evaluationofchemotherapeuticagentsagainstavarietyofcancerres.aacrjournals.org/content/22/7_part_2/559.full.pdf560...

EVALUATIONOF CHEMOTHERAPEUTICAGENTSAGAINST A VARIETY OFMOUSEASCITES TUMORS. III.*

R. J. Rutman, F. S. Lewis, S. Buckner, C. C. Price,F. Llevellyn+ and E. Owen"*"

(University of Pennsylvania, College of Chemistry, Philadelphia, Pa.)

The selection of a procedure for the evaluation of potential anticancer drugsnecessarily represents compromises between a variety of theoretical and practical considerations. Procedures can be chosen which are based on the precise quantitative comparison of related drugs (1,2); in contrast, emphasis may be placed on the scope of theantitumor action in a wide variety of tumors (3). In either case, practical implementation often reflects limitations imposed by space and resource considerations.

In an effort to compromise among several of these considerations, we have adopteda procedure based on the use of a wide spectrum of ascites tumors which can be maintained as frozen stock and which require only a single murine host.

By selection of the C3HxDBA/2 hybrid mouse (or the reciprocal cross )â€¢*â€¢*/it is

possible to attain stable and reproducible performance with a majority of the twentyascites tumors tested. Presented in this paper are results from sixteen of the tumorstested. The use of a single host and a frozen tumor bank obviates the need for severalinbred strains of mice and for continuous in vivo maintenance of tumor stocks, reducingspace requirements accordingly.^/

It is our purpose to report the results obtained in the standardization of thisprocedure, as well as the routine screening data obtained on the compounds listed inTable A. Table A lists the entry number, the University of Pennsylvania number and thetables in which the results appear.

MATERIALSAND METHODS

Animal Hosts: Male or female,^/ C3HxDBA/2 or DBA/2xC3H hosts, have been usedinterchangeably in the routine screening. Animals weighing 18 to 22 gr. are used, thevariation in weight in any given experimental or control group being confined to 2-3gr. The animals are housed in metal-topped plastic cages, given water and foodÂ§/ ad liband bedded on white pine shavings containing a small amount of an adsorbente/. Incominganimals are segregated for one week prior to use.

Frozen Tumor Bank: Following the design of Hauschka, et al. (4), the tumorslisted in Table B are maintained in a dry ice-alcohol bath at -75Â° to -78Â°C. Theprocedure for establishing the bank of frozen tumors is as follows: upon receipt of

* This work was supported by research grant CY-2189 from the National Cancer Institute,National Institutes of Health.

t Technicalassistants.\J Our appreciationis expressedto Dr. T. Hauschka,who recommendedthis host as

capableof supportinga very wide selectionof murineneoplasms.2J Animalshavebeen obtainedfromthe JacksonMemorialLaboratory,whoseassistance

is gratefullyacknowledged._3/ Usingthisprocedureit hasbeenpossibleto screenat the rateof 150 experimental

groupsper month (10mice/group)in a total facilitycomprising350 ft.2of floorspace. (Despitethe unavoidablecrowding,no epidemicshave been experienced.)

4/ In moreprecisestudiesof thealkylatingagents,to be reportedseparately,certainmale-femaledifferenceshavebeenobserved.

5/ Mousebreederchow,PurinaMillsor Purinacheckers.&/ Sterolite,Mineraland ChemicalCorporation,when used. (Thiswas laterdiscon

tinuedin favorof air purificationsystems.)

559

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560 CancerResearch Rutman etal.

tumorbearingmicethe ascitestumorsare removed,pooledand transferredto the hybridhost. A secondtransferis then made to note the growth characteristicsin the newhost and to secure specimensfor storageand for establishingthe relationbetweeninoculumsize and mean survivaltime (MST). One to 1-1/2 ml. of undilutedascitesfluidis transferredto Wheatonvialscontaining0.1 ml. glycerol(reagentgrade)andsealedwith cautionas to overheating.The sealedvials are quicklyfrozenin a dryice-alcoholbath, placedin identifiedspringclipson a speciallydesignedaluminumrack (Fig.l) and insertedintoa custombuilt stainlesssteel-compartmenteddry icechest (Fig.2). The chestshownin the photographaccomodatesfive racks, each oneof which can hold 98 vials. Irrespectiveof the extentof the use of a giventumor,transfersto stock mice are made at approximatelysix month intervalsto checkthestabilityof the frozentumorsand to restockthe bank.

TestProcedure:To preparefor screeningwitha giventumor,the frozensampleis rapidlythawedina 37Â°waterbath,dilutedsuitablywith0.15MNaCl, and transferredto two to four host animals. The ascites fluid is harvestedand transferredto asufficientnumberof secondpassageanimalsto securethe amountof tumorneededforthe experiment. It has been our experiencethat a moderateamountof variabilityincontrolMST valuesis observedfollowingthe firstpassagefromthe frozenstate,butthis is eliminatedfollowinga secondtransfer. In each test,ten to twentyanimalsare includedas controls,each experimentalgroup (i.e.,givendrug at givendosage)comprisingten animals. Animalsare givena standardinoculumof 10? ascitescellsina volumeof 0.2-0.5ml. of dilutedascitesfluid,drugadministrationis begun 24 hourslaterand is continuedfor five days. The animalsare kept under observationfor 90days,which is, for allbut threeof the tumors,7x or >7x the controlsurvivaltime.

DrugAdministration:All agentsare administeredafter solutionor suspension(andneutralization,if necessary)in 0.5ml. of 0.9percentNaCl. (Routineincorporation of antibioticswas testedand foundto be unnecessary.)

The preparationof uniformsuspensionsof insolubledrugshas provena difficultproblem. In our experience,vehiclessuchas glycerol,gums,and cellosolves,have allproducedvariablebut significantchangesin controlMST values. Therefore,preparationof insolublecompoundshasbeen confinedto vigorousmechanicalhomogenizing(tefloninglass)in isotonicsaline. With the exceptionof waxymaterials(e.g.,compounds450and 451 whichare sterolderivatives)thisprocedurehas provensatisfactory.

RESULTS

The first point of concern in the development of the test procedure was thestability of the various tumors after transfer through the hybrid host and aftervariable periods of storage at -75Â° to -78Â°C. Table C summarizes our experience overthe past four years (1957-61) in this connection and shows that thirteen of the sixteentumors in use yield reproducible MST values following periods of up to 18 months storagein the frozen state. Three of the tumors (the Ehrlich, P388 and 70429) appear to showchanges in virulence. In the case of the Ehrlich this change, which has occurredrepeatedly, results in conversion to a highly hemorrhagic ascites, from which we areunable to recover a stable non-hemorrhagic line. In such cases, a fresh specimen ofthe tumor has been substituted for old stock.

Tables 1 .through 16 present the raw data obtained with the various test andstandard compounds which have been screened through one or more of the ascites tumors.The results are classified by tumor. In the case of the Gardner lymphosarcoma, A#2Ljymphoma, the CM1Madenocarcinoma and the Ehrlich carcinoma (Tables 1,12,13,14 respectively), the tables are divided into sections, the A section covering alkylating agentsand using a "multiple of control survival" scale for the expression of cumulativeresults are expressed on a "cumulative mortality scale", as is also the case for alldata in Tables 2-11, 15 and 16. The separation into A and B sections was adopted forthe four alkylating-agent sensitive tumors (Tables 1,12,13,14) because data on longsurvivors is of particular importance in evaluating the relative performance of newalkylating agents.



Vol. 22, No. 7, Part 2 CancerChemotherapyScreening Data 561

For all compoundsreportedin Tables1-16, inclusive,the standardregimenoffivedaysof intraperitonealtreatmentcommencingon the firstday aftertumor inoculation has been employed. Similarly,a uniform intraperitonealinoculumof 10? tumorcellshas been used in each test. The tabulateddata show the mean survivaltimes(MET)for the experimentaland controlanimalsfor each individualexperimentwhichare the basis for calculationof the percentExtensionof the MST. In addition,dataon cumulativemortalityor survivalare given for each test.

.Eachof the tumorsused has also been testedagainstnine establishedchemo-therapeuticagents (3) shown in Table D, which were selectedto covera rangeofalkylatingagentsand antimetabolitesof interestto the investigators.These resultsare also includedin Tables 1-16, but since they are intendedto providestandardswith whichnew agentsmightbe compared,they havebeen subjectedto furtheranalysisin TablesE to G. This analysisis based on two measuresof effectiveness,namely,the RankIndex(R.I.)and the PerformanceIndex(P.I.). The firstis simplythe numericalorderof effectivenessof the agenton a giventumor;the secondis the relativeeffectivenessof the agentas comparedto the most effectiveagenton the particulartumor,and is calculatedby the relation.

p ... MaximumPercentExtensionMST (TestCompound)MaximumPercentExtensionMST (StandardCompound)

If a test compoundresultsin no significantincreasein the MST, i.e.,the MST-MSTControlx 100/MSTControl= <25%, then the P.I. is recordedas "0".

