemic effectiveness of the test compounds, two ratings are given.In such cases, the compounds are rated (a) with respect to subcutaneous, daily Aznethopterin employed as a standard, and (b ) with respect to the median survival time of theuntreated controls. The latter rating is computed as Mt- M-

Mc

R@ULTS

The results of the current experiments are shown in Tables I through V. Table Alists the compounds tested, the source of each, and the table in which the results appear. Â¶L@bleV presents detailed results of experiments involving the treatment of micewith advanced leukemia. For each experiment, Table V shows the compounds tested, thevehicle for each, and the dose levels employed. The route of drug administration andschedule of treatment employed are also noted. In addition, Thble V shows, for each experimental group, data on median and individual survival times and the number of survivors, if any.

Thble I rates the compounds on daily subcutaneous administration relative to theAmethopterin standard. Table I also presents summary results for each compound, andshows the molecular formula for each, the optimal daily dose level, and the median surviva].time observed at this level. If no dose level employed produced an increase inmedian survival time over that of the controls, no optimal daily dose is indicated inTable I.

Table II summarizes the influence of the schedule of treatment on the antileukemic effectiveness of Nor-nitrogen Mustard, Epoxypropidine, Vincaleukoblastine, and6-Azauracil. Thble III shows the infLuence of the route of administration on the relative antileukeiniceffectivenessof folic acid congeners. Table IV summarizes the influence of the route of administrationon the effectivenessof @b.@stargen,three purmnederivatives,and three glyoxalbisguanylhydrazones.

A. RElATIVE EFFECTIVEN@S OF COMPOUNDSON DAILY SUBCUTANEOUSTREkTMENT

1. Alky].atirig Agents (Thble I Section 1 Th.ble V Experiments DL-l24 l28@135 138 141 144 145 147 149 152 153 157 158 l6l@ and 163):

a . F@thyleneimines

MEPA, OPSPA, Thio-TEPA, TEM, and TEPA exhibited appreciable antileukemicactivity ranging fran 34 to 52 per cent of the Amethopterin effect. These data are inagreement with our previous observation (4) that the effects of the thiophosphoramides(Thio-TEPA; OPSPA) against advanced leukemia L-12l0 are comparable to those of thecorrespondingphosphoramides (TEPA; MEPA).

The observation that cr-Vinyl-l-aziridineethanol(NSC #45726) was active(40-43 per cent of the activity of Amethopterin) against systemic leukemia L-l2lO while@-Vmny1-l-aziridineethanol(NSC#45725) was relativelyinactivehas been previously re

ported by us elsewhere (8). It was suggested (8) that the antileu.kemic activity ofNSC #26806 (Tetramin),which is a mixture of these primary and secondary alcohols, wasdue to the a-Vinyl-l-aziridineethanol (NSC #45726) component. The detailed data of thepreviouslyreportedexperiments(8) are containedin the current report (Table V, Exps.DL-141, 144, and 152).




b. Nitrogen tvtistards

The 6-methyl derivative of Uracil Mustard (DOPAN) exhibited no advantage overUracil Mustard in this assay system ([email protected]).

Comparison of the optimal daily doses for I4istargen (1.80 and 3.00 mg/kg) andNor-nitrogen Mustard (108 mg/kg) indicates that for equal dose Nor-nitrogen Mustard isconsiderably less effective and less toxic than Mastargen. When compared in the sameexperiment, however, nor nitrogen mustard exhibited a slightly greater antileukemiceffectiveness than Mustargen at optimal levels of treatment (Exp. DL-l38).

C. Epoxides and Methanesu.lfonates

Epoxypropidine, as previously reported in this series (6) again produced anantileukemic effect of 19 per cent relative to I@methopterin. The methanesulfonatestested were inactive in the current experiment.

2. Purine Derivatives (Table I Section 2 Table V Experiments DL-lll139 and 151):

6-Mercaptopu.rine was the most active purine studied in these current experiments. As previously described (5,6), 6-tvlPwas more effective and less toxic whendissolved in dilute sodium hydroxide than when suspended in methylceliulose (Exp.DL-l39). Of the other purines tested, 6-Thioguanine showed the greatest activity (39per cent).

