The objective of this research is to determine the role of DNA damage and repair in the cell cycle phase-dependent cytotoxicity of anticancer drugs. These studies will take advantage of new technology developed in the areas of tumor cell synchronization (centrifugal elutriation) and detection of DNA damage in tissues (alkaline elution) thus allowing investigations to be conducted both in vitro and in vivo. While it is generally thought that many of the anticancer drugs in current use, including the alkylating agents, antitutmor antibiotics, and DNA intercalating drugs, have DNA as their principal molecular target in the cell, it will be necessary to test this hypothesis for many of these agents. We also propose to determine whether the DNA damage made by such drugs is susceptible to cellular DNA mechanisms and whether the action of repair contributes to cell survival. This aspect of the research will take advantage of the recently available repair-deficient mutants isolated from cultured mammalian cells. Finally, we intend to try to relate the findings from the basic studies above to the situation in an animal being treated with the antitumor agent by measuring the pharmacokinetics of the drug in the various animal's normal and tumor tissues in terms of the DNA damage produced and repair of that damage as a function of time following treatment. This information should greatly add to our understanding of the basic cellular and molecular mechanisms responsible for various aspects of cancer chemotherapy.
