The long-term goals of this research are characterization of the interaction of bleomycin with DNA and RNA and identification of the specific interactions that are critical to the expression of antitumor activity by bleomycin. For the period of requested support, the specific aims include characterization of the chemistry of RNA cleavage by bleomycin, better definition of the relationship between nucleic acid binding and cleavage, and determination of the mode(s) of nucleic acid binding by bleomycin through the use of appropriate physicochemical techniques, as well as structural analogs of bleomycin. The antitumor agent bleomycin is used clinically as a single agent and, especially in combination chemotherapy for the treatment of a number of neoplasms. Bleomycin is broadly efficacious against squamous cell carcinomas and malignant lymphomas. In spite of the obvious utility and importance of the bleomycins as antitumor agents there are numerous critical ambiguities about its mode of action at chemical and biochemical levels. It is believed that resolution of some of these ambiguities could provide important opportunities for therapeutic gain.
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