PRECLINICAL AND CLINICAL PHARMACOLOGY/EXPERIMENTAL THERAPEUTICS

临床前和临床药理学/实验治疗

• 批准号: 5201335
• 负责人: J GREM
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5201335
• 关键词: adenocarcinoma; clinical trials; colony stimulating factor; colorectal neoplasms; combination chemotherapy; dosage; drug administration rate /duration; drug interactions; drug screening /evaluation; fluorouracil; gastrointestinal neoplasms; human subject; human therapy evaluation; immunomodulators; interferon alpha; interferon gamma; leucovorin; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; tissue /cell culture

Administration of either fluorouracil (FUra) by protracted infusion or bolus FUra modulated by leucovorin results in response rates of 20%-30% in patients with advanced colorectal cancer is 10-11 months. 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 in clinical trials through the addition of other modulatory agents such as interferon alpha and gamma, and to reduce the toxicity with GM-CSF and alteration of the FUra infusion duration. We are also studying the interaction of other agents with FUra 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 (IC50 for a 24 hour exposure less than or equal to 10 mu M) 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.

氟尿嘧啶(Fura)长期输注或 亚叶酸钙调节的富拉丸剂的应答率为20%-30%。 晚期结直肠癌患者为10-11个月。因此，创新 迫切需要采取策略来改善慢性粒细胞白血病患者的预后 结直肠癌和其他腺癌发生在 胃肠道。我们正在采取几种方法。首先，我们是 在临床试验中努力提高5-FU/亚叶酸钙的活性 通过添加其他调节剂，如干扰素α 并降低GM-CSF的毒性和对小鼠胸腺的影响 富拉输液持续时间。我们也在研究其他人之间的相互作用 与Fura在实验室的试剂一起努力确定最佳剂量 以及潜在临床使用的药物组合序列。在……里面 此外，我们认为发现具有潜力的新代理商 抗胃肠道腺癌的活性是 最重要的是。我们对新药特别感兴趣 显示出强大的体外活性(24小时暴露的IC50小于或 相当于10微米)和/或体内对人结直肠癌的疗效 癌细胞系。旨在阐明最佳时间表的研究 这类机构的管理和行动机制对于 促进其在临床上的合理应用。我们一直有兴趣继续 实施一期临床试验，纳入生化或 作为反映细胞生物学活性的分子终点 特定的代理。我们的最终目标是开发新的药剂和药物 可能在治疗慢性阻塞性肺疾病患者中有用的联合疗法 发生在胃肠道的恶性肿瘤。这些治疗方法 策略也可能应用于其他上皮性病变的治疗 实体瘤包括乳腺癌和头颈癌。