ANTIFOLATE-INDUCED MISINCORPORATION OF UDR IN HUMAN CELL

抗叶酸，如脂溶性药物美托品(DDMP)，会引起细胞 在药物处理的细胞中积累外源性UDR作为DUMP。转储 累积导致可检测到的dUTP合成和利用 底物，导致DUMP在新的TMP中被错误结合 合成的DNA。用DDMP处理的细胞在产生 大分子DNA和小DNA的积累。这一观察结果可能 是修复导致新合成的DNA断裂的结果 或一个尚未指明的阻碍合成高的进展 分子量DNA。我们建议定义垃圾场的形态 误掺入损伤，并进一步阐明细胞的机制 对转储错误合并以取代TMP的回应。作为这些计划的一部分 调查我们将尝试定义导致倾倒的条件 在几个细胞系和菌株中的错误掺入。我们亦会研究 转储误掺对细胞毒性的直接后果， 诱变和共同致癌。最后，我们将调查是否 抗叶酸诱导转储引起的DNA合成和修复过程 误掺入对有毒和致突变的病毒有协同或拮抗作用 其他DNA交互代理的操作。

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.