We plan to continue our efforts to elucidate the molecular mechanisms whereby certain selective antitumor antibiotic inhibitors of nucleic acid synthesis and function act. We expect that this work will not only contribute to our understanding of how anticancer drugs work, but will lead to the development of agents with greater selectivity for neoplastic cells and lowered toxicity for the host. An important by-product of such studies will be the development of new tools for the study of the biological processes involved in gene synthesis, expression and maintenance of integrity. We shall be concerned with the basis of action of members (neocarzinostatin and auromomycin) of a family of macromolecular (so-called protein antibiotics) antitumor antibiotics. In earlier work, we have established that these agents damage DNA by inducing single-strand breaks in intact mammalian cells and in cell-free systems. We have isolated labile, non-protein chromophores from these antibiotics which account for the biological properties of the holo-antibiotic. Details of the interaction between the chromophore, released from its apoprotein, and DNA will be investigated. In particular, the roles of oxygen and reducing agent in the DNA-damaging reaction and the structural changes in the chromophore involved in its activation will be studied. Evidence for covalent interaction between activated chromophore and DNA will be sought. The possible role of free radicals in the reaction will be clarified. In addition to studying details of the binding of chromophore to its natural carrier molecule, its specific apoprotein, other vehicular forms of the drug, that provide stability to the chromophore, will be investigated. Finally, the steps involved in the uptake of drug by mammalian cells and in the release of chromophore from the apoprotein carrier for its interation with cellular DNA will be elucidated.
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