3. Pyrimidines (Table I Section 3 @bleV Experiments DL-120 and 122):

Dicb.loro-Daraprimshowed an effectiveness of 19 per cent relative to Arnethopterin. The data indicate, however, that drug toxicity was occasioned over the entiredose range employed (Exp. DL-l20). It is possible that Dichioro-Daraprim might havebeen more effective at lower daily dosage levels. 6-Azauracil was inactive (Exp.DL-l22). Mice receiving up to 1667 mg/kg/day of 6-Azauracil exhibited no evidence ofdrug toxicity or local tumor inhibition.

4. Steroids and Dietbylstilbestrol (Table I Section 4 Table V Experiments DL-145 150 151 and 154):

Prednisone was 16 per cent as effective as Ainethopterin. The other steroidswere relatively inactive. None of the steroids tested or Diethylstilbestrol elicitedbody weight loss over the dose range employed.

5. Glyoxalbisguanylhyd.razones (Table I Section 5 Table V ExperimentsDL-l20 133 and 160):

The high degree of antileukemic activity of the methyl derivatives of Glyoxalbisguanylhydrazone and the inactivity of Glyoxalbisguanylhydrazone itself, previously reported in this series (5, 6) were confirmed in the current experiments.

6. Colchicine Derivatives (Table I Section 6 Table V Experiment DL-l5l):

Colchinol and N-Acetyl colchinol were inactive at the doses employed in thisexperiment(Exp.DL-151).

7. Qp.inolineDerivatives(TableI Section 7 Table V Experiment DL-149):

None of the quinolinederivativestested demonstratedappreciable activity.




8. Podophyflotoxin Derivatives (Table I Section 8 Table V ExperimentDL-142):

The isopropylamine salt of Podophyllotoxin, Hydrogen glutarate, was IIper cent as active as Arnethopterin. Podophyllotoxin chloroacetate-a>.pyridinium chlorideand Podophyllotoxin itself showed little or no activity.

9. Folic acid Derivatives(TableI Section 9 Table V Experiments DL-l24and 125):

The current report shows the detailed data of previously published observations that brcanination or chlorination in the benzene ring of Ainethopterin results incompounds with greatly enhanced antileukemic activity on subcutaneous administration(7,9).

10. Other Cc*npounds (Table I Section 10 Table V Experiments DL-125 129135 144 145 146 160 and 163):

2-F@thylamino-1,3,4-thiadiazole was 50 per cent as effective as Ainethopterin(i@cp. DL-l44). In two experiments (DL-l63, 135), l-Methyl-l-nitroso urea was 37 and 16per cent as effective as Amethopterin. None of the remaining compounds elicited a relative effectiveness of more than 20 per cent.

B. INFUJ@CE OF THE SCHEDULEOF ThEATM@TONAMTILEUKFMLCEFFECTIVENESS(Table II and Table V Experiments DL-l22 129 135 and 144)

Table II summarizes the influence of treatment schedule on antileukemic activityof Nor-nitrogen Mustard, E@poxypropidine, Vincaleukoblastine, and 6-Azauracil. The detailed data of the experiments is shown in Table V. In Table II, the compounds arerated relative to Amethopterin given daily.

The antileukemic effectiveness of Nor-nitrogen Mustard, Epoxypropidine, or Vincaleukoblastine was not markedly increased by increasing the interval between treatments.6-Azauracil, which was inactive and nontoxic on daily administration, produced only aone clay increase in median survival time when given four times per day at a dose of 216mg/kg. On this schedule, however, weight loss was observed at a dose of 1000 mg/kg(total dose, 4000 mg/kg/day).

C. INFLUENCEOF THE ROUTEOF ADMENISTRATIONON THE ANTILEUKEMECEF@CTIVEN@ZSOF FOLIC ACID CONGENERS

(Table III and Thble V Experiments DL-124 and DL-125)

The diminution in the effectiveness of both 3',5'-Dichioroamethopterin andAinethopterin on oral administration has been previously reported from this laboratory(9). The current data confirms this observation, and in addition shows that 3'-Bromo5'-chloroaznethopterin and 3'-Bromoaznethopterin similarly exhibit decreased activitiesvia the oral route.

D. INFLUENCEOF THE ROUFEOF ADMENISTRATIONON THE ANTILEUKEMICEECTIVENEES OF OTHERCOMPOUNDS

(Table IV and Table V Experiments DL-111 120 128 and 133)

Table IV summarizes data comparing the activities of seven compounds employingvarious routes of administration. The detailed data are shown in Table V.

