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 成年人了虽然还没有患者被治愈，但最近的数据显示， 和其他机构的答复率为50%， 用高剂量烷化剂治疗转移性结肠癌。这是明确的 进口，以获得更好的了解生化机制， 肿瘤最终逃避了这种治疗。这次调查将 研究四个候选抗性基因在介导 结肠癌对高剂量烷化剂的抗性。这些基因是：突变体 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被 与对烷化剂的抗性有关。突变ras的转染 癌基因和金属硫蛋白家族基因在选择的细胞系中诱导 对某些烷化剂的抗性。谷胱甘肽的表达 mdr 1基因的转移酶和转移酶与烷化剂的获得相关 在几种细胞系中的药剂抗性。这四种表达方式 在一些结肠癌中已经记录了基因。该项目将 系统地探索这些基因中的每一个对 对高剂量美法仑耐药的结肠癌中的表达，高剂量 BCNU，或将美法仑或BCNU与药剂组合的治疗， 使肿瘤对这些烷化剂敏感。该项目将确定是否 这四个基因在结肠癌中的表达与未治疗的 对美法仑和BCNU的抗性或获得性抗性。该项目将 进一步使用基因转移技术来检测这些基因的表达， 结肠癌中的基因赋予对美法仑或BCNU的抗性。最后这 该项目将确定结肠癌，其中美法仑和BCNU 耐药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个独特的实验室模型中进行 结肠癌细胞系和裸鼠异种移植物的研究表明， 烷化剂敏感性和天然的和获得的烷化剂抗性。这些 研究将与患者组织中的发现相关 参与高剂量烷化剂治疗的临床研究， 转移性结肠癌这项调查将确定 模型系统中的观察结果对重要临床 如何提高人结肠癌对化疗药物的反应性 用高剂量烷基化剂处理。

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.