TableE summarizesour standardizationresultsfor severalmurinelymphocyticleukemias. It can be seenthat althoughamethopterinis the most effectiveagentonL-1210andP288,it isnot as effectiveon P388,a tetraploidline. Strikingcollateralincreasesin sensitivitytowards alkylating agents are noted in the L-1210anti-metaboliteresistantlines(L-ISIO^/R,L-1210TG/R),the sameresultbeingpresentbutlesspronouncedwith P288 R/2 (Amethopterinresistant).

The tumorscoveredin TableF are not onlyresistantto alkylatingagents,but,with the exceptionof 70429azaserineresistant(AZ/R),are refractoryto almostallof the agents. In particular,Hep 134 is not affectedby any standardagentexceptHN2 and this resultis only obtainedwith a considerabledegreeof variability. Inthe caseof 70429thedevelopmentof azaserineresistanceis accompaniedby a collateralchangein sensitivityto amethopterinand L-phenylalaninemustard.

The comparativeresponsesof sixtumorswhichare sensitiveto alkylatingagentsare shownin TableG. Of particularinterestin theseresultsis the markedsensitivityof lymphomaA#2 to six out of nine of the agents, in contrastto its resistancetocytoxan.Forthealkylatingagentsensitivetumorsas a group,sensitivityto HN2 seemsto be accompaniedby sensitivityto L-PAMand to BayerA-139,but not necessarilytoS-TEPAor cytoxan.Althoughsignificanteffectsare seenwith certainantimetabolites(5-FU,AzS on A#2, TG on MC1M and 815E176),the effectivenessis inferiorto that ofthe alkylatingagents. P815E176,selectedfor resistanceto 5-FU,showsa strikingincreasein sensitivityto A-139.

DISCUSSION

In this report,we have describedthe standardizationof a routinescreeningprocedurebasedon a largevarietyof ascitestumors,yet compatiblewith sharplimitationson the spaceand the resourcesavailablefor screening. The problemhas beenresolvedby usinga singlehostcompatiblewithall of the tumors,and by satisfactorilyestablishingthe reliabilityand reproducibilityof the procedurefor freezingandmaintainingtumors at -75 to -78Â°C(4).

Nine standardchemotherapeuticagentshavebeenarbitrarilyselectedas a basisfor the comparativeevaluationof new agents. Each tumor has been ratedas to its



562 CancerResearch Rutman rÃa/.

response to each one of the agents. Thus, the performance of a new agent can becompared with an overall profile of standard performance for a given tumor in order toassess its relative merit. With the development of the tumor bank, a routine procedureof screening new compounds against the Gardner or the A#2 (representing alkylating agentsensitive tumors), against Leukemia L-1210 and against Hep 134 or DBA/2 (representingthe highly refractory tumors of Table F) has gradually been adopted. In the case ofalkylating agents, a positive result is recorded if the resistant screens show asignificant effect (i.e. >25 percent increase over control M3T) or the sensitive screenshows a 100 percent increase over control survival. In the case of all other types ofagents, a significant result in any one of the three screens is considered a positiveresult. In general, a positive result is the basis for further screening and thisusually involves testing against the remaining tumors in each of the three groups.However, in the case of alkylating agents, a 100 percent increase in MST for A#2 orGardner is not an unusual result, so that for this group of agents, further testingis confined to the alkylating agent sensitive group unless unusual activity or chemo-therapeutic index is observed. In this connection, our accumulated data suggest thatthe A#2 lymphoma would be quite suitable for the quantitative determination of chemo-therapeutic indices.

Although the standardization program is empirical in nature, and not primarilyaimed at a systematic study of the tumors or agents, certain observations in thisdirection may be of significance. Referring to the data on the leukemias, Table E,it is noteworthy that amethopterin, while preserving its leading role against theoriginal lines of lymphocytic leukemias (L-1210 and P288), does not emerge as the mosteffective against leukemias as a class. Instead, cytoxan and L-phenylalanine mustard,by virtue of their effectiveness against the collateral sensitivity of the anti-metabolite resistant tumor lines, become the two most effective agents. An attempthas been made to exploit this collateral sensitivity to alkylating agents by followinga standard course of amethopterin treatment of L-1210 with single or multiple doses ofL-phenylalanine mustard. The combined therapy failed to show any advantage. This mayrelate to the recent report of Skipper, et al. (S) that the spread of ascites formleukemic cells to the cranial region has rendered the tumor refractory to furthertreatment. Again, in keeping with this same report (5), we have noted the loss ofeffectiveness against L-1210 if treatment with amethopterin or cytoxan is delayed tothe 5th day after inoculation of the tumor.

Of further interest is the pattern of results obtained with the alkylating agentson the L-1210 or P288 antimetabolite resistant lines. In the case of all three of thetumors employed, acquisition of sensitivity to one of the alkylating agents seems to beaccompanied by increased sensitivity to the rest of the agents; to be precise, four outof five of the agents are effective against each of the antimetabolite resistant tumors.We have shown separately that L-1210 TG/R cells are ten to fifty times more sensitiveto in vitro exposure to HN2 than are L-1210 cells. Taken in conjunction with thein vivo data, these results tend to support Schmidt's contention (6) that all alkylating

agents act by a common mechanism. It is not clear, however, whether the precisepatterns of collateral sensitivity for each of the tumors reflect the complexities ofthe host-tumor relation, variations in the uptake of specific agents by the cells ordifferences in the chemical details of alkylation (7,8,9).

Considering the screening procedure as a whole, it is clear that the choice ofthe ascites tumor form has biased the screen in favor of the alkylating agents. Thesummary results (Tables E,F,G) show that only amethopterin has effectiveness comparableto any of the alkylating agents, being approximately as effective as A-139 and much moreeffective than S-TEPA. It is likely that if a duplicate screen had been performed usingsolid versions of the same tumors, the bias towards alkylating agents would have beenreduced. Since, however, our major interest has been in the development of improvedalkylating agents, this has not appeared as a disadvantage. Furthermore, inclusion oftumors which are highly refractory to alkylating agents reduces the weight given toeffectiveness on sensitive tumors, if not accompanied by significant effects on theresistant ones.



Vol. 22, No. 7, Part 2 CancerChemotherapyScreeningData 563

The use of this procedure in evaluation of new agents is illustrated by thesummary data of Table H. Two alkylating agents (UP#385-hypoxanthine mustard andUP#475 - an aminoalkyl nitrogen mustard) appeared quite active and were therefore carefully screened through all sixteen tumors. Prom this screening it became obvious thatUP#385 maintained its high effectiveness only for the alkylating agent sensitive tumors.On the other hand, UP#475, which had previously been prepared by Creech (l), and wasindependently synthesized by us as part of a study of amino alkyl substitution,/ provedto be a highly active compound, more effective in some cases than the reference compounds. On the basis of the overall performance of UP#475, it would be rated to be asactive as any one of the reference compounds.

REFERENCES

1. Creech, H. J.; Brenninger, E.; Hankwitz, R. E., Jr.; Polsky, G. and Wilson, M. L.Quantitative Studies of the Effect of Nitrogen Mustard Analogs and Other AlkylatingAgents on Ascites Tumors in Mice. Can. Res., 20, Pt 2, 471, 1960.

2. Schmidt, L. H. Personal communication.

3. Gellhorn, A. and Hirschberg, E. Investigation of Diverse Systems for Cancer Chemotherapy Screening. Can. Res., Suppl. 3, 1, 1955.

4. Hauschka, S. ; Mitchell, J. T. and Wiederpruem, R. J. A Reliable Frozen Tissue Bank:Viability and Stability of 82 Neoplastia and Normal Cell Types after ProlongedStorage at -78OC. Can. Res., 19, 643, 1959.

5. Skipper, H. E. ; Schabel, F. M., Jr. ; Trader, M. W. and Thomson, J. R. ExperimentalEvaluation of Potential Anticancer Agents. VI. Anatomical Distribution of LeukemicCells and Failure of Chemotherapy. Can. Res., 21, 1154, 1961.

6. Schmidt, L. H. In Press, Cancer Chemotherapy Reports.

7. Strauss, B. S. Specificity of Mutagenic Effects of Alkylating Agents, Nature 191,730, 1961.

8. Fahmy, 0. G. and Fahmy, M. J. Cytogenetic Analysis of Carcinogens and Tumor Inhibitors in D. melanogoster XI. Gen., 46, 1111, 1961.

9. Alexander, P. and Mikulski, B. Effects of Radiomimetic Alkylating Agents onLjrmphoma Cells In Tissue Culture. Biochem. Pharmacol. 8, 51, 1961.

2/ Unpublished results - Rutman, R. J.; Lewis, F. S. ; Price, C. C.



564 CancerResearch Rutmanrta/.

FIGURE1

Aluminum rack with spring clamps to accommodate 98vials of frozen tumor (front and rear) in -75Â°to

-78Â°tumor bank.

FIGURE 2

Specially designed, custom built, two compartment dry ice-alcohol chest; center compartmentcontains insert for tumor storage racks; end compartment contains dry ice charge; circulation isvia holes in the stainless steel separator betweencenter and end compartment. Outside dimensions -36"x22"x36 3/4", compartment - 24"xl2"x24".



