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The genetic activity of the structurally similar antitumor antibiotics anthramycin, tomaymycin and sibiromycin was evaluated in the standard Ames Salmonella/microsome mutagenicity assay, a Salmonella typhimurium forward-mutation assay and the micronucleus test. None of the test drugs showed any significant genetic activity in forward or reverse Salmonella mutation assays. The ability of mouse-liver enzymes to produce mutagens from the drugs was examined in the Salmonella reverse-mutation assay and was generally negative. As the concentrations of sibiromycin increased, some activity was detected in the presence of liver S-9 fractions from Aroclor-induced mice. This observation could not be verified at higher concentrations in the reverse-mutation assay due to cytotoxicity, and in the forward-mutation assay due to interference with the selection process by S-9. Cytogenetic evaluation of anthramycin and tomaymycin in the micronucleus test also gave negative results. However, significant increases in the frequency of micronucleated polychromatic erythrocytes were observed in the bone marrow of sibiromycin-treated mice. The results suggest that, except for some possible activity of sibiromycin, these drugs are generally devoid of any marked genetic activity in the test systems employed.

The effects of excision repair and presence of plasmid pKM101 on the mutagenicities and cytotoxicities of the anthracycline derivatives Adriamycin, daunomycin, carminomycin, and 4-demethoxydoxorubicin were examined in strains of Salmonella typhimurium. Plasmid pKM101 has been shown to mediate inducible error-prone repair in S. typhimurium. While the test compounds were shown to produce a range of mutational responses in excision repair defective (uvrB-), pKM101-bearing strains of different his- backgrounds, proficiency in excision repair generally resulted in the elimination of mutagenic responses in all such strains except those that contain the hisG428 site. In the absence of pKM101, only hisD3052 uvrB- strain TA1538 was shown to be sensitive to anthracycline mutagenicity. A suspension (preincubation) test as well as a direct plating test showed that while proficiency in either excision repair (uvr+) or plasmid pKM101 error-prone repair afforded cellular protection against anthracycline cytotoxicity, plasmid-free uvrB- strains were most sensitive to anthracycline cytotoxicity.

The industrial solvent N-methyl-2-pyrrolidinone (NMP) and its hydrolysis product, 4-(methylamino)butanoic acid (N-MeGABA), were examined for mutagenicity and cytotoxicity in the Ames Salmonella/microsome assay. In order to detect a broad range of possible mutagenic endpoints, the following strains were used in the assay: base-pair substitution strains TA100, TA102 and TA104; frameshift strains TA97 and TA98; and repair proficient strains TA2638, UTH8413 and UTH8414. In the standard plate incorporation assay, six log-linear doses of each compound were tested; doses ranged from 0.01 to 1000 mumol/plate for NMP, and 0.01 to 316 mumol/plate for N-MeGABA. Neither compound was detectably mutagenic when tested in the presence and absence of metabolic activation by Aroclor-induced rat liver S9. NMP did show significant responses with strains TA102 and TA104 that were less than two-fold over background, but no clear dose-response relationships were evident. A preincubation modification of the assay was also performed, using strains TA98 and TA104. Mutagenic activity was not observed for NMP, while N-MeGABA showed significant responses with TA104 but dose-related mutagenicity was not established. Preincubation testing revealed both NMP and N-MeGABA to be cytotoxic to the test population of Salmonella at the highest treatment doses.