TUMOR CELL KINETICS AND S-PHASE SENSITIZATION

越来越多的实验室和临床证据表明，增殖 许多常见的实体肿瘤是快速的，而且肿瘤细胞的增殖 治疗期间可能会降低局部控制率和存活率。一家诊所 改善快速增殖的人类肿瘤对肿瘤反应的策略 使用的是S相特定的放化疗增敏剂等 卤代嘧啶类似物(IUdR、BUDR、BUDR、FUDR、FU)和 嘧啶酮类似物(IPdR，FRdR)。这些药物被吸食后 仅由合成DNA的细胞代谢，从而增加肿瘤 核扩散应导致放射增敏和 化学增敏。然而，S期的特异性药物摄取被邻近 和/或限制剂量的正常组织可能会限制治疗收益。 然而，最近呈阳性的临床病例越来越多。 应用这些S时相在几种常见肿瘤中的试验 致敏剂，表明临床致敏是实现的，尽管 通常会增加局部和全身毒性。尽管如此， 令人印象深刻的临床数据，这些药物辐射的基本机制 而药物与药物之间的相互作用也鲜为人知。 我们的实验数据表明，胸腺嘧啶核苷类似物(IUdR，BUDR)可以 显著增加初始辐射损伤，而尿苷类似物 (FU，FUDR)可通过以下途径改变细胞动力学和脱氧核苷酸库 对辐射损害的后续影响。因此，虽然有两组 卤代嘧啶具有相似的代谢途径，细胞和 放射增敏的分子机制及其可能 化学增敏作用似乎有所不同。我们建议进一步调查 两组嘧啶类似物在两个相关的人类肿瘤系统中的作用 在体外和体内，目标是最大限度地提高治疗效果 在未来的临床试验中取得进展。嘧啶酮类似物也将是 在体内进行了研究。 这些研究的总体目标仍然是：1) 放射性核素细胞和分子机制的研究 卤代嘧啶类化合物对人体的化学增敏作用 结直肠癌和膀胱癌细胞；2)生化检测 调节胸腺嘧啶核苷代谢的关键酶[包括 胸苷激酶(TK)和胸苷酸合酶(TS)]来增强放射性 和/或S相敏剂对人结直肠癌和结肠癌的增敏作用 膀胱癌细胞；3)体外/体内改变的检查 活体细胞动力学与药物摄取肿瘤及剂量受限的正常组织 在不同的治疗方案下提高治疗收益 含卤代嘧啶及相关化合物。近距离生物统计学 要实现这些目标，协作是必要的。

Increasing laboratory and clinically evidence suggests that proliferation of many common solid tumors is rapid and that tumor cell proliferation during treatment may decrease local control and survival. A clinical strategy to improve tumor response in rapidly proliferating human tumors is use S-phase specific radio- and chemosensitizers such as the halogenated pyrimidine analogs (IUdR, BudR, BudR, FudR, FU) and pyrimidinone analogs (IPdR, FRdR). These drugs are taken up and metabolized only by cells synthesizing DNA so that increased tumor proliferation should result in increased radiosensitization and chemosensitization. However, S-phase specific drug uptake by adjacent and/or dose-limiting normal tissue could limit the therapeutic gain. Nevertheless, there are an increasing number of recent positive clinical trials in several different common tumors using these S-phase sensitizers, suggesting clinical sensitization was achieved although usually with increased local and systemic toxicities. In spite of these impressive clinical data, the basic mechanisms of these drug-radiation and drug-drug interactions are poorly understood. Our experimental data suggest that the thymidine analogs (IUdR,BUdR) can significantly increase initial radiation damage while the uridine analogs (FU,FUdR) can alter cell kinetics and deoxynucleotides pools with consequent effects on radiation damage. Thus, while 2 groups of halogenated pyrimidine share similar metabolic pathways, the cellular and molecular mechanisms of radiosensitization and probably chemosensitization appear different. We propose to further investigate both groups of pyrimidine analogs in two relevant human tumor systems both in vitro and in vivo with the goal of maximizing the therapeutic gain in future clinical trials. The pyrimidinone analogs will also be studied in vivo. The overall objectives of these studies continue to be: 1) The examination of cellular and molecular mechanisms of radio-and chemosensitization by the halopyrimidines and related compounds in human colorectal and bladder cancer cells; 2) The examination of biochemical modulation of the key enzymes of thymidine metabolism [including thymidine kinase (TK) and thymidylate synthase (TS)] to enhance radio- and/or chemosensitization by S-phase sensitizers in human colorectal and bladder cancer cells; and 3) The examination of alterations in vitro/in vivo cell kinetics and drug uptake tumor and dose-limiting normal tissues to enhance the therapeutic gain following various treatment schedules with halopyrimidines and related compounds. Close biostatistical collaboration is necessary to realize these objectives.