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TABLE B

ASCITES TUMORS USED IN SCREENING PROGRAM

TUMOR TYPE SOURCE

A#2DBA/2Ehrlich

Gardner(6C3HED)Hep 134L-1210L-1210-AM/RL-1210-TG/R

MC1MP288P288-R/2

P388P815P815E1767042970429 AzR-1

LymphomaThymomaCarcinoma

LymphosarcomaParenchyma!CellLymphocyticLeukemia-diploidLymphocyticLeukemia-amethopterinresistantLymphocyticLeukemia-thioguanineresistantMammaryadenocarcinomaLymphocyticLeukemia-diploldLymphocyticLeukemia-amethopterinresistantLymphocyticLeukemia-tetraploidMast CellMast Cell-fluorouracilresistantPlasma CellPlasmaCell-azaserineresistant

RoswellParkRoswellParkInstitutefor CancerResearch,Fox Chase

Universityof PennsylvaniaNationalInstitutesof HealthNationalInstitutesof HealthNationalInstitutesof HealthNationalInstitutesof HealthRoswellParkNationalInstitutesof HealthNationalInstitutesof HealthNationalInstitutesof HealthNationalInstitutesof HealthNationalInstitutesof HealthNationalInstitutesof HealthNationalInstitutesof Health

TABLE C

THE REPRODUCIBILITY OF MEAN SURVIVAL TIMESFOR 16 FROZEIJASCITES TUMORS

(IO7cellsinoculatedintraperitoneallyintoC3D2mice after removalfrom-75Â°storageaccordingto protocolunder "Methods")

TUMORA#2DBA/2EhrlichGardnerHep

134L-1210L-1210-AM/RL-1210-TG/RMC1MP288P288-R/2P388P815P815E1767042970429

AzR-1NO.

TESTS*6573362250875555355No.MICE1201001407201204405016014010010010010060100100MEAN

SURVIVALTIMES(days)195810.016.110.612.516.37.27.59.616.19.77.89.511.110.830.631.919597.814.512.512.216.07.07.29.515.98.29.411.512.611.330.922.319609.0-14.612.413.47.47.79.114.9_10.312.4-_36.6-19618.214.215.912.4-8.0---_9.5---34.125.4AVERAGE

Â±<T8.2

Â±0.8314.3Â±0.6512.2

Â±2.912.7Â±1.8114.7Â±2.287.3Â±0.577.4Â±0.479.3i0.3015.5Â±1.678.1i0.459.7Â±0.4212.0Â±2.5512.1Â±1.0511.2Â±0.8333.8Â±4.8425.4Â±4.55

* Refersto the numberof separatewithdrawalsfromthe frozentumorbank, exceptin the caseofthe L-1210and the Gardnertumors,each of which involve>12 separatewithdrawals.



572 CancerResearch Rutmanrtfl/.

TABLE D

LIST OF SELECTED REFERENCE COMPOUNDS

UPNO.97440441176456SYMBOLHN2L-PAMCtxS-TEPAA-

139NAMENitrogen

mustardL-phenylalanlnemustardCytoxanThio

tri-ethylenephosphorand.deEthylimino-benzoquinoneUP

NO.6960436434SYMBOLAmethopTO5-

FUAzSNAMEAmethopterin

(Methotrexate)2-Thioguanine5-

FluorouracilAzaserine

TABLEE

COMPARATIVE EFFECTIVENESS OF STANDARD AGENTS ONSIX ASCITES FORM MURINE LYMPHOCYTIC LEUKEMIAS

(Datagivenas: Bank Indexperformnce

see text,page 561.;

HN2L-PAMCtxS-TEPAA-

139AmethopTG5-

FUAzSL-1210Orig.8

04

0.404

0.408

06

0.301**

~1.020.603

0.506

0.30Tg/R1

~1.03

0.552

0.594

0.456

06

06

05

0.366

0Am/R4

0.192

0.651

"1.06

03

0.39606

04

0.496

0P288Orig.6

04

0.302

0.90604

0.301

~1.03

0.606

06

0R/26

01-i.o2

0.604

0.423

0.596

06

06

06

0P3881

1.05

0.691"1.07

03

0.824

0.757

060.447

0ALL

LEUK.Â»R.I.521743668P.I.0.470.791.00.200.530.600.260.330.07

TABLE F

COMPARATIVE EFFECTIVENESS OF STANDARD AGENTS

ON FOUR RESISTANT ASCITES TUMORS OF MICE(Protocol as in Table E)

HN2L-PAMCtxS-TEPAA-

139AmethopTG5-

FUAzSDBA/25011.030.5050503

0.5020.905050Hep

13411.0202020202

02020207042911.040.6750.557020.90705070.5520.9070429AZ/R30.2911.0.-505020.425040.1650R.I.213644454P.I..841.0.550.34.36.34.27.34

* Average for the 6 leukemias. P.I. normalized by letting highest average value Â»1.** Underline indicates best performance, i.e., maximum extension MST.




TABLE G

COMPARATIVE EFFECTIVENESS OF STANDARD AGENTS ON SIXN-MUSTARD SENSITIVE MOUSE ASCITES TUMORS

(Protocol as on Table E)

HN2L-PAMCtxS-TEPAA-

139AmethopTG5-

FUAzSA#220.9011.0707030.45706050.1540.206C3HED20.9120.9111.08040.7760.5770.1450.7280Ehrlich11.020.6530.406040.25606050.1560MC1M20.8211.06050.0730.346040.296060P81540.4811.030.6120.7050.3970.2660.3570.2690P815E17640.2220.4670.1540.2211.060.1830.2480.1880.18AVERAGER.I.214537568P.I.0.861.00.430.200.650.200.200.300.07

TABLE H

COMPARATIVE EFFECTIVENESS OF TWO NEW ALKYLATINGAGENTS AGAINST ASCITES TUMORS

UP No.:COMPOUND:TUMORSA#2

DBA/2Ehrlich6C3HEDHep

134L-1210L-1210 Am/RL-1210 Tg/R

MC1MP288P288

R2P388P815P815E1767042970429

AzR-15856-hydroxy-9-

[(3-bis(ÃŸ-chloro

ethyl )amino )propyl]purineR.I.tf322265

5__.â€ž724P.I.0.78

0.00.880.910.33

0.300.50

0.160.00.00.00.00.260.910.26475l-bis[(ÃŸ-chloroethyl)-2-

amino]ethaneR.I.Â»33

212

3221445_244P.I.0.83

0.700.882.710.88

0.550.570.801.210.300.380.730.0O.SZ0.550.19

R.I. Â»Rank Index,P.I. Â«PerformanceIndex. Figuresshowthe relativeeffectivenesscomparedtothe nine referenceagentsof TablesE - G.

# Meansthat effectof test compoundis greaterthan that of the nth rankingreferencecompound.The blank spacesunderR.I. indicatethat the test compoundis less effectivethan the leasteffectivereferencecompound.




TABLE 1A

EFFECTS OF ALKYLATING AGENTS ON GARDNER LYMPHOSARCOMA

UPNo.DOSE mg/kgSURVIVAL

DATAExptl/Control

MSTAlkylating

Agents-htistard89D97S141141B17

6S223252289299326328329336343349351A

t*10.015.025.030.035.040.050.075.0*

0.40.60.8*

1.03.018.036.072.01.02.03.04.02.00.50.50.100.250.75Â«

1.0200.00.52.07.010.02.55.010.025.0100.05.010.025.05.010.025.00.40.251.02.02.510.050.0100.02.510.020.05.020.0100.021.1/13.322.0/12.822.8/12.418.1/14.625.

8/11.7>45. 0/16.410.0/13.06.6/13.031.1/12.3>

36. 7/12.226.1/10.6>

28.7/12.510.2/12.220.8/14.218.4/13.929.7/13.98.

1/11.911.8/11.99.0/11.98.6/11.914.2/12.610.4/11.913.

1/13.912.9/13.917.0/13.96.2/12.37.3/12.412.9/14.212.4/11.912.5/11.912.2/12.311.

4/12.312.7/12.912.3/12.312.2/12.912.0/13.111.8/12.812.1/13.412.1/13.44.8/13.413.2/13.412.3/13.413.1/13.427.1/18.314.1/18.33.

3/11.62.2/11.620.2/14.8>

38. 7/14.811.7/12.811.5/12.812.4/14.814.0/14.811.3/12.825.0/14.8>

35.9/14.846.3/13.0Percent

ExtensionofVB1597284120>174153>201146>13046321144837>16269>143256Pe:l.Sx2040453540601075609050303050101010402080103050â€¢cent

Sui

2x1020401530501050409035201050101010302060102030-vivlng

Â£

3x10103030402530303020105010101020301030it

Multi]

5x1020103020201510105010202020>le

of M

7x510201010101010203T>7x10202020101010101020

* PooledData.




