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Investigation of the Activity of Cytoxan Against Leukemia L1210 in Mice

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Investigation of the Activity of Cytoxan Against Leukemia L1210 in Mice Investigation of the Activity of Cytoxan against Leukemia L1210 in Mice JOHN M. VENDITTI, STEWART R. HUMPHREYS, AND ABRAHAM GOLDIN (Laboratory of Chemical Pharmacology, National Canter Institute,* Bethesda, Md.) Two prime limiting factors in the treatment of dichloroamethopterin and 3'-bromo-5'-chloro- neoplastic disease are (a) the toxicity of active amethopterin, were capable of eliciting extensive anti-tumor agents for the host, and (b) the origin, survival time and apparently cured some of the during therapy, of resistance to the agent being mice, even when treatment was initiated after the employed. The origin of resistant variant sublines disease was frankly systemic (11). However, to therapy with folic acid antagonists, antipurines, despite the marked effectiveness of the antifolics glutamine antagonists, etc., has been amply in this system, host toxicity and the origin of re- demonstrated (5, 6, 22, 25-31, 86, 37). sistant variants, particularly following very ex- For purposes of overcoming the limitation of tensive treatment, appeared to limit the useful- drug toxicity in therapy, a primary objective of ness of therapy (20). screening programs and of detailed structure- In seeking additional anti-leukemic compounds activity studies within active groups of compounds with differing modes of action for use in conjunc- has been to uncover drugs with increased anti- tion with folic acid antagonists, purine and pyrimi- tumor activity and reduced host toxicity (7, 17, dine antagonists, etc., the nitrogen mustard 21, 35, 39, 41). With respect to the origin of re- derivative, N,N-bis (f~-chloroethyl)-N',O-propyl- sistance to treatment, the effort has been twofold: enephosphoric acid ester diamide (Cytoxan I) (1) (a) To uncover more active congeners within the was selected for more extensive study. This cyclic same structural series (2, 7, 17, 41) and (b) to ob- nitrogen mustard phosphamide ester appeared to tain drugs which inhibit at sites in different be of particular interest because of (a) its marked metabolic pathways or at different loci within the inhibitory action against a variety of experimen- same metabolic pathway (8, 38, 40). Such com- tal tumors, and its apparently greater specificity pounds have been employed in clinical studies of of anti-tumor action as compared with a number concomitant and sequential therapy (9). Combina- of other alkylating agents (1, 8, 4, 19, 23, 24), (b) tions of drugs presumed to act at different sites the postulated mechanism for increased specificity, have been employed in studies of anti-tumor involving splitting off of the phosphamide group synergism, empirically or in attempts at multiple and release of mustard activity at the tumor site biochemical blockade (12). (8), and (c) the apparent dissimilarity of this In this laboratory, assay procedures for the action as compared with that of the folic acid quantitative evaluation of chemotherapeutic antagonists, antipurines, antipyrimidines, etc. agents have been developed with the use of early The current study was conducted to character- and advanced leukemia L1210 in mice (14, 15). ize the effectiveness of Cytoxan against leukemia With these procedures, various purine and pyrimi- L1210 and to determine its effectiveness against dine antagonists, nitrogen mustard, and folic acid an antifolic-resistant subline and an antipurine- antagonists etc. (18), demonstrated definite thera- resistant subline of leukemia L1210. peutic effectiveness. The folic acid antagonists were particularly effective in increasing the sur- MATERIALS AND METHODS vival time of mice with this leukemia (17, 18). Al- The general procedures for the assay of drug effectiveness are similar to those used previously in this laboratory (14, 15, though amethopterin was markedly effective in 18). this system, it was surpassed in therapeutic The experiments were conducted in ~0-28-gm. BDFI activity by various halogenated derivatives of (C57BL/6 X DBA/~)FI hybrid, CDBA (BALB/c An X amethopterin (11, 17). Notably, two of the di- DBA/2J)F1 hybrid, or D~BC (ZBC X DBA/~) hybrid mice. halogenated derivatives of amethopterin, 3'5'- Cytoxan, Mead Johnson brand of cyclophosphamide, was formerly designated as Endoxan ("Summary of data on En- * National Institutes of Health, Public Health Service, U.S. doxan," A. G. Astawerke). The Cytoxan used in these experi- Department of Health, Education, and Welfare. ments was obtained from Mead Johnson through the Cancer Received for publication June ~, 1959. Chemotherapy National Service Center. 986 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1959 American Association for Cancer Research. VENDITTI et al.