Z4istargenwas no more effectivewhen given intravenouslythan when given subcutaneously (Exp. DL-128).

The activities of 6-Mercaptopurine, 6-Thioguanine,and 2-Aznino-6-(l-methyl-4-nitro-5-imidazo].ylthio)-purmnewere compared on oral and subcutaneous administration




(&p. DL-lll). All three displayed similar activities via either route of administration although in each case more drug was required orally to give an effect comparableto that observed on subcutaneous injection.

Both of the methyl derivatives of Glyoxalbisguanyihydrazone were slightly moreactive subcutaneously than orally. Of interest is the observation that Glyoxalbisguanyihydrazone, inactive when given subcutaneously, displayed some activity when givenorally (Exps. DL-l20 and 133).

REFERENCES

1. Goldin, A., Venditti, J. M., Humphreys, S. B., and Mantel, N. ?vbdification ofTreatment Schedules in the Management of Advanced Muse Leukemia with Amethopterin.J. Nat. Cancer Inst. @7:2O3-2l2, 1956.

2. _______________________________. Quantitative Evaluation of ChemotherapeuticAgents Against Advanced Leukemia in Mice. J. Nat. Cancer Inst. @j:495-5ll, 1958.

3. Goldin, A. , Venditti, J. M. , Humphreys , S. R. , Shuster, L., Darrow, R. A. , andMantel, N. Advanced Leukemia as a Tool for Chemotherapeutic Studies. Acta UnioInternat. Contra Cancrum @:642-65O, 1960.

4. 001dm, A. , Venditti, J. M. , Kline, I. , and Mantel, N. Evaluation of AntileukemicAgents E@rrploying Advanced Leukemia L-l2lO in Mice. In â€œCancer Chemotherapy Screening Data IVâ€•(J. Leiter, ed. ) Cancer Research @:429-466,1959.

5. _______________________________. Evaluation of Antileukemic Agents BaployingAdvanced Leukemia L-l2lO in Mice II. In â€œCancerChemotherapy Screening Data VIâ€•(J. Leiter, ed.) Cancer Research @Q:382-448,1960.

6. ________________________________. Evaluation of Antileukemic Agents @nployingAdvanced Leukemia L-l2lO in Mice IV. In â€œCancerChemotherapy Screening Data IXâ€•(J. Leiter, ed. ) Cancer Research @:27-92,1961.

7. Venditti, J. M., Humphreys, S. R., Mantel, N., Kline, I., and Goldin, A. Evaluation of Antileukemic Agents Fknploying Advanced Leukemia L-l2lO in Mice III. Congeners of Folic Acid. In â€œCancerChemotherapyScreeningData VIIIâ€•(J. Leiter, ed.)Cancer Research @Q:698-733, 1960.

8. Venditti, 3. M., Goldin, A., and Kline, I. Comparison of the Effectiveness ofTetramin and Its Components Against Advanced Leukemia L-l2lO in Mice. In CancerChemotherapy Reports No. @j:73-76, 1961.

9. Venditti, J. M., Schrecker, A. W., Mead, J. A. R., Kline, I., and Goldin, A. Influence of the Route of Administration on the Relative Effectiveness of 3,, 5' -Dichloroamethopterin and Amethopterin Against Advanced Leukemia (L-l2lO) in Mice.Cancer Research @Q:l45l-1456, 1960.

ACKNOWLEDGEMENTS

The authors wish to thank Dr. Charles G. Zubrod, Dr. G. Burroughs Mider, Dr. CarlG. Baker, Dr. Kenneth M. Endicott, Dr. l4irray J. Shear, Professor E. K. Marshall, Jr.,Dr. Stuart M. Sessans, Dr. Joseph Leiter, Dr. Robert D. Coghill, Mr. George A. Brandner,Dr. I@ward Bond, Dr. Ronald B. Ross, Dr. Erwin P. Voilmer, and Dr. Saul Schepartz fortheir interest in this program.

We are grateful to Dr. Anthony W. Scbrecker, Dr. J. A. R. Mead, Dr. Michael A.Chirigos, Mr. Stewart R. Hunxphreys, Dr. John P. Glynn, and Mr. Leonard D. Mitchell fortheir helpful suggestions, and to Naomi T. FitzGibbon, Dorothy A. Osborne, Sam C.Mangano, James J. Mrse, and Miriam Gang for their help in the preparation of the manuscript and tables.



