The mechanism of cellular action of anticancer bleomycin is being investigated from interrelated studies at cellular and molecular levels, using genetic mutants, molecular cloning, characterizations and sequence analyses, chromatography and spectrophotometry, electrophoretic analyses, enzyme assays, and radiolabeled bleomycin. Over the long term, elucidation of the genetic and biochemical control of cellular responses to an antitumor agent should also improve our understanding of the DNA repair pathways, recovery processes and enzymes important in such responses. One of the long-term goals is to determine which properties of bleomycin group antibiotics correlate with antitumor effectiveness. The important anticancer bleomycins are widely used in combination chemotherapy and radiotherapy and as a single agent. Focusing upon genomic structures in cells, specific aims include determining 1) genetic, molecular and cellular functions in certain mutants genetically altered in their resistance to lethal effects of bleomycins, and 2) nuclear genes and gene products which control chromatin lesions and their repair following the chemical action of bleomycins. These have significant implications for clinical cancer management. The genetic sophistication, molecular flexibility and availability of mutant strains of eucaryotic Saccharomyces cerevisiae permit these studies and technical approaches. The validity of this model is strongly established by the correlation of results between yeast and patient/human/mammalian cells. There are no well-characterized human or other mammalian cell line which are genetically stable, contain a variety of genetic markers and are quantitatively and genetically manipulable like s. cerevisiae.
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