TABLE 1A(Continued)

EFFECTS OF ALKYIATING AGENTS ON GARDNER LYMPHOSARCOMA

UP

No.DOSE mg/kgSURVIVAL

DATAExptl/Control

MSTAlkylating

Agents -Mustard351B

t351C

t351D

t351E

t3523533543553583593623693703854112.55.010.020.030.050.02.010.020.010.020.030.040.05.020.02.510.02.510.02.510.02.510.0*

5.0*7.5Â«10.012.515.0Â«20.010.025.00.50.751.01.52.02.52.5*

5.05.07.510.012.515.020.01.02.55.00.5*

1.01.5*

2.02.55.02.5*

5.010.0>

25. 9/11.76.8/11.74.1/11.73.6/11.73.6/11.73.6/11.710.

6/13.011.8/13.014.0/13.012.5/12.115.2/12.111.6/11.3>

21.3/11.3>16. 4/11.64.6/11.612.4/14.811.9/14.813.8/14.811.6/14.812.

3/14.812.8/14.818.

7/14.818.9/14.816.5/14.020.3/14.042.5/13.6>

39. 0/16.4>47.7>

20.4/14.013.0/13.913.3/13.927.4/16.4>

32. 8/14.8>45. 0/16.426.0/12.1>16.3/16.45.8/13.99.4/14.86.8/15.1>

44. 6/16.4>38. 4/16.4>35.0/16.416.5/16.47.2/16.46.4/16.417.4/14.87.8/14.82.1/16.419.3/13.4>

20.0/14.118.1/12.1>27.8/11.6>

50. 6/14.87.5/14.814.5/18.326.3/14.113.6/12.5Percent

ExtensionofMST>12126>

97412628312001382294567>124>174114>172>134>11344114507140>24283Pe

1.5x601010202020102020206040653540507080106060401020553080905510rcent

Sui

2x301010201020105503050203050606010603030101030207045-viving3x201010105453045103020602010403030101020104015it

Multi

5x1010525303051010103020201051030pie

of M

7x10105520305101010202010510303T>7x10102030510101020201051030

* Pooled Data.




TABLE1A(Continued)

EFFECTS OF ALKYLATING AGENTS ON GARDNER LÃ•MPHOSARCOMA

UPNo.DOSE mg/fcgSURVIVAL

DATAExptl/Control

MSTAlkylating

AgentE -Â»astard419426427428439440S441S449450458459S4744754804844864874934965005015025031.02.52.510.01.32.55.07.510.015.01.2510.020.02.5*

5.07.510.015.030.045.010.0Â«10.05.010.015.01.03.05.01.02.00.51.02.03.015.01.02.03.01.02.03.01.02.03.02.02.55.010.02.55.010.01.02.05.025.010.025.0>37.

5/13.05.3/13.07.6/13.65.3/13.613.0/13.611.7/11.612.7/11.622.4/11.58.1/11.6>

61. 7/11.5>32. 0/13.612.7/18.35.8/18.332.7/10.622.8/14.518.8/10.68.1/18.333.8/10.617.0/10.616.3/10.622.1/13.812.3/13.89.5/

7.211.3/7.216.9/7.2>

16. 9/10.628.3/10.625.0/10.614.2/11.515.8/11.5>

76. 4/11.5>75.9/11.5>43.1/11.57.0/11.511.9/12.8>78.3/11.546.5/11.57.6/11.5>

73. 1/11.5>71.2/11.514.3/11.513.8/11.515.3/11.521.9/11.58.9/12.812.3/12.813.3/12.813.9/12.812.4/12.811.9/12.813.0/12.819.5/12.8>55.4/12.813.8/12.822.3/12.813.6/12.812.0/12.8Percent

Extensionof16T>18995436135206505821960536032571343743559274589304>53552.033915233475Pe]l.Sx5060101004010040701007050303050801010060102010010090100100100100201060209030-cent

Su]

2x502090408020301002010201010409050100100901001001001002020108020-viving

i

3x402090303010602010203090100809070100901020107020It

Â»liti]5x20602010108080208040808050xLeof M

7x203010707010805060205T>7x10201060701080303020

* Pooled Data.




TABLE 1A(Concluded)

EFFECTS OF ALKYLATING AGENTS ON GARDNER LYMPHOSARCOMA

UPNo.DOSEmg/k6SURVIVAL

DATAExptl/Control

NETAlky

lating Agents-Mjstard5045055165205215225235245255.010.025.02.55.010.010.015.020.01.03.05.010.01.03.05.010.01.03.05.010.01.03.05.010.01.03.05.010.01.03.05.010.013.2/12.813.8/12.813.5/12.812.3/12.812.8/12.813.7/12.89.4/

8.59.2/8.56.6/

8.516.2/12.116.1/12.139.2/12.16.6/12.112.3/12.140.0/12.124.0/12.112.9/12.112.0/12.1>

21.6/12.1>38.5/12.1>30.4/12.111.7/12.18.4/12.19.3/12.111.3/12.19.5/12.110.7/12.18.7/12.19.2/12.111.2/12.113.5/12.110.6/12.111.8/12.1PercentExt

ensionofMST343310PeÃ1.5x20601001080301020605010â€¢cent

Sui

2x7060301010504010â€¢viving

t

3x5050205030it

Multll

5x30202020ile

of Â«

7x10>T >7x102020



578 CancerResearch Rutmanrfa/.

TABLE IB

EFFECT OF AGENTS OTHER THAN ALKYIATING AGENTS ON GARDNER LYMPHOSARCOMA

UPNo.DOSEmg/kgBenzimidazoles1371617182025283038404243444855666873136163164172213214259260361412413452200.0200.0200.080.0200.060.0200.0100.0200.050.0100.0200.050.0250.0130.080.050.050.050.0100.0100.0200.060.050.0150.0200.0200.025.0100.0250.0200.0200.0200.0200.0100.050.05.010.010.0100.0Pyrimidines64658610210510610750.055.075.0110.0300.0100.0200.0300.0200.0200.0200.0100.0300.0290.0SURVIVAL

DATAExptl/ControlMST15.6/17.515.6/17.515.0/17.524.3/17.513.6/14.513.9/17.513.2/13.317.4/17.511.7/12.615.1/17.517.2/17.511.6/12.615.6/17.54.6/12.115.4/17.515.8/17.516.5/17.515.9/17.515.8/17.517.6/17.517.4/17.59.9/12.615.1/17.517.6/17.511.9/12.614.7/13.313.1/13.311.6/16.41.0/12.11.0/12.114.4/17.510.8/13.312.1/12.112.0/12.111.3/13.415.1/12.513.0/12.511.3/12.57.8/12.82.0/

7.214.6/14.51.0/13.39.2/12.32.4/13.31.0/13.313.4/14.511.8/13.32.1/13.311.8/12.111.2/12.17.9/13.411.4/13.44.8/13.314.6/13.3PercentExtensionof

MST33Percent

Cumulative Mortality(day ofdeath)201512212131014312141441272111110910941212n94240141514141514144151514101411121112312215601515141316151115151616111515111471111118016161816171115161617171718161617121313141312121112815141112416100201617861518143215174814197222021191925381418351633141511161414141445171415217117151141412141414151418



Vol. 22, No. 7, Part 2 Cancer Chemotherapy Screening Data 579

TABLE IB(Continued


UPNo.DOSEmg/kgPyrimidines110127135139140162182184195206211225A-2238-1247276278280320321322338339356436S100.0300.0200.0200.0100.0250.0100.0200.025.050.0100.060.0200.0300.0200.050.0200.050.0100.0250.0200.0200.0250.050.0100.0200.0200.050.0200.0100.0100.0100.05.0Antimetabolites60S69S237-2271337434S497499506Â»1.02.03.755.07.515.02.0100.0100.02.5*

5.010.025.0100.0*

5.0100.015.025.015.030.0SURVIVAL

DATAExptl/ControlMST14.1/16.411.0/13.313.6/13.311.0/12.113.6/14.29.1/13.310.9/12.34.6/14.214.7/18.320.9/18.311.3/13.313.8/13.310.8/13.32.1/13.32.9/13.413.0/12.912.7/12.913.3/13.414.1/13.012.0/12.112.0/12.113.0/13.311.6/12.113.0/13.49.7/13.97.1/12.911.4/12.912.6/13.47.2/12.913.8/13.012.8/13.014.2/13.422.1/12.518.1/14.113.7/11.719.1/17.58.6/10.620.4/17.510.3/12.615.

3/11.713.5/13.011.

5/13.013.8/13.914.3/15.110.1/12.82.6/12.81.0/13.015.0/14.413.4/12.813.2/12.813.0/12.811.0/12.112.2/12.1Percent

ExtensionofMST76Percent

CumulativeMortality(dayofdeath)2012712513573621112117114311113111217171887127111195121281140117111141812121111115441112111081412121271211601213113211212117127142117141918141081212801414152913132141412121411121423201721921111914151191001814151415141414164214201334151522201814141414351214141428192235432228122314211514242413111231414141414

* PooledData.




