GROWTH FACTOR RECEPTOR DIRECTED THERAPY IN CANCER

生长因子及其细胞表面受体对细胞生长至关重要 生长调控。编码EGF、HER-2的一个或多个erb B原癌基因 和HER-3受体被扩增和/或在大约两个- 人类三分之一的乳腺癌。人HER-2受体在人体内的过表达 乳腺癌和卵巢癌与不良预后相关，并可预测 对临床化疗的反应。生长调节回路 参与HER-2/neu受体和自分泌/旁分泌激活 HERG是一种新提纯的配体，被认为可以促进恶性肿瘤的发生。 结合HER-2受体的单抗具有细胞抑制作用 抑制HER-2过表达细胞的生长。新实验室 研究表明，抗受体激活HER-2/neu受体 抗体增强了细胞对药物的敏感性--破坏DNA--而且， 从而最大限度地杀灭肿瘤细胞。人乳腺和卵巢模型的建立 HER-2受体或Heregine过表达和不过表达的肿瘤 已在我们的实验室建立，并将用于研究： *一种新的人源化HER-2/neu单抗的抗癌作用 受体单独及与化疗药物(顺铂)联合应用 和烷化剂)，破坏细胞DNA。临床前数据将是 收集人源化抗体的疗效和治疗方案 用于临床试验的HER-2受体。假设的 抗受体抗体联合应用的治疗优势 将对细胞毒性药物进行测试，旨在优化体内条件 以达到最大的杀细胞效果。此数据是继续运行所必需的 这些药物的临床试验。 HER-2/neu受体或hereglin基因的临床意义 在耐药中的表达。检测HER-2基因在胚胎发生中的作用 对化疗耐药，亲本细胞具有单拷贝，低 HER-2基因和分子工程子代细胞的表达 HER-2基因多拷贝、高表达与亲缘关系的比较 对药物敏感。高表达Heregine基因的肿瘤细胞 也将用于测试自分泌/旁分泌激活的效果 HER-2的药物敏感性。 *DNA修复在协同抗肿瘤作用中的调节作用 抗受体抗体和顺铂。形成和修复的措施 顺铂-DNA加合物和非计划DNA合成将进行 验证DNA修复途径受生长因子影响的假说 受体信号通路。配体或受体过表达的影响 并将其与抗受体抗体进行比较。 这种基本的和翻译的研究方法旨在 继续并支持一种新的治疗方案的临床试验 乳腺癌和卵巢癌。对青枯菌生物学作用的新认识 Hereglin和HER-2受体将被应用于新的策略 靶向和利用表面过表达的生长因子受体 恶性细胞的数量。

Growth factors and their cell surface receptors are crucial for cell growth regulation. One or more erb B proto-oncogenes encoding EGF, HER-2 and HER-3 receptors are amplified and/or overexpressed in about two- thirds of human breast cancers. Overexpression of HER-2 receptor in human breast and ovarian cancer correlates with poor outcome and may predict response to chemotherapy in the clinic. A growth-regulatory circuit involving HER-2/neu receptor and autocrine/paracrine activation by heregulin, a newly-purified ligand, is postulated to advance malignancy. Monoclonal antibodies that bind HER-2 receptors exert a cytostatic effect in suppressing growth of cells with HER-2 overexpression. New laboratory work suggests that activation of HER-2/neu receptors by antireceptor antibody enhances cellular sensitivity to drugs that -damage DNA- and, thereby, maximizes tumor cell killing. Models of human breast and ovarian cancers with and without overexpression of HER-2 receptors or heregulin have been established in our laboratory and will be used to study: * Anticancer effects of a new humanized monoclonal antibody to HER-2/neu receptor alone and in combination with chemotherapeutic drugs (cisplatin and alkylators) that damage cellular DNA. Preclinical data will be collected on efficacy and treatment schedules for a humanized antibody to HER-2 receptor designed for use in clinical trials. The postulated therapeutic advantage of combined therapy with antireceptor antibody and cytotoxic drugs will be tested, with aims to optimize in vivo conditions for maximal cytocidal effects. This data-is required to continue ongoing clinical trials with these agents. * Clinical significance of HER-2/neu receptor or heregulin gene expression in drug resistance. To test the role of HER-2 gene in genesis of chemotherapy resistance, parental cells with single-copy, low expression of HER-2 gene and molecularly-engineered daughter cells with multi-copy, high expression of HER-2 gene will be compared for relative drug sensitivity. Tumor cells engineered for overexpression of heregulin will also be used to test effects of autocrine/paracrine activation of HER-2 on drug sensitivity. * Modulation of DNA repair in synergistic antitumor effects of antireceptor antibody and cisplatin. Measure of the formation and repair of cisplatin-DNA adducts and unscheduled DNA synthesis will be done to test the hypothesis that DNA repair pathways are altered by growth factor receptor signaling pathways. Effects of ligand or receptor overexpression and of antireceptor antibody will be compared. This basic and translational research approach is aimed toward continuation and support of clinical trials of a novel treatment option in breast and ovarian cancer. New knowledge on biologic actions of heregulin and HER-2 receptors will be applied toward new strategies to target and exploit overexpressed growth factor receptors at the surfaces of malignant cells.