PRECLINICAL AND CLINICAL PHARMACOLOGY/EXPERIMENTAL THERAPEUTICS

事实证明，结直肠癌对大多数化疗药物都是耐药的。 最好的药物是5-氟尿嘧啶(5-FU)。最近的一项荟萃分析 亚叶酸钙调节的5-FU团注与对照的随机临床试验 5-FU单独推注表明，亚叶酸钙的加入导致了一个 患者的应答率大约翻了一番，达到22% 可测量的疾病；然而，中位生存期没有改善：11-12 月份。大多数答复是部分的，不是持久的。因此， 迫切需要创新的策略来改善该病的预后。 结直肠癌和其他腺癌患者发生在 胃肠道。我们正在采取几种方法。首先，我们是 试图通过添加5-FU/亚叶酸来提高5-FU/亚叶酸钙的活性 其他调节剂，如干扰素α和伽马，N- (膦-乙酰基)-L-天冬氨酸，和GM-CSF在临床试验中。我们也是 其他药物与5-FU相互作用的实验室研究 努力确定用于治疗的最佳剂量和药物组合顺序 潜在的临床应用。此外，我们认为识别新的 具有潜在抗腺癌活性的药物 胃肠道是最重要的。我们特别是 对显示出强大的体外活性的新药感兴趣(1C50 24小时暴露等于或小于10微摩尔)和/或在体内 对人结直肠癌细胞株的作用。设计的研究 阐明最佳给药方案和给药机制 这些药物的作用对于促进它们的临床合理使用至关重要。 我们继续对实施第一阶段临床计划感兴趣 将生化或分子终点作为 反映特定制剂的生物活性。我们的终极 目标是开发新的药剂和药物组合，这些药物可能对 恶性肿瘤患者的治疗 胃肠道。这些治疗策略也可能有 在其他上皮性实体肿瘤治疗中的应用 乳腺癌和头颈癌。

Colorectal cancer has proven refractory to most chemotherapeutic agents. The best available agent is 5-fluorouracil (5-FU). A recent meta-analysis of randomized clinical trials of bolus 5-FU modulated by leucovorin versus bolus 5-FU alone indicated that the addition of leucovorin resulted in an approximate doubling of the response rate to 22% in patients with measurable disease; median survival, however, was not improved: 11-12 months. The majority of responses were partial and were not durable. Thus, innovative strategies are crucially needed to improve the prognosis of patients with colorectal cancer and other adenocarcinomas arising in the gastrointestinal tract. We are taking several approaches. First, we are trying to improve the activity of 5-FU/leucovorin through the addition of other modulatory agents such as interferons alpha and gamma, N- (phosphonacetyl)-L-aspartate, and GM-CSF in clinical trials. We are also studying the interaction of other agents with 5-FU in the laboratory in an effort to define optimal doses and sequences of drug combinations for potential clinical use. In addition, we believe the identification of new agents with potential activity against adenocarcinomas of the gastrointestinal tract is of paramount importance. We are particularly interested in new drugs which display potent in vitro activity (1C50 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. We have continuing interest in the implementation of Phase I clinical trials which incorporate biochemical or molecular endpoints as a reflection of the biologic activity of the particular agent. Our ultimate goal is to develop new agents and drug combinations which may be useful in the treatment of patients with malignancies arising in the gastrointestinal tract. These therapeutic strategies may also have application in the treatment of other epithelial solid tumors including breast cancer and head and neck cancer.