The goals of this research project are: 1) to elucidate the mechanism by which o-phenanthroline (OP) causes degradation of DNA, 2) to determine whether the inhibition of DNA synthesis by OP, seen in cultured mammalian cells, is the result of DNA degradation and 3) to utilize OPA as a model to study the mechanism of action of a variety of structurally more complex antitumor agents which are known to result in DNA fragmentation. Preliminary studies in our laboratory have shown that OP, in the presence of O2, Cu (11) and a reducing agent, causes rapid and extensive degradation of DNA, and that a reduced product of O2, possibly hydroxyl radical, is required for DNA degradation. We plan to elucidate the mechanism of DNA degradation by determining: 1) the requirements for degradation, 2) the binding affinity of OP for DNA, 3) the products of degradation, 4) the cleavage specificty and 5) the stoichiometry of the reaction. We plan to investigate the effects of OP on cultured mammalian cells to determine whether cellular DNA is degraded by OP and whether this accounts for the inhibitory effect of OP on DNA synthesis in cells in culture. Similar experiments will also be carried out with several antitumor agents which are known to result in DNA fragmentation. These include adriamycin, daunorubicin, streptonigrin neocarzinostatin and cis-platinum.