ORIGIN AND CYTO-TOXIC PROPERTIES OF BASE PROPENALS DERIVED FROM DNA

  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (3) , 1127-1131
Abstract
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) = 1-2 .mu.M]. 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 = 1-6 .mu.M). A single injection of this compound, administered on the 1st 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 (Ki = 5.1 .mu.M) and DNA polymerase-.alpha.. Base propenals, rather than damaged DNA, evidently account for some of the cytotoxic effects of bleomycin. Nucleoside propenals represent a novel class of site-directed inhibitors.