The long-term objective of the proposed program of studies of anticancer drugs is to determine their mechanisms of action in vivo, genetic and other toxic effects in mitosis specificities for particular DNA sequences, and cell-phase dependent inhibitory effects. Specific studies of bleomycin are proposed. This proposal describes development of a three-pronged program of studies of agents active in treatments of cancers encompassing investigations of: 1) genetic and other toxic effects in mitosis, 2) elucidation of other modes of action by studies of DNA damage and repair, and by studies of mutant strains, and 3) isolation and characterization of mutants altered in their resistance to cell killing by bleomycin. Proposed studies include determinations of dose-dependent cell killing in normal and mutant strains, relative toxicities, mutagenicities and recombinogenicities, and dose-dependent DNA scissions and their repair in normal and several mutant strains. The program of studies should not only provide knowledge directly applicable to treatments of tumors, it should provide basic science information as well. It is advisable to conduct the proposed comparative studies in eucaryotic cells where organization of the genetic material is akin to higher organisms, yet where the genetic sophistication and molecular flexibility permit such studies. It is hoped the proposed program can eventually be extended to include studies of additional chemotherapeutic agents for cancer. The long-term plan of the program uses the knowledge gained in the precise eucaryotic system to design studies in systems of human tumor or other mammalian cells.
