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Cyanazine is a member of the chloro-s-triazine class of herbicides. Other triazine herbicides have been shown to induce mammary-gland tumors in rats, although the response is unique to the Sprague-Dawley strain. Cyanazine is nongenotoxic. The present study was conducted to evaluate the chronic toxicity and oncogenic potential of cyanazine. Groups of 62 male and female rats were fed diets containing cyanazine at concentrations of 1, 5, 25, or 50 ppm for up to 2 yr. Mean body weight and body weight gain of male and female rats of the 25- and 50-ppm groups were significantly reduced over the course of the study. Food consumption and food efficiency were also reduced in these groups. Survival was not adversely affected in the treatment groups compared to controls. A significant increase in the incidence of masses of the inguinal region was noted among female rats of the 50-ppm group. These masses were correlated with a significant increase in the incidence of female rats with mammary-gland adenocarcinomas and carcinosarcomas. The incidence of rats with malignant mammary-gland tumors was elevated in the 5-, 25-, and 50-ppm groups, although the incidence within the 5-ppm group was within historical controls. There were no other toxicologically significant observations with respect to ophthalmological, clinical laboratory, or pathological evaluations. Under the conditions of this study, the no-observed-adverse-effect level was 5 ppm. Research into the mechanism of action suggests these mammary tumors are mediated through a prolactin mechanism that is thought to be of low relevance to humans.

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The spiro attachment of an epoxide group to a tetrahydropyran ring in the trichothecene mycotoxins has prompted this study of the mutagenicity and alkylation rates of the trichothecene, anguidine, and 5 related model oxaspiro compounds. While the model compounds were weak alkylating agents of 4-(4-nitrobenzyl)pyridine as a test nucleophile, anguidine lacks such activity. Also, while mutagenicity was not established for anguidine in Salmonella TA100, 3 of the oxaspiro compounds were weakly mutagenic and 2 compounds were toxic to the bacteria. The toxicity and mutagenicity of the model compounds are more related to their polarity than to their alkylation rates.

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10 aryl propylene oxides and 6 aryl butylene oxides were synthesized. Dose-mutagenicity relationships were studied for these compounds and for 1,2-epoxybutane, using both the preincubation and plate incorporation Ames tests with Salmonella typhimurium strains TA100 and TA1535. Structure-mutagenicity relationships were further examined by concurrent testing at single doses with the plate incorporation assay in strain TA100. In both series of compounds, mutagenicity showed very correlation to chemical reactivity, molar volume and partition values. However, all compounds were mutagenic in at least one system with the propylene oxides being more mutagenic than the corresponding butylene oxide derivatives. The naphthyl derivatives in each series were the most mutagenic.

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The bulbs of Pancratium littorale collected in Hawaii were found to contain a new phenanthridone biosynthetic product designated pancratistatin (4a) that proved to be effective (38-106% life extension at 0.75-12.5 mg/kg dose levels) against the murine P-388 lymphocytic leukemia. Pancratistatin also markedly inhibited (ED50, 0.01 microgram/ml) growth of the P-388 in vitro cell line and in vivo murine M-5076 ovary sarcoma (53-84% life extension at 0.38-3.0 mg/kg). An X-ray crystal structure determination of pancratistatin monomethyl ether (4c) and a detailed high resolution (400 MHz) nmr study of pancratistatin and its pentaacetate (4b) completed assignment of structure 4a. Companion antineoplastic constituents of P. littorale were found to be narciclasine (2c) and its 7-deoxy derivative (2a). The structure of 7-deoxynarciclasine (2c) was also confirmed by an X-ray crystallographic analysis.

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A series of 5 para-substituted alpha-methylstyrene oxide derivatives have been synthesized and together with alpha-methylstyrene oxide as well as styrene oxide have been studied as to their mutagenicity with the TA100 and TA1535 strains of Salmonella typhimurium. A multiple regression analysis model has been developed which describes the mutagenicity of the alpha-methylstyrene oxides in TA100. An increase in van der Waals volume was the most important variable in the model with greater improvement occurring with inclusion of the Hammett values for the para substituents on the compounds. The alpha-methylstyrene oxides were less active alkylating agents with 4-(p-nitrobenzyl)pyridine than styrene oxide and with pyridine all reactivity was at the beta-epoxide carbon. However all the alpha-methylstyrene oxide derivatives, except for the bromo compound where toxicity was evident, showed mutagenicity values either greater or comparable to that of styrene oxide. These studies would indicate that reactivity at the beta-carbon should also be a factor in describing the mutagenicity of the parent styrene oxide series.

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Amaryllis belladonna bulbs were examined for constituents inhibitory against the murine P-388 lymphocytic leukemia (PS system). Two in vitro active alkaloids, acetylcaranine (2; 9PS ED50 0.23 microgram/ml) and ambelline (3; 9PS ED50 1.6 micrograms/ml), were isolated accompanied by undulatine. However, the non-chiral anhydrolycorinium chloride (5) was found to be the principal antineoplastic (3 PS, 64-69% life extension at dose levels 10 to 20 mg/kg in vivo, ED50 1.4 micrograms/ml in vitro) component. Quaternary chloride 5 has not been located previously among plant or animal biosynthetic products.

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