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Origin and Cytotoxic Properties of Base Propenals Derived from DNA¹

Department of Pharmacological Sciences, State University of New York, Stony Brook, New York 11794

Base propenals arise from DNA by a Fe(II)-bleomycin-mediated reaction which leads to strand scission. These compounds undergo addition-elimination reactions with thiols and other nucleophilic groups under physiological conditions and form an addition product with glutathione. Thymine- and adenine-N¹-propenals inhibit DNA synthesis in HeLa cells; both compounds are cytotoxic [50% inhibiting concentration (IC₅₀) = 1 to 2 µM]. A structurally related nucleoside, thymidine-N³-propenal, designed as a metabolic pathway inhibitor, inhibits growth of HeLa, L1210 leukemia, Lewis lung carcinoma, B16 melanoma, and DLD-1 human colon carcinoma cells in culture (IC₅₀ = 1 to 6 µM). A single injection of this compound, administered on the first day following transplant of L1210 leukemia cells, increased the mean survival time of mice by 50% (T/C = 154). Thymidine-N³-propenal selectively blocks DNA synthesis in HeLa cells and inhibits thymidine kinase (K_i = 5.1 µM) and DNA polymerase-. We suggest that base propenals, rather than damaged DNA, account for some of the cytotoxic effects of bleomycin and that nucleoside propenals represent a novel class of site-directed inhibitors.

¹ This work was supported, in part, by Grant CA17395 from the National Cancer Institute and Grant CH-240 from the American Cancer Society.

² To whom requests for reprints should be addressed.

Received 7/ 9/84. Accepted 11/ 1/84.

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