The long-term objectives of this research are the development of bleomycin analogues having improved antitumor efficacy, and an altered spectrum of antitumor activity. For the period of requested support, the specific aims include the identification of BLM analogues with altered functional properties at a molecular level. Key parameters of function include mode and selectivity of DNA and RNA cleavage, targeting of specific RNAs and resistance to degradation. The antitumor agent bleomycin is used clinically, both as a single agent and in combination chemotherapy for the treatment of several types of cancer. For example, bleomycin is efficacious against squamous cell carcinomas and malignant lymphomas. In spite of the obvious utility and importance of the bleomycins as antitumor agents, there are clear opportunities to alter the molecular behavior of bleomycin, and thereby potentially improve its antitumor efficacy.
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