PRECLINICAL AND CLINICAL PHARMACOLOGY/EXPERIMENTAL THERAPEUTICS

结直肠癌已被证明对大多数化疗药物是难治的; 最好的治疗方法是5-氟尿嘧啶（5-FU）， 亚叶酸 对9项随机试验的综合分析表明， 在5-FU中加入亚叶酸， 反应率从13%上升到25%。 大多数答复都是片面的， 不耐用。 因此，尽管5-FU的生物化学调节与 甲酰四氢叶酸已经取得了一些成功，创新策略至关重要， 需要改善结直肠癌患者的预后。 我们 目前的调查集中在两个领域。 首先是 鉴定具有潜在抗 胃肠道腺癌。 特别感兴趣的 是在体外表现出强效活性的新药 (IC50暴露24小时等于或小于10微摩尔）和/或 对人结肠直肠癌细胞系的体内功效。 研究 旨在阐明最佳给药方案， 这些代理人的作用机制是至关重要的，以促进其合理的 临床应用。 第二条调查路线包括相互作用 其他药物与5-FU，试图确定最佳剂量， 用于潜在临床用途的药物组合的序列。 最后我们 正在进行I期临床试验， 除了临床终点外，分子终点也反映了 特定药剂的生物活性。 最终目标是 开发新的药剂和药物组合， 治疗胃肠道和乳腺恶性肿瘤患者。

Colorectal cancer has proven refractory to most chemotherapeutic agents; the best available therapy is 5-fluorouracil (5-FU) modulated with leucovorin. A composite analysis of nine randomized trials indicates that the addition of leucovorin to 5-FU approximately doubles the response rate from 13% to 25%. The majority of responses are partial and not durable. Thus, although biochemical modulation of 5-FU with leucovorin has met with some success, innovative strategies are crucially needed to improve the prognosis of patients with colorectal cancer. Our current investigations focus on two areas. The first is the identification of new agents with potential activity against adenocarcinomas of the gastrointestinal tract. Of particular interest are new drugs which display potent in vitro activity (IC50 for a 24 hour exposure equal to or less than 10 micromoles) and/or in vivo efficacy against human colorectal carcinoma cell lines. Studies designed to elucidate the optimal schedule of administration and mechanism of action of such agents are vital to facilitate their rational clinical use. The second line of investigation includes the interaction of other agents with 5-FU in an attempt to define optimal doses and sequences of drug combinations for potential clinical use. Finally, we are implementing Phase I clinical trials which incorporate biochemical or molecular endpoints in addition to clinical endpoints as a reflection of the biologic activity of the particular agent. The ultimate goal is to develop new agents and drug combinations which may be useful in the treatment of patients with gastrointestinal and breast malignancies.