TABLE IB(Concluded)


UPNo.DOSEmg/kgAntimetabolites5265275.025.050.05.025.050.0Miscellaneous9103571160171212219261265275286324325327344-1346414420448454530200.0200.0180.0250.0190.0100.0100.0250.0250.0250.0300.025.050.050.050.050.07.510.0*15.0Â«20.025.015.01.02.55.010.015.050.010.050.025.050.0100.010.025.050.010.025.050.0SURVIVAL

DATAExptl/ControlMST10.6/12.110.8/12.112.0/12.111.7/12.114.0/12.111.1/12.113.6/13.311.

8/14.512.8/13.311.1/13.314.2/13.32.0/13.38.9/13.313.6/12.112.5/12.112.5/12.112.6/13.34.9/12.18.7/16.412.2/12.911.3/12.914.4/14.813.4/14.814.3/12.220.9/13.4>16.9/11.917.1/14.89.6/12.112.7/18.310.7/11.69.2/11.66.3/13.69.6/12.12.1/13.013.2/13.612.7/13.013.8/13.812.4/13.87.3/

7.27.5/7.211.8/12.87.7/

7.213.1/12.114.2/12.111.2/12.1Percent


CumulativeMortality(dayofdeath)207988981051111211111112131295119745127124111184088109911111261111441214121410108107960111012141112121212141416n12111011771280141313161214512141531141521281414100141415151416191514132821490141422714151533161640534312141211712314221514991410161514

* Pooled Data.




TABLE 2

EFFECT OF TEST COMPOUNDS ON L-1210 ORIGINAL LYMPHOCYTIC LEUKEMIA

UPNo.DOSEmg/kgSURVIVAL

DATAExptl/ControlMSTAlky

lating Agents -Mustard89D97S141176S336385419427428439440S441S459S47447548048448648749149249335.00.81.01.51.251.752.02.52.253.02.55.010.025.01.53.00.52.04.01.07.515.01.020.05.0Â«

7.510.015.020.025.030.060.04.08.01.02.00.5*

1.0*2.0Â«3.010.025.02.03.02.03.01.02.03.050.0100.050.0100.01.02.03.050.07.8/

7.38.2/7.010.

O/8.08.6/8.09.3/8.08.6/8.07.4/8.07.3/8.07.9/8.07.2/8.08.2/7.26.0/7.24.0/7.2O/

7.27.I/7.07.6/

7.07.4/7.09.1/7.09.0/7.08.4/7.37.9/7.28.I/7.08.9/

7.37.8/7.010.

2/7.910.2/9.57.8/

9.56.0/9.55.9/9.55.9/9.58.3/

7.010.I/7.09.2/

7.09.0/7.07.I/7.07.2/

7.08.4/7.08.7/

7.210.7/7.29.5/

7.27.2/7.27.0/7.29.9/7.07.2/

7.010.5/7.09.4/

7.07.2/7.07.6/7.07.0/7.06.5/7.07.7/9.25.8/7.05.0/7.08.3/7.08.5/7.06.5/7.02.0/

7.0Percent


Cumulative Mortality(day ofdeath)207797855565797a89774408897652810789955488601098777779878898n810101075801088579881012107791097778559100891211121088981078081081010111091181213966691410118810111312971281211897877799112

* Pooled Data.




TABLE 2(Continued)

EFFECT OF TEST COMPOUNDS ON L-1210 ORIGINAL LYMPHOCYTIC LEUKEMIA


DATAExptl/ControlMSTAlkylating

Agents -Mustard49549650050151652052152252352452552852950.0100.050.075.0100.050.0100.0Â«

1.0*2.02.5*

3.05.05.0Â«10.0<15.020.01.03.05.010.01.03.05.010.01.03.05.010.01.03.05.010.01.03.05.010.01.03.05.010.0100.0300.0400.0500.0750.05.010.025.0Benzimidazoles4522.05.05.7/

7.04.7/7.07.3/7.08.3/7.07.4/7.06.9/7.07.3/7.08.3/7.18.0/7.08.7/7.28.2/7.07.1/7.010.7/7.010.2/7.810.6/7.86.6/

8.58.3/8.57.8/8.57.7/

8.55.3/8.58.4/8.58.4/8.58.2/8.55.6/8.57.4/8.57.9/8.59.0/8.58.I/8.57.7/

8.57.9/8.58.6/8.59.4/8.57.9/8.58.0/8.57.4/8.57.7/8.59.0/8.58.2/8.58.0/8.58.5/8.57.0/7.27.0/7.27.I/7.27.I/7.26.8/

7.27.I/7.27.2/

7.27.2/7.27.0/

7.27.1/ 7.2Percent


Cumulative Mortality(day ofdeath)205577877577555575775404810974487777787786058779899758998897880588778971111898891097777771007799989991098251414710997101111791010101410101111101012111010107788789978

* Pooled Data.




TABLE Z(Concluded)

EFFECT OF TEST COMPOUNDS ON L-1210 ORIGIHAL LYMPHOCYTIC LEUKEMIA

UPNo.DOSEng/fcgPyrimidines162436S100.05.010.0Antimetabolites5060S69S394432434S49849950650.05.01.02.02.54.05.010.025.050.05.010.050.0100.05.010.015.030.0Miscellaneous344-142443845449451451553053110.020.030.0100.025.050.050.0100.010.025.00.250.500.750.250.500.751.010.025.050.05.010.025.0SURVIVAL

DATAExptl/ControlVÃ‹12.6/

7.38.9/7.010.4/7.010.

7/7.011.4/7.011.8/7.511.8/7.512.O/7.09.8/

7.59.9/7.07.0/7.27.0/7.27.3/7.07.8/7.09.0/7.07.0/7.27.0/7.27.0/7.27.0/7.28.3/8.56.9/8.56.7/

6.07.9/6.07.3/6.07.0/7.27.I/7.28.4/

7.27.0/7.27.0/7.27.1/7.27.0/

7.28.2/7.07.5/7.07.8/7.08.6/7.07.5/7.06.5/7.06.2/7.08.5/8.58.7/8.58.0/8.57.I/7.27.I/7.27.4/

7.2Percent





584 CancerResearch

TABLE 3

EFFECT OF TEST COMPOUNDS ON L-1210 Tg/R LEUKEMIA


DATAExptl/ControlM3TAlkylating

Agents -Mustard97S176S336358385427428439440S441S449450459S4744754804844864874914924934955005015020.10.4*

0.85.00.510.00.11.02.02.54.05.0*

7.515.01.02.020.00.11.02.55.010.050.0100.05.0Â«

5.0S.O2.00.51.02.03.010.025.02.03.03.01.02.03.0*

50.0Â»100.0*

50.0Â»100.0*

1.0Â«2.0*3.050.0100.0*

50.0100.01.0Â»

2.02.5*

3.0*30.0*

60.021.

2/9.714.3/9.715.I/9.613.9/9.310.7/9.212.2/9.49.8/

9.712.6/9.717.2/9.913.8/9.713.6/9.412.3/9.712.3/9.615.9/9.713.3/9.413.5/9.418.I/9.29.9/

9.713.2/9.715.6/9.715.5/9.710.3/9.715.9/9.77.8/

9.711.2/9.49.2/

9.48.8/9.38.6/

9.716.7/9.717.6/9.717.3/9.77.4/

9.710.3/8.86.I/8.818.2/9.77.I/9.715.7/9.78.7/

9.77.5/9.78.7/9.77.5/9.37.3/9.39.I/9.3B.9/

9.313.3/9.313.I/9.39.5/

9.37.8/9.48.2/9.49.I/9.38.9/

9.311.6/8.811.9/9.311.5/8.88.8/

9.310.4/9.313.9/ 9.3Percent


Cumulative Martality(day ofdeath)2012121210119111512111441110914891288715149978811997881110106940141610151112151617781415148761210787601412141417181191817710517178771389912111114801415181412191216191199181918112171071099148121216100901619161114111423161715151915169012141821121910121210102121228141125822111014810111016151110101010141414121419

* Pooled Data.




TABLE 3(Concluded)

EFFECT OF TEST COMPOUNDS ON L-1210 Tg/R LEUKEMIA

UPNo.DOSE ag/kgSURVIVAL

DATAExptl/ControlM3TAlkylating

Agents-Mustard5055085095105115125163.57.03.57.03.57.03.57.03.57.02.03.54.08.0Benzlmidazoles4522.05.0Pyrimidlnes162436S200.05.0Antimetabolites60S69S394432434S4984995.07.52.04.010.025.050.05.050.0100.05.010.0Miscellaneous1042443844845449451451550.0100.025.050.025.050.0100.010.025.00.10.20.51.00.10.20.51.09.

I/9.27.9/9.27.2/9.27.4/9.27.3/9.27.8/9.26.9/9.27.4/9.27.7/9.27.3/

9.213.O/9.28.9/

9.211.9/9.214.4/9.29.2/

8.86.5/8.87.4/

9.412.9/9.38.9/

9.97.5/9.47.7/9.37.6/9.38.6/8.88.7/8.89.4/

9.211.8/9.39.3/

8.88.7/8.89.4/8.89.2/8.89.9/

9.48.4/8.89.3/8.87.7/8.89.2/9.46.7/8.87.4/8.89.3/8.88.2/8.89.4/

9.210.O/9.210.2/9.29.8/

9.29.9/9.210.

