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The Relationship between Metabolism, DNA Binding, and Carcinogenicity of 15,16-Dihydro-11-methylcyclopenta[a]phenanthren-17-one in the Presence of a Microsomal Enzyme Inhibitor

Chemistry Department, Imperial Cancer Research Fund Laboratories, Lincoln's Inn Fields, London WC2A 3PX, England

The mean latent period for skin tumor production by the carcinogen 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one (Compound IVb) in the mouse was 30 weeks for a dose of 60 µg/week and about 45 weeks for 60 µg/week, while at 0.6 µg/week, no tumors were observed during 100 weeks. Simultaneous administration of the closely related noncarcinogen (IVa) (54 µg/week) together with the carcinogen at 60 µg/week had no effect on the mean latent period. Simultaneous administration of a threefold quantity of the microsomal enzyme inhibitor 7,8-benzoflavone (I) with the carcinogen at the highest dose increased the mean latent period to 38 weeks, while at the intermediate dose it completely suppressed tumor formation.

Neither ketone IVa nor IVb bound covalently to calf thymus DNA in vitro without prior metabolic activation. After incubation with rat liver microsomes and NADPH in the presence of air, both ketones bound covalently to added DNA in vitro, the noncarcinogen (IVa) about four times more extensively than the carcinogen (IVb), roughly in proportion to the overall extents to which these ketones were metabolized. In contrast, overall metabolism of the carcinogen (IVb) was somewhat increased by the addition of a threefold quantity of the inhibitor (I) to the incubation mixture, but binding to added DNA was almost completely prevented.

These results are discussed in connection with the hypothesis that cellular DNA is the target of the carcinogen (IVb) for tumor initiation.

¹ Recipient of a research bursary from the Imperial Cancer Research Fund. Present address: Metabolic Studies Laboratory, G. D. Searle & Co. Ltd., Lane End Road, High Wycombe, Bucks HP12 4HL, England.

Received 6/17/74. Accepted 10/14/74.