--Antileukemic Activity of Cytox(m itt Mice 987 The hybrids employed are designated with the individual ex- RESULTS periments. The transplantable tumors employed were the sensitive The results are summarized in Tables 2-4 and leukemia (LI~10) (32) carried in DBA/~J mice, an amethop- Charts 1-3. terin-resistant subline of LI~10 (M46R) carried in CDBA hy- Table 2 shows summary data of a series of ex- brids (~0), and an 8-azaguanine-resistant variant (33) carried periments comparing the relative effectiveness of in DBA/~ mice. For each experiment the mice were/,dven in- oculations subcutaneously in the right hind leg of 0.1 or 0.~ ml. daily administration of Cytoxan, various other of a uniform saline suspension of leukemic cells from stock mice alkylating agents, and amethopterin in increasing with advanced leukemia. The sensitive leukemia (LI~10) and the survival time of mice with systemic leukemia. the amethopterin-resistant LI~10 (M46R) inocula were pre- At the optimal daily dose (62.5 mg/kg) (Table 2, pared from leukemic spleen tissue. The 8-azaguanine-resistant Exp. 1), Cytoxan increased the median survival LI~10 inoctdum was prepared from ascitic fluid. The concen- tration of the experimental tumor inoculum ranged from 3 X time of the nfice from 11.0 days (untreated con- 105 to 3 )< 10 e cells per mouse for the various experiments. trois) to 26.5 days. The extension in survival time TABLE 1 LIST OF COMPOUNDS Compound name Chemical designation Molecular formula Vehicle Source Cytoxan (Endoxan) N,N-Bis-(f/-chloroethyl)-N',O-propyl- CrHIsCI2N202P-H20 0.85% saline Mead Johnson ene phosphoric acid ester diamide Nitrogen mustard (HN~) 2,2'-Dichloro-N-methyldiethylamine, CzttHC]2N-HCI 0.85% saline Merck hydrochloride Triethylene melamine 2,4,6-Tris(1-aziridinyl)-s-triazine CgHI~N~ 0.85% saline l~derle (TEM) Degranol 1,6-Bis(2-cnloroethylamino)-l,6-dide- CIoH2.~CIaN~O4-~ 0.85% saline Medimpex oxy-D-mannitol,dihydrochloride Chlorambucil 4- {p-[Bis(~-chloroethyl)amino]phenyl }- C14H~gCI~.NOo. MC* Burroughs-Well- butyric acid come Hydroquinone mustard a~,a6-Bis[bis(~-chloroethyl)amino]-2,5- CI~LI~4CI4N.,O2 9 2HC1 MC C. Weatherbee, xylohydroquinone dihydrochloride Millikin Univ. DL-Sarcolysin 3-{ p-[Bis(2-chloroethyl)amino]phenyl I - Cj~H1sCIo_N.~O2"HC1 H,O J. tI. Burckhal- DL-alanine, hydrochloride ter Univ. of Kansas L-Sarcolysin 3- {p-[Bis(2-chloroethyl)amino]phenyl }- CI.~HlsCI2N202-HCI H.,O Chester Beatty L-alanine, hydrochloride Research Inst. Nitromin 2,2'-Dichloro-N-methyl diethylamine, CsHIIC12NO- HCI H20 Takeda N-oxide hydrochloride Uracil mustard 5-[Bis(2-chloroethyl) amino]uracil CsHI~CI~N~O2 5% EtOH- Up john saline Amethopterin 4-amino-N l~ C20H2..NsO~ ~% NaHCO~ Am. Cyanamid acid Co. 6-Mercaptopurine 6-Purinethiol C~H4N4S Dil. NaOH Burroughs-Well- come * MC = 0.5 per cent methyl cellulo~ solution. Uracil mustard was kindly provided by Dr. John S. Evans, Research Division, Upjohn Co. Amethopterin was obtained from the Lederle Research Div., American Cyanamid Co. The remaining compounds were obtained from the Cancer Chemotherapy National Service Center, National Cancer Inst. The treatment of advanced leukemia was initiated 7-11 provided by Cytoxan, in this experiment, was 97 days following tumor implantation (2-4 days prior to the per cent as great as that observed with ameth- median day of death of untreated controls) when all the mice displayed palpable local tumors. In all cases, when tested, the opterin. The antileukemic action of Cytoxan was disease had become systemic. This was evidenced by the death also reflected in an inhibitory effect on the growth from tumor of normal mice given implants subcutaneously of of the local tumor at the site of leukemic inocula- spleens from mice selected at random from those to be treated tion. At the optimal dose, the local tumor, ap- (18). The treatment of early leukemia was initiated two days proximately 7-9 mm. in diameter, was non- following tumor implantation. The compounds employed, their sources, and vehicles are palpable after about 1 week of treatment. Relative listed in Table 1. They were administered subcutaneously in to amethopterin, employed as a standard, Cytoxan the axillary area in the constant volume of 0.01 ml/gm of displayed greater antileukemic activity than did mouse weight. Each compound was administered over a wide any of the other alkylating agents tested. Uracil range of doses. There were usually ten mice at each dose level and twenty untreated controls. The experimental design, in- mustard, in one of two experiments (Table 2, Exp. cluding dosages and schedules of treatment, is indicated in the 2), appeared to be next in effectiveness among the individual experiments. alkylating agents, producing an increase in Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1959 American Association for Cancer Research. 988 Cancer Research Vol.
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