O/9.29.7/9.29.I/ 9.2Percent


Cumulative Mortality(day ofdeath)208455714947777575897997407712812155778899797988609877771071277119998710101099809797879879101210101010911101010100101012101010891091511151711119141089911101014n111111111111108911121111111411111112




TABLE 4

EFFECT OF TEST COMPOUNDS ON L-1210 AM/R LEUKEMIA



Agents -Mustard89D97S176S336419427428439440S441S459S47548049650050150250435.00.85.00.51.07.51.020.04.08.030.060.04.08.01.02.05.010.07.515.025.030.02.55.0100.050.0Benz

imidazoles45212.5Pyrimidines162436S100.05.0Antimetabolites69S432434S4994.050.05.050.075.08.2/

8.09.7/7.07.9/7.27.3/

7.010.7/8.08.I/8.010.5/8.07.8/

7.012.2/7.216.8/7.212.5/7.222.2/7.211.6/7.29.I/7.211.O/7.216.4/7.27.8/

7.78.8/7.78.4/7.77.6/7.77.2/7.77.0/7.78.8/7.77.2/7.7S.I/7.77.8/7.73.6/

7.75.9/

8.010.1/7.27.2/

7.27.0/7.08.5/7.24.6/7.74.7/

7.7Percent






TABLE 5

EFFECTOF TEST COMPOUNDSON P288 LYMPHOCYTICLEUKEMIA



Agents-Mustard97S17

6S385419427428440S441S458459S4754844860.42.55.01.02.04.02.05.010.020.02.010.02.454.37.530.060.05.010.02.55.010.00.51.02.01.05.010.02.05.0Pyrimidlnes436S5.0Antimetabolltes60S69S434S5.02.04.05.0Miscellaneous47948550.050.08.5/7.88.0/8.69.5/8.67.0/7.78.0/7.79.5/7.79.I/8.17.9/

8.17.3/8.18.5/8.19.0/8.14.4/8.19.0/

7.710.2/7.79.1/

7.711.3/8.616.4/8.66.8/

7.77.7/7.77.6/

7.710.1/7.77.I/7.77.9/

8.19.6/8.110.

6/8.19.6/8.15.6/8.13.9/8.18.5/8.17.5/8.19.5/

8.613.

7/8.613.2/7.714.0/

7.710.O/8.66.2/

8.16.4/8.1Percent






TABLE 6

EFFECT OF TEST COMPOUNDS ON P288-R2 LYMPHOCYTIC LEUKEMIA

UPNo.DOSEmg/kgSURVIVAL

DATAExptl/ControlMSTAUcylating

Agents-Mustard97S176S385419427428440S441S458459S4744754804844864934965005015025040.42.55.01.02.04.01.02.015.020.01.02.02.454.37.530.060.05.010.02.54.05.08.010.01.02.01.02.05.010.01.02.02.03.01.02.07.515.025.030.02.55.0100.050.0Benzimi

Â¿LazÃ³les45212.5Pyrimidines436S5.011.

2/9.011.O/9.910.2/9.910.7/9.010.6/9.010.9/9.011.4/9.910.8/9.911.6/9.911.6/9.911.O/9.99.7/

9.911.I/9.011.5/9.014.9/9.013.7/9.911.O/9.97.9/

9.07.6/9.08.7/

9.013.5/9.912.I/9.07.9/

9.97.5/9.09.5/9.99.4/

9.912.2/9.912.8/9.911.0/10.311.1/10.311.

6/9.97.7/9.910.

4/9.97.I/9.911.2/9.99.8/

9.910.5/10.311.3/10.311.

7/10.310.3/10.313.9/10.37.4/10.36.7/10.310.

7/10.35.0/10.310.

5/ 9.9Percent

ExtensionofMST23161616U232765421136342835Percent




Vol. 22, No. 7, Part 2 Cmcer Chemotherapy Screening Data 589

TABLE 6(Concluded)

EFFECT OF TEST COMPOUNDS ON P288-R2 LYMPHOCYTIC LEUKEMIA

UPNo.DOSEAntimetabolites60S69S434S4992.04.06.02.04.05.050.075.0SURVIVAL

DATAExptl/Control10.

9/9.59.9/9.510.

3/9.59.5/9.010.

I/9.011.O/9.99.7/10.36.8/10.3Percent

ExtensionofNET11Percent




590 Cmcer Research Rutman et al.

TABLE 7

EFFECT OF TEST COMPOUNDS ON P388 LYMPHOCYTIC LEUKEMIA


DATAExptl/ControlNETAlkylating

Agents-Mustard97S176S385419427428440S441S459S4744754844864870.2*

0.40.81.22.55.00.51.02.04.01.0*

2.05.010.015.020.00.5*

1.0*2.010.01.02.05.07.510.010.020.030.040.060.00.51.05.01.02.00.5*

1.0*2.0*

1.02.05.010.02.03.01.02.0Pyrimidines436S5.05.0Ant

imetabolites60S69S434S5.02.55.0*

5.015.0/11.519.8/13.216.7/11.520.4/11.511.

4/9.911.6/9.912.2/11.512.9/11.513.8/11.513.0/11.514.

5/8.911.2/12.47.6/14.916.

2/4.912.3/9.914.2/12.413.6/11.513.8/10.719.3/12.14.0/14.913.0/11.514.9/11.515.8/11.517.3/11.517.4/11.514.0/11.515.5/11.514.

0/9.920.5/11.515.O/9.911.6/11.511.

7/11.519.2/11.59.5/

9.911.4/9.918.0/14.917.5/12.418.4/12.418.0/12.412.

9/9.95.7/14.93.6/14.914.

2/9.911.8/9.912.9/9.910.4/9.914.5/11.513.

8/9.912.8/11.516.

I/9.915.1/9.913.3/10.7Percent



Â»PooledData.




TABLE 7(Concluded)

EFFECTOF TEST COMPOUNDSON P388 LYMPHOCYTICLEUKEMIA

OPNo.DOSEmg/kgMiscellaneous45447948510.050.050.050.0SURVIVAL

DATAExptl/Control

MST11.0/11.511.9/11.513.8/14.912.9/14.9PercentExtensionof MST2010910Percent

d(de4011unulativelyofdea601114Mortalitith)8012r10012141514




TABLE 8

EFFECT OF TEST COMPOUNDS ON P815 MAST CELL TUMOR



Agents -Mustard89D97S141B176S336358385419427438439440S441S459S47447548448649340.00.4*

0.850.02.55.00.4*10.01.02.04.01.02.07.515.020.01.02.020.0*

5.010.05.030.060.04.08.01.02.01.02.01.02.02.03.01.02.0Pyrimidines162436S50.05.0Antimetabolites60S69S434S4355.02.04.05.01.0Miscellaneous10100.010.4/11.114.2/11.117.0/11.510.9/11.114.

7/13.3>24.2/13.310.6/11.112.5/11.511.6/11.113.0/11.114.8/11.915.7/13.314.0/13.312.3/11.117.4/13.319.6/13.314.5/12.216.1/12.610.4/11.124.2/11.57.8/11.115.4/11.922.4/13.321.0/13.319.6/13.37.9/13.315.

1/13.315.5/13.315.2/13.315.6/13.314.7/13.313.9/13.314.2/13.37.6/13.315.6/13.315.0/13.37.9/11.915.6/11.917.0/11.916.7/13.315.9/13.314.6/11.911.3/11.98.2/n.iPercent



* Pooled Data.



Vol. 22, No. 7, Part 2 CancerChemotherapy Screening Data 593

TABLE 9

EFFECT OF TEST COMPOUNDS ON FLUOROURACIL-RESISTANT

MAST CELL TUMOR, P815E176

UPNo.DOSE Å“g/kgSURVIVAL


lating Agents -Mustard97S176S358385419427428440S441S459S4744754844864874930.82.55.010.04.01.02.015.025.02.05.05.02.04.08.01.02.01.02.01.02.01.01.02.01.02.0Pyrimidines162436S50.05.0Antijnetabolites60S69S434S4355.02.04.05.01.015.

