TUMOR CELL KINETICS AND S-PHASE SENSITIZATION

越来越多的实验室和临床证据表明， 许多常见的实体瘤是快速的， 可能会降低局部控制和生存率。 临床 改善快速增殖人类肿瘤中肿瘤反应的策略 使用S期特异性放射和化学增敏剂，如 卤代嘧啶类似物（IUdR、BudR、BudR、FudR、FU）和 嘧啶酮类似物（IPdR，FRdR）。 这些药物被服用， 仅由合成DNA的细胞代谢，从而增加肿瘤 增殖应导致放射增敏性增加， 化学增敏 然而，S期特异性药物摄取的邻近 和/或剂量限制的正常组织可能限制治疗增益。 尽管如此，最近有越来越多的阳性临床 在几种不同的常见肿瘤中使用这些S期 致敏剂，表明达到了临床致敏作用，尽管 通常伴随局部和全身毒性增加。 尽管有这些 令人印象深刻的临床数据，这些药物辐射的基本机制， 药物间的相互作用还知之甚少。 我们的实验数据表明，胸苷类似物（IUdR，BUdR）可以 显著增加初始辐射损伤，而尿苷类似物 (FU，FUdR）可以改变细胞动力学和脱氧核苷酸池， 对辐射损伤的影响。 因此，虽然两组 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， 化疗敏感性不同。 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 在体外和体内，目的是最大化治疗效果， 在未来的临床试验中取得进展。 嘧啶酮类似物也将是 在体内研究。 这些研究的总体目标仍然是：1） 检查放射性和放射性的细胞和分子机制 卤代嘧啶及其相关化合物对人体的化学增敏作用 结直肠癌和膀胱癌细胞; 2）生化检查 调节胸苷代谢的关键酶[包括 胸苷激酶（TK）和胸苷酸合成酶（TS）]，以增强放射性- 和/或S期敏化剂的化学增敏作用， 膀胱癌细胞;和3）在体外/体内检查改变 体内细胞动力学和药物摄取肿瘤和剂量限制性正常组织 为了提高各种治疗方案后的治疗效果 卤代嘧啶和相关化合物。 关闭生物统计 要实现这些目标，就必须开展合作。

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.