Origin and cytotoxic properties of base propenals derived from DNA.
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 microM]. 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 microM). 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 (Ki = 5.1 microM) and DNA polymerase-alpha. 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.
Grollman
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Takeshita
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Pillai
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Johnson
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000378:metabolism / Q000494:pharmacology*; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009696:Nucleic Acids / Q000096:biosynthesis; D013936:Thymidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors; D013941:Thymine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D009696:Nucleic Acids; D001761:Bleomycin; C044551:3-(thymin-1'-yl)-2-propenal; C044552:3-(3-oxoprop-2-enyl)thymidine; D013937:Thymidine Kinase; D004257:DNA Polymerase II; D005978:Glutathione; D013941:Thymine; D013936:Thymidine