PRECLINICAL AND CLINICAL PHARMACOLOGY/EXPERIMENTAL THERAPEUTICS

结直肠癌已被证明对大多数化疗药物无效。 最好的药物是5-氟尿嘧啶（5-FU）。最近的一项荟萃分析 的随机临床试验， 单独推注5-FU表明加入亚叶酸导致 患者的缓解率约为22%， 可测量的疾病;中位生存期，但是，没有改善：11-12 个月大多数答复是不全面的，而且不持久。因此，在本发明中， 迫切需要创新战略来改善 结直肠癌和其他腺癌患者出现在 胃肠道我们正在采取几种办法。首先，我们 试图通过添加以下物质来提高5-FU/亚叶酸的活性 其它调节剂如干扰素α、干扰素γ，以及， 临床试验中的N-（膦酰乙酰基）-L-酒石酸。我们也 在实验室中研究其他药物与5-FU的相互作用， 努力确定药物组合的最佳剂量和顺序， 潜在的临床应用。此外，我们认为， 具有潜在的抗癌活性的药物 胃肠道是最重要的。我们特别 对显示出有效体外活性的新药感兴趣（1C 50， 小于或等于10微摩尔的24小时暴露）和/或体内 对人结肠直肠癌细胞系的功效。设计的研究 阐明最佳给药方案和机制， 这类药物的作用对于促进其合理的临床应用至关重要。 我们对实施I期临床试验持续感兴趣。 将生化或分子终点作为 反映特定药剂的生物活性;我们的最终 我们的目标是开发新的药物和药物组合， 治疗恶性肿瘤的患者， 胃肠道这些治疗策略也可能具有 在治疗其它上皮实体瘤中的应用， 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 interferon alpha, interferon gamma, and, N-(phosphonacetyl)-L-aspartatic acid 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 less than or equal to 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.