5/10.115.1/11.818.4/11.812.4/10.113.4/10.114.3/11.814.2/11.818.3/11.819.5/11.814.6/10.124.8/10.112.8/10.116.1/11.840.9/11.87.2/11.815.1/11.815.8/11.818.6/11.827.4/11.817.5/11.822.9/11.814.7/11.814.6/11.817.0/11.816.2/11.816.3/11.87.0/10.112.4/10.116.4/10.117.0/11.86.6/11.812.3/10.112.9/10.1Percent


CumulativeMortality(dayofdeath)201714121421912281417161812141412145118401414n121422123014151914141616960151812151418211516182417171612168016191423261871633192115181717171710017172114171717232517321724528171824K5221521617192221716182171419




TABLE 10

EFFECT OF TEST COMPOUMDS ON 70429 PLASMA CELL TUMOR

UPNo.DOSEmgAeSURVIVAL


Agents -Mustard97S336385428440S441S450459S480493496500501502503504505*

0.4*0.80.42.02.5*

4.01.0*

2.02.54.05.08.025.050.05.02.03.04.05.015.01.0*

2.02.55.010.02.55.010.01.02.05.025.05.010.025.05.010.025.02.55.010.0Benzimldazoles45210.0Pyri

midines436S5.0Ant

imetabolites60S69S434S497*

5.02.04.0*

5.0100.045.5/30.945.4/30.938.4/32.842.3/32.840.4/29.045.9/26.938.4/29.028.6/32.833.3/29.0>

43.0/32.838.2/29.023.5/32.841.3/32.822.5/29.028.5/29.051.6/31.447.4/31.432.1/31.429.2/31.427.7/31.4>47.4/>41.820.3/36.628.0/31.426.9/31.429.9/31.425.3/31.428.1/31.434.6/31.422.5/31.423.4/31.436.5/31.429.0/31.430.7/31.432.2/31.433.0/31.427.5/31.431.5/31.434.6/31.423.8/31.425.9/31.428.9/31.415.5/31.435.1/35.426.4/30.9>46.6/>41.8>11.3/M1.841.8/30.927.1/31.4Percent



* Pooled Data.




TABLE 10(Concluded)

EFFECT OF TEST COMPOUNDS ON 70439 PLASMA CELL TUMOR

UPNo.DOSEmg/kgAnt

imetabolites49950650715.025.025.050.025.050.0Miscellaneous1045450.025.0SURVIVAL

DATAKxptl/ControlMST29.7/31.432.3/31.433.2/31.430.5/31.434.1/31.413.6/31.419.9/29.028.4/31.4Percent

ExtensionofMSTPercent





TABLE 11

EFFECTS OF TEST COMPOUNDS ON 70429AZR-1 PLASMA CELL TUMOR

UPNo.DOSE ingAsSURVIVAL


lating Agents -Mustard97S141B176S385419427428440S459S4754844864874930.40.81.035.070.02.55.01.02.02.54.00.51.05.010.01.02.55.07.515.030.045.060.02.02.55.07.52.55.010.01.02.01.02.01.02.01.02.0Antimetabolites60S69S434S5.02.04.05.0Pyrlmldlnes436S5.033.4/27.533.2/23.248.3/31.931.4/31.934.4/31.920.0/21.518.6/21.531.9/27.631.8/23.248.6/31.926.2/23.227.3/23.228.8/23.225.9/23.229.7/23.221.6/23.259.6/23.229.2/23.225.8/23.26.6/25.45.6/25.44.9/25.44.6/25.417.5/23.224.6/23.219.2/23.25.9/23.230.1/23.26.8/23.24.0/23.231.5/21.513.8/21.528.7/21.536.3/21.513.5/21.514.3/21.533.1/21.521.8/21.516.7/21.534.9/21.517.1/21.5726.1/21.527.1/21.5Percent


Cumulative Mortality(day ofdeath)20232639283077262833102414242871410571183225324728338828118311421402944311593123262530746261448251242626831359,10'3112103371660342623283243312931262933231018332933401011352314828298040385335353033653531363330333330297364351138422122393137331004547603836373541367338353930423890367377554238398457550384050282650373650425235



Vol. 22, No. 7, Part 2 Cmcer Chemotherapy Screening Data 597

TABLE 12A

EFFECT OF ALKYLATINGAGENTS ON A No. 2 LÃ•MPHOMA

UPNo.DOSEnÂ«AeSURVIVAL


lating Agents -Mustard89D973141B17

63358385419427438440S441S459S47548048648749149349349549650050150335.070.0*

0.40.850.01.03.03.04.010.04.00.40.81.34.08.012.00.51.03.05.05.010.015.030.045.060.03.03.04.05.00.51.02.010.035.00.51.03.01.03.55.050.0100.050.0100.01.02.03.050.0100.050.0100.050.0100.01.02.530.060.016.

O/7.86.3/7.8>56.6/7.8>50.5/

7.810.3/7.88.I/8.27.7/

8.36.8/8.28.3/

8.212.6/7.8>64.9/

7.89.4/7.8>38.3/7.8>39.7/

7.87.0/7.86.7/

7.812.9/7.8>31.6/

7.8>53.7/7.8>36.4/

7.880.I/7.87.4/

7.88.2/7.88.3/8.28.3/8.29.6/

8.210.3/8.213.9/8.2>41.6/

8.237.7/8.216.9/8.3>35.1/

7.8>49.0/7.8>65.7/

7.86.6/8.46.6/8.48.8/

7.810.4/7.828.3/7.8>

73. 3/17.5>67. 3/17.5>61. 4/17.57.7/

9.96.7/9.98.4/9.97.2/

9.9>35.3/9.99.7/

9.9>11.1/9.98.2/9.97.7/

9.913.3/9.99.8/

9.97.8/9.97.7/

9.9>81.2/8.4>49.1/8.4>10.9/9.9>18.6/

9.9Percent


Surviving at Multiple ofMST1.5x2010060102010070801020609010010070901005080100100101010010090100802020907020402x2010060101004070204080901009010040709010010909090808010703x20746010100702030608010060403060609010707070606010705x104090402020502080401030407060502050507x702050208020106040>7x5030203030205010702Â»10204060605020501080401040

* Pooled Data.




TABLE 12A(Concluded)

EFFECT OF ALKYLATING AGENTS ON A No. Z LYMPHOMA

UPNo.DOSESURVIVAL

DATAExptl/Control

MSTAlky

lating Agents-Mustard5055085095105115127.515.025.07.515.025.07.515.025.07.515.025.07.515.025.07.515.025.07.2/

9.97.2/9.96.6/9.98.0/9.98.5/9.97.8/9.97.5/9.97.I/9.97.0/

9.97.2/9.97.0/9.97.2/9.97.4/9.98.0/9.9Q.I/9.97.8/9.97.5/9.98.3/

9.9Percent

Extensionof MSTPej 1.5xâ€¢cent

Sui

2xâ€¢viving

i

3xit

Multi]

5x>le

ofMÂ£7x>T

>7x




TABLE 12B

EFFECT OF AGENTS OTHER THAN ALKYLATING AGENTS ON A No. 2 LYMPHOMA

UPNo.DOSEmg/kgBenzimldazoles4522.05.0Pyrimidines162436S50.05.0Ant

imetaboulÃ©s60S69S394434S4984995.02.03.04.05.010.025.05.050.0100.05.010.0Miscellaneous424438454494100.025.050.050.0100.010.025.0Exptl/Control

NET7.5/

8.47.1/8.47.0/

7.818.8/7.812.

8/7.811.7/8.210.5/8.28.0/

8.28.0/8.27.7/8.47.0/8.421.

2/7.87.0/8.47.3/8.47.4/8.47.5/8.47.

I/8.47.I/8.47.0/

8.46.1/8.45.5/

8.47.0/8.48.2/

8.4SURVIVAL

DATAPercent

ExtensionofMST644327172I20151154"ercent

Ci(di401785imulativelyofdeat6079877775Mortalityh)808714988217777r

1009872117182311810722888108887721




TABLE 13A

EFFECT OF AUCYIATING AGENTS ON EHRLICH CARCINOMA


DATAExptl/Control

MSTAlkylating

Agents -Mustard89D97S141B176S336358385419427428440S441S459S47447548048448648749349650050135.0*

0.40.835.01.01.52.0Â»

3.04.00.410.02.54.01.02.07.515.025.0*

1.0*2.02.55.07.525.050.02.03.0*

4.05.08.01.02.00.51.02.02.55.07.51.02.02.03.01.02.00.51.02.07.510.015.025.07.512.525.01.02.55.049.3/15.645.4/13.177.8/15.664.8/10.68.2/

8.27.6/8.68.4/8.27.3/8.48.0/

8.22.7/15.612.

2/9.4^64.0/10.6>40.

5/15.6>51.4/9.311.

9/9.37.6/9.38.4/9.36.9/

9.340.4/12.428.0/12.4>44.0/15.6>51.9/15.6>40.6/15.617.1/15.637.6/15.616.

9/15.722.9/15.720.2/12.112.5/15.76.4/

8.66.4/9.37.4/

9.337.2/9.340.6/9.39.9/

9.313.0/13.58.0/13.58.4/13.538.

2/9.38.3/9.324.

6/9.37.1/9.37.7/

9.37.5/9.324.4/13.547.8/13.547.5/13.59.3/13.510.5/13.510.2/13.512.5/13.57.2/13.56.5/13.56.5/13.512.5/13.524.3/13.57.9/13.5Percent

Extensionof MST152240400510305001604502820813318223216014046673003373101658125425280PeÃl.Sx60658070708090100201070354080506070552060602080106040708070â€¢cent

Sui

2x5050707060604080206535407030502010605010703030708040â€¢viving

!

3x403070705050208050254040304040507020207050it

Multi]

5x3030707030502050301530203040404020104040sie

ofK7x30257070305020301530202020202010104040ÃŽT

>7x3025707030502020153020202020104040

* PooledData.