CancerResearch Goldin and Venditti164

It is a pleasure to acknowledge the valuable assistance of E. Waynn Artis and thefollowing in the execution of these experiments:

Haywood WatersDunlap Scott, Jr.Carroll L. JackrnonLenwood KeysGeorgiana SandersDavid Gordonlymond WilliamsflnmaMcCullough

Melissa WashingtonWilma ToddDacota JordanJames KeysJohn DavisRobert WheelerJames McllwainEdward Stephens

Philip Freedenberg



ENTRYNSC No.COMPOUND NAIâ‚¬TABLENU@3OURCIâ€”â€”â€”â€”â€”No.IIIIIIIVV


TABLEA

LIST OF CO@OUNDS

27558 74&:/ Amethopterin 229A x x x x x

27559 745 Bis(1-aziridinyl )morpholino-phosphine oxide(MEEA) 229A x x

27560 750 Methanesulfonic acid, tetramethylene ester(?,@rleran) 37 x x

27561 752 6-Purinethio]., 2-amino- (6-Thioguanine) 37 x x x

27562 755 6-Purinethiol,hydrate (6-Mercaptopurinehydrate) 37 x x x

27563 762 Diethy].amine, 2, 2'-dich].oro-N-metby].(wistargen) 4 x x x

27564 305]. N-Metby].formamide 49 x x

27565 3052 Methanesulfonic acid, nonamethylene ester(Nonane) 49 x x

27566 3062 Pyrimidine,2,4-diaznino-5-(3',4'-dicklorophenyl)-6-ethyl- (DichJ.oro-Daraprlm) 37 x x

27567 3070 4,4'-Stilbenediol,a,a'-dietbyl(Dietbyistilbestrol) 43 x x

27568 3425 as-Triazine-3,5(2E,4E)-dlone (6-Azauracil) 201 x x x

27569 4238 2- (@-Dimethy1aminostyry1)-].-methy1quino1iniumiodide 285& x x

27570 4239 4- (@-Dimethy].aminostyry].)-1-methy1quino1iniumiodide 285A x x

27571 4730 ].,3,4-Thiadiazo].e,2-etby].amino- 229A x x

27572 6396 Trls(].-aziridinyl)phosphine sulfide(Thio-T@A) 229A x x

27573 9703 17, 21-Dihyd.roxy-pregn-4-ene-3,].]., 20-trione(Cortisone) 43 x x

27574 9705 U@, 21-Dihydroxypregn-4-ene-3, 20-dione(Corticosterone) 43 x x

27575 9706 2,4,6-Tris(1-azfridixyl)-s-triazine (TEM) 229A x x

27576 9717 Tris(l-aziridiny].)-phoaphine oxide (TEPA) 1 x x

27577 9894 4,4'- (1, 2-Diethyletbylene)-diphenyl(Rexestrol) 43 x x

27578 10023 Pregna-1, 4-diene-3,11,20-trione,17, 2].-dibydroxy- (Prednisone) 43 x x

@:/NSCNo.740In Tables I-IV.

Is used as a standard. The test compounds are rated relative to NSC No. 740



@2RYNo.NSC

No.C@OTR1D NAI.@TABLE

NU@ERâ€”

Iâ€” IIIIIâ€” IVâ€” V

166 Cancer Research Goldin and Vendirxi

TABlE A - (Continued)

LIST OF COMPOUNDS

27579 10429 Bis(l-aziridiny].)ixrpholino-pbosphine sulfide(oPsPA) 59E x x

27580 10482 @.dnoline,4-(p@-dimetbyl)-aminoatyryl-,dihydrochioride 285A x x

27581 10483 ].l@,].7,2].-Prihydroxy-pregn-4-ene-3, 20 dione(Cortisol) 43 x x

27582 10873 Diethy].amine,2, 2'-dichloro-, hydrochlorIde(Nor-Nitrogen titistard) 27 x x x

