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Mutagenicity of Cancer Chemotherapeutic Agents in the Sa/Mone//A/Mi Erosome Test

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Mutagenicity of Cancer Chemotherapeutic Agents in the Sa/Mone//A/Mi Erosome Test [CANCER RESEARCH 37, 2209-2213, July 1977] Mutagenicity of Cancer Chemotherapeutic Agents in the Sa/mon e//a/Mi erosome Test William F. Benedict,1 Mary S. Baker, Lynne Haroun, Edmund Choi, and Bruce N. Ames2 Division ot Hematology-Oncology, Department of Medicine, Childrens Hospital, Los Angeles, California 90027 [W. F. B., M. S. B.¡,and Department oí Biochemistry, University of California, Berkeley, California 94720 ¡L.H., E. C., B. N. A.¡ SUMMARY This study examines several of these agents in the Salmo- ne//a/microsome mutagenesis test system (3-5, 24, 27). Seventeen cancer Chemotherapeutic agents were tested This in vitro test makes use of a set of histidine mutants of S. for their ability to mutate Salmonella typhimurium tester typhimurium for detecting mutagens and a mammalian liver strains in the Sa/moneWa/microsome mutagenicity test. microsomal preparation for converting carcinogens to their There was a high correlation between the mutagenicity and active, mutagenic forms. The test system has been validated carcinogenicity of a given agent. Carcinogens positive in in several recent studies (23-25, 32, 43). the test were Adriamycin, daunomycin, 1-propanol-3,3'-imi- nodimethanesulfonate, cyclophosphamide, isophospha- mide, hycanthone, chlornaphazin, nitrogen mustard, uracil MATERIALS AND METHODS mustard, melphalan, and thio-tepa. Two carcinogens, acti- nomycin D and bleomycin, were not detected as mutagens. Chemicals. The following drugs were obtained from The presumptive noncarcinogen, methotrexate, was nega Harry B. Wood, Drug Development Branch, Division of Can tive in the test. Tilorone and 6-mercaptopurine, tentatively cer Treatment, National Cancer Institute, Bethesda, Md.: classified as noncarcinogens, were mutagenic. The carci actinomycin D, Adriamycin, bleomycin, chlornaphazin, cy nogenicity of c/s-dichlorodiammineplatinum(ll), which was clophosphamide, isophosphamide, 6-mercaptopurine, positive in the test, has not been determined. methotrexate, 1-propanol-3,3'-iminodimethanesulfonate, thio-tepa [tris(1-aziridinyl)phosphine sulfide], and uracil mustard. Melphalan and hycanthone were obtained from INTRODUCTION Richard Adamson, Laboratory of Chemical Pharmacology, National Cancer Institute, Bethesda, Md., and tilorone was A number of short-term assays for screening potential received from Gerald Mayer, Merrell National Laboratories, chemical carcinogens/mutagens have been developed over Cincinnati, Ohio. Daunomycin-HCI was the gift of N. Ba- the last few years. Cancer Chemotherapeutic drugs are one chur, National Institutes of Health, Baltimore, Md. c/s-Di- group of agents that may be particularly suited for examin chlorodiammineplatinum(ll) was purchased from Strem ing the relationship among results from short-term in vitro Chemicals, Danvers, Maine, and nitrogen mustard was pur assays and in vivo carcinogenicity studies and chemical chased from Aldrich Chemical Co., Inc., Milwaukee, Wis. carcinogenesis in man. Several of these agents have been Mutagenesis Assay. Assays were performed as previ ously described (3-5). S. typhimurium tester strains TA1535, tested for their in vivo carcinogenicity, and some are sus TA1537, TA98, and TA100 were utilized (4, 27). The liver S-9 pected of being carcinogenic in man. The continued clinical fraction was prepared from male Sprague-Dawley rats (Hor- use of these agents may lead to further documentation of their carcinogenic potential. Recent studies on the ability of ton Animal Labs, Oakland, Calif.), given injections of various cancer Chemotherapeutic agents to produce mor Aroclor 1254 (Analabs, Inc., North Haven, Conn.) 5 days phological transformation in the C3H/10T/2 clone 8 mouse prior to sacrifice. The drugs were dissolved in water or cell line and rapid chromosomal damage in the A(T,)C1-3 dimethyl sulfoxide and added directly to the top agar at several concentrations ranging from nontoxic to highly cy- hamster cell line (6) have demonstrated that there is a high correlation between the ability of an agent to produce trans totoxic. formation or chromosomal damage and its capacity to be carcinogenic in vivo. RESULTS Chemotherapeutic Drugs Mutagenic in the Salmonella 1 Recipient of Grant CA-14226 from the National Cancer Institute, NIH, and Test. Chart 1 indicates those drugs found positive for muta the Council for Tobacco Research, U.S.A., Inc., and Career Development Award CA-70996 from the National Cancer Institute. To whom requests for genesis in the Salmonella system. In cases where more than reprints should be addressed. 