CLINICAL TRIALS FOR THE TREATMENT OF COLON CANCER

人类结肠癌对大多数化疗药物仍然具有抗药性。这个 该项目的目标是开发和测试以下基本策略 克服结肠癌烷化剂耐药性。我们将进行 生化调节剂的临床试验研究 在对BCNU和BCNU耐药的人结肠癌细胞系中进行的研究 马法兰，它们在体外和体内生长在无菌小鼠身上。烷基化剂 抗药性将通过利用调节一个或多个 以下系统中的一种：吡啶核苷酸池、聚(ADP-核糖) 代谢、硫醇代谢、钙调蛋白代谢多药耐药 和烷基鸟嘌呤烷基转移酶。已演示的调节剂 在实验室的有效性将与体内研究相结合 BCNU和马法兰。最初，我们将确定最大耐受量 以及各调节剂的生化调节量。接下来，我们将结合 固定剂量的调节剂(以达到所需的生化或 药代动力学终点)，并逐渐增加BCNU或 并将决定这两类药物之间的相互作用。 在药代动力学、毒性、生化调节和 抗肿瘤作用。稍后，我们将通过以下方式优化抗结肠癌的效果 将烷化剂升级到需要自体的更高剂量 骨髓抢救。最后，我们将对冒号验证此方法 通过进行第二期和第三期临床试验来治疗癌症。

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.