27583 11318 @x-fluorocortIsol 43 x x

27584 3.2198 Testosterone, 4, 5cx-dlhydro-Scz-metby].-,propionate 43 x x

27585 14575 9H-Purlne-6-thiol,9-etby]. 20 x x

27586 15186 @z-fluorocortisol,2l-acetate 4 x x

27587 17261 2, 5.-Bis(l-azIrldinyl)-3, 6-diprcpoxy-@-benzoquinone (E-39) 210 x x

27588 18016 Metbanesu.1.fonic acid, 2-chloroetbyl ester 213A x x

27569 18271 Propionamide,N,N'-/@, 6-bia(l-aziridix@].-p-benzoquinon-2,5-ylene@7bIs- 233B x x

27590 18439 Anhline,N,N-bia(2-chloroetbyl)-2,3-din@thoxy- 5 x x

27591 19487 9li-Purine-6-thiol,9-cyc].c@entyl- 20 x x

27592 19488 9E-Purine-.6-thiol,9-butyl- 20 x x

27593 22183 G].yoxa].bisguanylbydrazone n@noau].f@tepentahydrate 253 x x x

27594 22185 Methylg]yoxalbisguat@r].bydrazone [email protected]@nohydrate 253 x x x

27595 23436 2,4-Bis(l-aziridinyl)-6-methyl-5-nitropyrimidine 58A x x

27596 23891 2-@is(2-cb].oroethyl)amincmethylJbenzimidazo].e,hydrochloride 67A x x

27597 23909 Urea,l-methyl-l-nitroso- 20 x x

27598 24818 POdOphy].lOtOXin 217 x x

27599 26805 Methanesu].fonic acid, ethyl ester 42 x x

27600 26806 l-Aziridineetbanol,cz-vinyl-nhixture with@-vinyl-l-aziridineetbanol (Tetra@in

mixed isomers) 4P x x



No.NSCNo.COMPOUND NAIâ‚¬TABLE

NU@ER3OURCEâ€”â€”â€”â€”â€”IIIIIIIVV

Goldin and Venditti Cancer ChemotherapyScreening Data 167

TABLE A - (Concluded)

LIST OF COMPOUNDS

27601 29630 Glutaznic acld,N-(3,5-dicbloro-4-(((2,4-diamino-6-pteridyl)-methylJznethylaniino)-benzoyl)- (3',5'-Dichloroainethopterin) 229A x x x

27602 32946 Metbylglyoxalbisguanylhydrazone dihydrochloride monobydrate 253 x x x

27603 32970 Colchino]. 140F x x

27604 34462 Uracil,5-@is(2-chloroethyl)amInoJ(Uracilmustard) 35 x x

27605 36570 Pod.ophyllotoxin, hydrogen glutarate, isoproW].aminesalt 2].? x x

27606 38887 Purine,2-amono-6-(1-metbyl-4@-nitro-5-iznidazo].ylthio)- 37 x x x

27607 43146 3-Pyridinol,5-@is(2-chloroetbyl)aminometby].J-4- (methoxymetbyl)-2-methyl-,dibydrocb].oride, dihydrate 4 x x

27608 44629 Uracil,5-/bis(2-chloroethyl)aminoJ-6-methyl- (DOPAN) 748 x x

27609 45725 l-Aziridineethanol, n-vinyl- (Tetraininisomer primary) 4P x x

27610 45726 l-Aziridineethanol,a-vinyl- (Tetraminisomer secondary) 4P x x

27611 46380 Uric acid, 6-thio- 62A x x

27612 49842 Vincaleukoblastine, sulfate, hydrate 365A x x x

27613 51045 Colchinol,n-acetyl 140F x x

27614 3'-Bromoamethqpterin (?@bnobromoamethopterin) 229k x x x

27615 3'-Bron@-5'-chloroamethopterin 229A x x x

27616 Para-amino-benzoy].g].utamic acid 229A x x

27617 2, 2'-Dichloro-N-isopropy]. diethy].amine,hydrochloride (SK-l03) 25 x x

27618 l,].'-Bis(2,3-epoxypropyl)-4,4'-dipiperidy].(Epoxyprcpidine) 365 x x x

27619 Leurosine 365 x x

27620 Podophy].lotoxin ch.loroacetate-w-pyridiniumchloride 21F x x



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1962;22:157-220. Cancer Res Abraham Goldin, John M. Venditti and Ira Kline Leukemia L-1210 in Mice. V.Evaluation of Antileukemic Agents Employing Advanced

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