1 strain was reverted by the drug, that strain showing 2 Recipient of Energy Research and Development Administration Contract E (04-3)34, PA156. greatest activity was selected. Strain TA1535, sensitive to Received December 28, 1976; accepted April 15, 1977. chemicals causing base-pair substitutions, is reverted by JULY 1977 2209 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1977 American Association for Cancer Research. D E l-Propanol-3,3'- Cyclophosphomide Isophosphomide iminodimetfiane- sulfonate 0 4 8 10 048 0 800 0 200 400 0 800 1600 G H I J UJ cis-Dichlorodiamine- Hycanthone Chlornaphazin 6-Mercapto- Tilorone platinum purine 0 20 40 20 40 0 10 2O 30 2000 4000 1000 M N K Thio-TEPA 800 . Nitrogen Mustard Uracil Mustard . Melphalan 600 400 200 0 0 20 40 0 40 80 0 200 400 0 400 800 1200 jjg / PLATE Chart 1. Dose-response curves of chemotherapeutic agents. Results shown in C to£,/. and K to N are with strain TA1535; in A.B. and G with strain TA98; m F and H with TA100; and in J with TA1537 S-9 (20 ¿¿I)wasadded for the activation of Chlornaphazin and melphalan: 300 M' were added for the activation of cyclophosphamide and isophosphamide. , without S-9; , with S-9. malphalan, thio-tepa, 1-propanol-3,3'-iminodimethanesul- phosphamide are active only in the presence of the S-9 fonate, and ¡sophosphamide, and (as previously shown) by fraction. nitrogen mustard (2), uracil mustard (Ref. 25; H. Rosen Strain TA100 is the same as TA1535 but contains an R- kranz, personal communication), 6-mercaptopurine (16, factor plasmid (27). As previously reported, this strain is 33), and cyclophosphamide (Ref. 26 and M. Legator, per reverted by c/s-dichlorodiammineplatinum(ll) (29) and sonal communication). [Most of these results have been Chlornaphazin (25). Mutagenic activity with Chlornaphazin quoted in the test validation study (25)]. With the exception was increased in the presence of S-9. of 6-mercaptopurine, a purine analog, these drugs are all As previously shown, Adriamycin (Ref. 25; M. Legator, alkylating agents. The activity of melphalan is increased personal communication), daunomycin (5), and hycanthone approximately 3-fold by incubating in the presence of the (15, 25) revert the frameshift tester strain TA1538 and/or its liver S-9 preparation, while cyclophosphamide and iso R-factor derivative, strain TA98. 2210 CANCER RESEARCH VOL. 37 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1977 American Association for Cancer Research. Mutagenicity of Chemotherapeutic Agents Tilorone at high concentrations (2 mg/plate) reverts the Sa//T7one//a/microsome system. In addition to being carci frameshift tester strain TA1537. nogenic in animal studies, some of the agents are sus Chemotherapeutic Drugs Not Mutagenic in the Salmo pected of being carcinogenic in man. Bladder tumors have nella Test. Actinomycin D, bleomycin, and (as previously been reported in patients receiving long-term treatment shown) methotrexate (16, 28, 48) were not mutagenic in with cyclophosphamide (46) [the urine of patients treated Salmonella. Each drug was tested at several concentrations with cyclophosphamide is mutagenic in Salmonella (28)] over a 100-fold range (actinomycin D, 0.01 to 50 /¿g/plate; and following treatment with Chlornaphazin (45). There is a bleomycin, 0.01 to 1.0 jug/plate; methotrexate, 10 to 1000 marked increase in acute myelogenous leukemia in patients /tg/plate), in which no plate was significantly higher than treated with melphalan for multiple myeloma (37), and sev controls, and no dose response was observed. All 4 tester eral cases of acute myeloblastic leukemia have been re strains were utilized, and each compound was tested both ported in patients receiving thio-tepa for the treatment of in the presence (20 /xl/plate) and absence of S-9. solid tumors (39). It will be important to determine whether Relation between Mutagenesis and Carcinogenesis. the other Chemotherapeutic agents that have been shown to The relationship between the ability of Chemotherapeutic be mutagenic in the Salmonella system also yield a high risk agents to mutate the Salmonella tester strains and their of primary or secondary cancers following exposure to known capacity to produce tumors in vivo is shown in Table these drugs. 1. In general, those agents that mutate the Salmonella tester A few of the carcinogenic cancer Chemotherapeutic strains are also carcinogenic. Only 2 agents, actinomycin D agents are not detected in the Salmonella test. Actinomycin and bleomycin, have been shown to be carcinogenic in vivo D and bleomycin [and also Natulan (Procarbazine) (25)] but were not mutagenic in Salmonella. Tilorone and 6- have not shown any mutagenic activity in the Salmonella mercaptopurine, which are mutagenic in Salmonella, are tester strains thus far. Actinomycin D was not cytotoxic to tentatively classified as noncarcinogens. the Salmonella at a concentration of 10 ¿¿g/plate.There fore, it is likely that little actinomycin D is accumulated
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