ALTERED GENE EXPRESSION IN ALKYLATING AGENT RESISTANT HUMAN COLON CANCER

结肠癌是美国癌症死亡的第二大原因 成年人。虽然还没有病人被治愈，但来自这两个国家的最新数据 和其他机构已经显示出50%的应答率 大剂量烷化剂治疗转移性结肠癌。天气晴朗 进口以通过以下方式更好地了解生化机制 肿瘤最终逃脱了这种疗法。这项调查将 研究四个候选抗病基因在介导小麦赤霉病发生中的作用 结肠癌对大剂量烷化剂的耐药性。这些基因是：突变的 Ras癌基因、金属硫蛋白家族基因、谷胱甘肽转移酶和 MDR-1基因。在模型系统中，这四个基因中的每一个都是 与抗烷基化剂有关。突变型ras基因的转染 部分呼叫线中的癌基因和金属硫蛋白家族基因诱导 对某些烷基化剂的耐受性。两种谷胱甘肽的表达 转移酶和mdr-1基因与烷化剂获得性相关 几种细胞系的药剂耐药性。这四种语言中每一种的表达 基因已经在一些结肠癌中被记录下来。这个项目将 系统地探索这些基因中的每一个对 结肠癌对大剂量马法兰、大剂量马法兰耐药的表达 BCNU，或将马法兰或BCNU与药物相结合的治疗方法 使肿瘤对这些烷化剂敏感。该项目将定义是否 这四种基因在结肠癌中的表达与幼稚 对马法兰和BCNU的抗性或获得性抗性。这个项目将 进一步利用基因转移技术检测这些基因的表达 结肠癌中的基因对马法兰或BCNU具有耐药性。最后，这一点 该项目将识别结肠癌，其中马法兰和BCNU 抗性是由新的机制介导的，而不是由 这四个基因。这些研究将在一种独特的实验室模型中进行 结肠癌呼叫系和裸鼠移植瘤的研究 烷化剂敏感性和天然和后天获得的烷化剂抵抗力。这些 研究将与患者组织中的研究结果相关联 参与大剂量烷化剂治疗慢性前列腺癌的临床研究 转移性结肠癌。因此，这项调查将确定 模型系统中的观测对重要临床的适用性 如何提高人结肠癌对化疗药物的敏感性问题 使用大剂量烷化剂进行治疗。

Colon carcinoma is the second leading cause of cancer death among American adults. While no patients have yet been cured, recent data from both this and other institutions has demonstrated a response rate of 50% in metastatic colon cancer treated with high dose alkylators. It is of clear import to obtain greater understanding of the biochemical mechanisms by which the tumors ultimately elude this therapy. This investigation will examine the role of four candidate resistance genes in mediating the resistance of colon cancer to high dose alkylators. These genes are: mutant ras oncogenes, metallothionein family genes, glutathione transferases, and the mdr 1 gene. In model systems each of these four genes have been associated with resistance to alkylating agents. Transfection of mutant ras oncogenes and metallothionein family genes in selected call lines induce resistance to some alkylating agents. Expression of both glutathione transferases and of the mdr 1 gene correlates with acquisition of alkylator agent resistance in several cell lines. Expression of each of these four genes has been documented in some colon carcinomas. This project will systematically explore the contribution that each of these genes makes to expression in colon cancer of resistance to high dose melphalan, high dose BCNU, or treatment combining either melphalan or BCNU with an agent to sensitize tumors to these alkylators. This project will define whether expression in colon cancer of these four genes correlates with either naive resistance or acquired resistance to melphalan and BCNU. This project will further use gene transfer technology to examine whether expression of these genes in colon cancer confers resistance to melphalan or BCNU. Lastly, this project will identify colon carcinomas in which melphalan and BCNU resistance are mediated by novel mechanisms other than those encoded by these four genes. These studies will be done in a unique laboratory model of colon carcinoma call lines and nude mouse xenografts which exhibit alkylator sensitivity and naive and acquired alkylator resistance. These studies will be correlated with findings in tissues from patients participating in a clinical study of high dose alkylator treatment for metastatic colon cancer. This investigation will thus determine the applicability of observations in model systems to the important clinical problem of how to improve the responsiveness of human colon carcinoma to treatment with high dose alkylators.