In this proposal, we combine chemical and biochemical approaches to examine fundamental questions relating to the mechanism of action and toxicity of bleomycin. We recently isolated a series of nucleoside base-propenals produced by the action of bleomycin on DNA. These compounds proved highly cytotoxic and resemble bleomycin in their effects on tumor cells in culture. These observations lead to the development of a novel family of structurally-related site-directed inhibitors and suggest the possible involvement of base propenals in the toxic actions of bleomycin. We propose to explore the molecular basis by which bleomycin produces strand-scission in DNA and to define the mechanisms involved in the production of base propenals and free bases which are released during this process. Experiments have been designed to precisely identify products of reactions in which oligonucleotides of defined base sequence are cleaved by bleomycin. The action of """"""""activated"""""""" bleomycin on organic molecules will be utilized to establish chemical mechanisms involved. The reaction of ionizing radiation with DNA, a process which resembles the action of bleomycin, will also be examined. Finally, we propose a series of studies to test the hypothesis that base propenals produced by the action of bleomycin on nuclear DNA account for the cytostatic and cytotoxic properties of the drug. Results of these experiments should contribute to an understanding of radical mechanisms involved in the degradation of DNA by drugs, chemical and gamma-irradiation. They hold potential significance for the design and development of new analogs of bleomycin.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA039663-01
Application #
3178945
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1985-09-30
Project End
1986-11-30
Budget Start
1985-09-30
Budget End
1986-11-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794