ANTIFOLATE-INDUCED MISINCORPORATION OF UDR IN HUMAN CELL

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Antifolates, such as the lipid-soluble drug metoprine (DDMP), cause cells to accumulate exogenous UdR as dUMP in drug-treated cells. dUMP accumulation results in detectable dUTP synthesis, and utilization as substrate, leading to misincorporation of dUMP in place of TMP in newly synthesized DNA. Cells treated with DDMP are impaired in production of high molecular weight DNA and accumulate small DNA. This observation may be a consequence of repair-induced fragmentation of newly synthesized DNA or an as yet unspecified block to the progression of synthesis of high molecular weight DNA. We propose to define the morphology of the dUMP misincorporation lesion, and to further delineate the mechanism of cellular response to dUMP misincorporation in place of TMP. As part of these investigations we will attempt to define the conditions that lead to dUMP misincorporation in several cell lines and strains. We will also study the direct consequences of dUMP misincorporation for cell toxicity, mutagenesis, and cocarcinogenesis. Finally, we will investigate whether the process of DNA synthesis and repair caused by antifolate-induced dUMP misincorporation is synergistic or antagonistic to the toxic and mutagenic action of other DNA interactive agents.