The objective of this research is to define a molecular basis for the cytotoxicity of bleamycin. Several lines of evidence suggest that DNA strand scission alone may not account for the cytotoxic effects of this important antitumor agent. An important clue has recently been provided by the identification of several nucleoside base N-propenals produced by the action of bleamycin on DNA. These unsaturated aldehydes are highly cytotoxic to tumor cells in culture and inhibit DNA synthesis. The proposed research tests a novel hypothesis that base propenals produced by the action of bleamycin on nuclear DNA inhibit critical cellular processes, thereby accounting for the cytostatic and cytotoxic properties of this drug. Additional experiments have been designed to define the molecular basis by which bleamycin produces single and double strand breaks in DNA, to explore chemical mechanism(s) responsible for DNA degradation, and to characterize adducts formed between base propenals and DNA. Cytotoxicity reflects the chemotherapeutic potential of bleamycin and underlies its principal side effect, pulmonary fibrosis. The studies proposed are directly relevant to cancer chemotherapy and have implications for the development of new analogs of bleamycin. This research should also help to illuminate radical mechanisms involved in degradation of DNA by other drugs, chemicals, and gamma-irradiation.
