CLINICAL TRIALS FOR THE TREATMENT OF COLON CANCER

人类结肠癌对大多数化疗药物仍有耐药性。的 本项目的目标是开发和测试基本原理策略， 克服结肠癌烷化剂耐药性。我们会进行 基于结果的生化调节剂的临床试验 在对BCNU耐药的人结肠癌细胞系中进行的研究， 美法仑，其在体外和体内在无胸腺小鼠中生长。烷化剂 通过利用调节一种或多种抗肿瘤活性的试剂 以下系统：吡啶核苷酸池，聚（ADP-核糖） 代谢，巯基代谢，钙调素代谢，多药耐药 和烷基鸟嘌呤烷基转移酶。调节剂显示 在实验室中有效的将在体内研究， 卡努亚和美法仑。首先，我们将确定最大耐受剂量 以及各调节剂的生化调节剂量。接下来，我们将联合收割机 调节剂以固定剂量（以实现所需的生化或 药代动力学终点），BCNU剂量逐渐升高，或 美法仑，并将确定这2类药物的相互作用 在药代动力学、毒性、生化调节和 抗肿瘤作用稍后，我们将优化抗结肠癌效果， 将烷化剂逐步增加到更高的剂量， 骨髓拯救最后，我们将针对冒号验证此方法 通过进行II期和III期临床试验。

Human colon cancer remains resistant to most chemotherapeutic agents. The goal of this Project is to develop and test rationale strategies for overcoming colon cancer alkylating agent resistance. We will conduct clinical trials of biochemical modulating agent based on the results of studies undertaken in human colon cancer cell lines, resistant to BCNU and melphalan, which are grown in vitro and in vivo in athymic mice. Alkylator resistance will be overcome by utilizing agents which modulate one or more of the following systems: pyridine nucleotide pools, poly(ADP-ribose) metabolism, thiol metabolism, calmodulin metabolism multi-drug resistance and of alkylguanine alkyltransferase. Modulating agents demonstrated effective in the laboratory will be studied in vivo in combination with BCNU and melphalan. Initially, we will determine the maximum tolerated dose and biochemical modulating dose of each modulator. Next, we will combine the modulator at a fixed dose (to achieve a desired biochemical or pharmacokinetic endpoint) with progressively higher doses of BCNU or melphalan, and will determine the interaction of these 2 classes of agents in studies of pharmacokinetics, toxicity, biochemical modulation, and anti-tumor effect. Later, we will optimize the anti-colon cancer effect by escalating the alkylating agents to higher doses which require autologous bone marrow rescue. Finally, we will validate this approach for colon cancer by conducting Phase II and III clinical trials.