ENDOGENOUS OPIOID MODULATION OF HUMAN PANCREATIC CANCER

胰腺癌是癌症相关死亡的第四大原因， 美国对该病的起源、发病机制或治疗知之甚少。 这个肿瘤阿片样物质生长因子（OGF），[Met 5]-脑啡肽，是一种 特别靶向细胞的天然抑制肽 增殖性事件OGF对细胞生长的抑制活性是 由zeta阿片受体介导。CCF是一个负增长因素， 胰腺癌在体外和体内，阻断OGF的作用， 强效阿片拮抗剂纳洛酮增加胰腺癌细胞 增殖，表明OGF的紧张活性。OGF和zeta 受体在胰腺肿瘤细胞中。这项补助金假设， 天然阿片肽抑制人胰腺癌的生长，和 是通过一种独特的阿片受体实现的为了验证这个假设，我们 建议：（l）研究内源性阿片类药物的细胞机制 对人胰腺肿瘤细胞功能的作用，包括DNA合成 和细胞周期。(2)研究自分泌生产的 阿片肽与人胰腺癌生长相关。(3)定义 阿片肽-受体相互作用的调节特性 人类胰腺癌细胞。 (4)克隆并测序 zeta阿片受体在人类胰腺肿瘤，并阐明 使用过表达研究这种受体的功能。(5)了解 内源性阿片活性的机制，关于发病率 和裸鼠异种移植物中人胰腺肿瘤的生长。这些 研究将有助于理解人类癌症的生物学， 可能为胰腺癌的治疗策略提供线索。 肿瘤形成从拟议的调查中获得的信息将 第一个发现天然抑制物质及其受体 调节胰腺癌的基因这项研究是一项 细胞和分子肿瘤学的长期计划，旨在 定义了人类胰腺癌的基本原理。

Pancreatic cancer is the 4th leading cause of cancer-related deaths in the U.S. Little is known about the origin, pathogenesis, or treatment of this neoplasia. The opioid growth factor (OGF), [Met5]-enkephalin, is a native inhibitory peptide that is particularly targeted to cell proliferative events. The repressive activity of OGF on cell growth is mediated by the zeta opioid receptor. CCF is a negative growth factor in pancreatic cancer both in vitro and in vivo, Blockade of OGF action by the potent opioid antagonist naltrexone increases pancreatic cancer cell proliferation, indicating the tonic activity of OGF. Both OGF and zeta receptor are in pancreatic tumor cells. This grant hypothesizes that a native opioid peptide inhibits the growth of human pancreatic cancer, and does so through a unique opioid receptor. To test this hypothesis, we propose to: (l) Examine the cellular mechanisms of endogenous opioid action on human pancreatic tumor cell function, including DNA synthesis and the cell cycle. (2) Investigate the autocrine production of the opioid peptide related to growth of human pancreatic cancer. (3) Define the regulatory properties of opioid peptide-receptor interaction with respect to human pancreatic cancer cells. (4) Clone and sequence the zeta opioid receptor in human pancreatic neoplasia, and elucidate the function of this receptor using overexpression studies. (5) Learn about the mechanisms of endogenous opioid activity with regard to the incidence and growth of human pancreatic tumors from xenografts in nude mice. These studies will contribute to comprehending the biology of human cancer, and may provide clues to strategies for the treatment of pancreatic neoplasia. Information derived from the proposed investigation would be the first to identify a natural inhibitory substance and its receptor that serve to regulate pancreatic cancer. This research is part of a long-range program in cellular and molecular oncology which seeks to define the fundamental principles underlying pancreatic cancer in humans.