Vol. 22, No. 7, Part 2 Cancer Chemotherapy Screening Data 601


EFFECT OF ALKYLATING AGENTS ON EHRLICH CARCINOMA

UPNo.DOSE Å“g/k8SURVIVAL


Agents -Mustard50250350450550.0100.050.0100.050.025.050.075.0100.031.7/13.55.9/13.510.

5/13.513.1/13.512.6/13.57.8/13.55.0/13.54.9/13.54.4/13.5Percent

Extensionof Ã•CT135PeÃl.Sx70â€¢cent

Svu

2x70-viving

E

3x20it

Mjlti

Sxpie

ofH7x3T

>7x




TABLE 13B

EFFECT OF AGENTS OTHER THAN ALKYIATING AGENTS ON EHRLICH CARCINOMA

UPNo.DOSEmg/kgBenzimidazoles4527.512.5Pyrimldines436S5.0Antlmetabolites60S69S434S4995.02.55.05.025.050.075.0Miscellaneous10344.150.010.015.020.0SURVIVAL

DATAExptl/ControlMST18.2/13.510.7/13.523.7/15.611.

3/15.611.8/8.69.2/

8.617.6/15.610.8/13.512.0/13.511.6/13.515.9/15.621.5/25.418.5/25.49.9/25.4Percent






TABLE 14A

EFFECT OF AIKYLATING AGENTS OH MCIM MAMMARY ADENOCARCINOMA

UPNo.DOSE "Â«AÃŸSURVIVAL


Agents -Mustard89D97S141-

B176S358385419427428439440S441S459S47447548648749149249349549650050140.0*

0.4*0.850.02.55.010.01.02.00.61.25.07.510.0*

1.02.020.05.010.010.050.0100.04.08.01.02.55.012.525.037.550.00.51.02.01.02.01.02.55.012.525.037.550.0100.050.0100.01.02.03.050.0100.050.0100.050.0100.02.03.017.6/16.4>44.8/14.7>42.9/15.422.7/16.420.9/16.520.6/16.519.7/16.423.0/16.426.7/16.4>

36.2/13.0>43.1/13.012.5/13.017.1/16.413.6/13.0>43.5/14.7>26.

0/13.014.7/16.4>62.7/16.414.2/16.421.4/18.18.7/18.113.3/18.137.9/16.57.4/16.5y

26. 1/15.6?34. 0/15.67.5/15.6>

50. 9/15.625.0/15.68.9/15.67.0/15.631.9/13.0>46.

2/13.0>72.3/13.0>29.3/13.0>38.6/13.0>40.9/15.638.0/15.6>48.0/15.630.2/15.6>34.9/15.6>38.9/15.611.8/14.78.5/14.710.4/14.76.0/14.726.3/14.7>

50. 8/14.7>20.1/14.77.2/14.710.9/14.714.2/14.715.3/14.715.6/14.713.3/14.730.3/14.7>38.6/14.7Percent


Surviving at Multiple ofMST1.5x6565301010206070101080501010010401010405080609080100607090901008040806090201010901002x405510206050407030508010606010040506050100402040308020101080803x52010504010502020402050902040202030202030104010105x5102015104010202030501020102020103010107x101015104010202030501020101020103010>7x10101510401020203050102010102010301010

* PooledData.



604 CancerResearch


EFFECT OF ALKYIATING AGENTS ON MCIM MAMMARY ADENOCARCINOMA


DATAExptl/Control

MSTAlkylating

Agents -Mustard5055085095105115125163.57.03.57.03.57.0

3.57.03.57.03.57.0

3.04.08.014.2/14.313.4/14.315.5/14.316.6/14.312.8/14.36.0/14.3

13.4/14.314.1/14.314.

2/14.314.1/14.315.0/14.314.7/14.3

17.1/14.36.5/14.3

>45.1/14.3Percent

Extensionof MST215Pe1.5x20101030

80rcent

Su.

2x101030

80rviving

i

3x1040it

Multi.

5xale

of M

7x;T>7x30




TABLE 14B

EFFECT OF AGENTS OTHER THAN AIKYLATING AGENTS ON MCIM MAMMARY ADENOCARCINOMA

UPNo.DOSEmg/kgBenzimidazoles458Pyrimidir436SAntimetat60S69S434S499Miscellar105145156.09.0Ães5.0olites5.02.04.05.040.0leous50.0100.00.10.20.50.10.20.5SURVIVAL

DATAExptl/ControlMST13.8/14.711.0/14.719.0/16.534.3/16.57.8/16.5.6.0/16.519.2/16.59.5/14.716.0/18.17.2/16.415.0/14.312.0/14.314.1/14.312.5/14.316.2/14.324.7/14.3Percent






TABLE 15

EFFECT OF TEST COMPOUNDS ON Hep 134 PARENCHYMA! CELL TUMOR



Agents -Mustard89D973141B176S193252326336352358362385411419426427428440S441S449450459S47447548448648749125.050.0*

0.4*0.835.070.01.53.01.00.550.01.02.010.050.07.515.01.02.0*

1.02.54.05.0*

1.02.01.02.55.015.025.0Â«

1.0*2.04.08.030.060.05.010.05.010.04.08.01.02.01.02.01.02.01.02.00.5*

1.0Â»2.03.050.0100.016.0/18.518.0/18.522.7/21.818.6/21.820.1/18.510.8/18.59.3/15.58.2/15.515.5/15.111.2/18.513.8/15.19.0/15.13.3/15.11.0/18.515.8/18.513.8/18.515.5/18.510.1/18.57.1/18.517.2/15.913.7/18.59.5/13.317.5/15.113.4/15.311.6/15.513.0/15.111.6/15.114.8/15.19.0/15.56.3/15.520.7/14.612.6/14.417.7/15.512.4/15.512.8/15.57.1/15.510.3/13.313.

6/13.39.8/13.312.3/13.37.7/15.57.0/15.511.3/15.57.6/15.525.6/15.513.2/15.512.9/15.57.0/15.520.2/15.57.0/15.58.2/11.711.3/13.629.3/13.98.6/14.07.6/14.46.8/14.4Percent



* PooledData.




TABLE15(Concluded)

EFFECT OF TEST COMPOUNDS ON Hep 134 PARENCHYMAL CELL TUMOR



Agents-Mustard49249349549650050150550850951051151251650.0100.01.02.03.050.0100.050.0100.050.0100.02.03.03.57.03.57.03.57.03.57.03.57.03.57.02.04.08.0Pyrimidines162436S15.030.05.0Benzimidazoles4526.09.0Antimetabolites60S69S434S498499*

5.02.55.05.0200.040.0Miscellaneous1044851451550.025.050.00.10.20.50.10.20.55.6/14.45.8/14.47.6/14.46.6/14.45.0/14.45.3/14.45.3/14.46.1/14.46.6/14.47.1/14.47.0/14.410.9/14.47.1/14.48.4/11.711.0/11.77.8/11.76.9/11.75.7/11.76.3/11.78.8/11.78.2/11.79.2/11.78.2/11.710.3/11.78.7/11.713.3/11.79.9/11.77.5/11.78.0/13.37.0/13.313.6/18.56.0/14.48.6/14.48.7/15.96.0/15.56.6/15.514.6/18.514.0/14.48.8/14.412.0/13.312.5/13.312.8/13.36.7/11.79.4/11.721.6/11.710.3/11.712.7/11.723.0/11.7Percent


CumulativeMortality(dayofdeath)2024451065756610661247512127810115618611404435776566611555148111212720206075511868813771410132180745777119118O1115137811997112210077108787101587158131313988131013131513222113147167151077161515151616131632131532

* PooledData.




TABLE16

EFFECTOF TEST COMPOUNDSON DBA/2THYMOMA


DATAExptl/Control

unirE>-LAlkylating

Agents-Mustard97S176S385419427428440S441S458459S4744754844864870.42.55.00.51.02.04.01.02.015.020.01.02.02.454.3*

7.5Â»15.030.045.060.030.060.05.010.020.02.54.05.08.010.01.02.01.02.01.02.02.03.01.02.0Pyrlmidines436S5.0Antimetabolites60S69S434S5.02.02.54.05.05.015.

5/14.615.6/14.416.3/14.414.1/14.615.9/14.614.7/14.617.1/14.623.3/14.413.3/14.417.4/14.415.5/14.418.1/14.417.0/14.416.0/14.619.0/14.621.

7/14.26.6/13.66.4/13.45.1/13.44.1/13.417.3/15.318.3/15.39.7/14.69.4/14.66.0/14.69.6/14.619.5/14.415.9/14.613.

7/14.47.1/14.615.9/14.418.4/14.419.4/14.419.7/14.420.3/14.418.4/14.415.3/14.48.0/14.419.5/14.419.7/14.417.3/14.420.8/14.418.3/14.617.9/14.413.6/14.611.0/14.416.1/14.4Percent

ExtensionofÃŽ6T6226305335283537412835374525Percent


* PooledData.



1962;22:559-608. Cancer Res R. J. Rutman, F. S. Lewis, S. Buckner, et al. Mouse Ascites Tumors. IIIEvaluation of Chemotherapeutic Agents against a Variety of

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