ENDOGENOUS OPIOID MODULATION OF HUMAN PANCREATIC CANCER

胰腺癌是#年癌症相关死亡的第四大原因。 美国人对该病的起源、发病机制或治疗知之甚少 这个肿瘤。阿片类生长因子(OGF)，脑啡肽，是一种 针对细胞的天然抑制性多肽 增殖性事件。OGF对细胞生长的抑制活性为 由Zeta阿片受体介导。CCF是一个负增长因素 体外和体内胰腺癌，阻断OGF的作用 强效阿片拮抗剂纳曲酮增加胰腺癌细胞 增殖，提示OGF具有补强活性。OGF和Zeta都是 受体存在于胰腺肿瘤细胞中。这笔拨款假设一个 天然阿片肽抑制人胰腺癌生长 这是通过一种独特的阿片受体实现的。为了检验这一假设，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影响，包括DNA合成 以及细胞周期。(2)调查自分泌物的产生 阿片肽与人胰腺癌生长相关。(3)界定 阿片肽-受体相互作用的调节特性 尊重人类胰腺癌细胞。(4)克隆并测序 Zeta阿片受体在人胰腺肿瘤中的表达 利用过表达研究该受体的功能。(5)了解 内源性阿片类药物活性与发病的关系 以及裸鼠移植的人胰腺肿瘤的生长。这些 研究将有助于理解人类癌症的生物学，以及 可能为胰腺癌的治疗策略提供线索 肿瘤。从拟议的调查中获得的信息将是 首次鉴定出一种天然抑制物质及其受体 用来调控胰腺癌。这项研究是 细胞和分子肿瘤学的远程计划，旨在 明确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.