BIOLOGY OF ENDOMETRIAL CARCINOMA IN THE NUDE MOUSE MODEL

描述(改编自申请人的摘要)：以前的研究 导致了裸鼠模型的发展 雌激素依赖和非雌激素依赖的研究体系 子宫内膜癌。一系列可移植的子宫内膜癌 具有不同的组织学分级、类固醇受体状态和敏感性 已经确定了荷尔蒙的关系，首席研究员已经 描述了三苯氧胺()在该模型中的“雌激素样”作用 系统。此外，一种利用和联合治疗方案 醋酸甲羟孕酮抑制子宫内膜癌生长的实验研究 在裸鼠身上已经开发出并具有独特功能的本系统 这些肿瘤对孕激素(P)治疗产生抵抗力 类似于子宫内膜癌患者的典型病例。 拟议的研究将利用这一模型系统：1)确定 P介导的肿瘤细胞停滞是否涉及诱导细胞凋亡 在子宫内膜癌细胞中，2)决定是否发生 对P治疗的抵抗涉及孕酮(PR)的下调 或雌激素受体(ER)，3)制定改进的治疗策略 /P联合治疗抑制子宫内膜癌生长 4)诱导低分化腺癌分化。 维甲酸联合5-氮胞苷和内质网转染子宫内膜的实验研究 或PR进入子宫内膜癌细胞作为恢复激素的手段 对内分泌治疗的敏感性和改善反应。有建议说 从这些研究中得出的生物学原理将形成 子宫内膜癌药物治疗战略框架。

DESCRIPTION (Adapted from the applicant's abstract): Previous studies from this laboratory have led to the development of a nude mouse model system for the study of estrogen-dependent and estrogen-independent endometrial cancer. A series of transplantable endometrial carcinomas of differing histologic grade, steroid receptor status and sensitivities to hormones have been established and the principal investigator has described an "estrogen-like" effect of Tamoxifen (TAM) in this model system. Furthermore, a combination therapy regime utilizing TAM and medroxyprogesterone acetate (MPA) to inhibit endometrial cancer growth in the nude mouse has been developed and a unique feature of this system is that these tumors develop resistance to progestin (P) therapy analogous to that typically observed in humans with endometrial cancer. The proposed studies will utilize this model system to: 1) determine whether P-mediated tumor cell arrest involves the induction of apoptosis in endometrial cancer cells, 2) determine whether the development of resistance to P therapy involves the downregulation of progesterone (PR) or estrogen receptor (ER), 3) develop improved treatment strategies for inhibiting endometrial cancer growth by combination TAM/P therapy, and 4) to induce differentiation of poorly differentiated adenocarcinoma of the endometrium with retinoids and 5-azacytidine or by transfecting ER or PR into endometrial carcinoma cells as a means for restoring hormone sensitivity and improving response to endocrine therapy. It is suggested that biological principles derived from these studies will form the framework for drug treatment strategies for endometrial cancer.