HYPOTHALAMIC HORMONES IN PANCREATIC CANCER

下丘脑激素类似物生长抑素与黄体生成 激素释放激素(LH-RH)单独或联合应用 将在大鼠和仓鼠模型中进行移植的腺泡和 胰腺导管癌及荷人裸鼠或大鼠的实验研究 胰腺癌细胞系，如SW-1990、COLO 357、PANC-1、RWP- 1和2，Capan-2和Mia Paca-2。亚硝胺染毒的仓鼠 (B.O.P.)诱导的胰腺肿瘤也将被使用。我们的研究 将包括：1)胰腺肿瘤生长情况的调查 (A)D-Phe的新的生长抑素类似物-- Cys-Tyr-D-Trp-Lys_Val-Cys-Trp-NH2(RC-160)类和微胶囊 这些类似物在聚(D，L-丙交酯-乙交酯共聚物)中的处方 (PLGA)，连续交付30天。超过300个这样的人 生长抑素类似物的合成和一些，如RC-160和 RC-121，具有超活性和抗肿瘤活性，(B) 激动剂D-色氨酸-6-黄体生成素-RH在PLGA中的微胶囊，(C) 生长抑素类似物微胶囊与D-色氨酸的结合 6-LH-RH，(D)生长抑素类似物或D-Trp- 含化疗药物的6-黄体生成素-RH微囊。 异环磷酰胺、丝裂霉素C和顺铂；e)N-Ac-D-微囊 P-C1-Phe-1，2，D-Trp-3，D-Arg-6，D-Ala-10-Lh-RH(拮抗剂I)，或 另一种与其他药物联合使用的拮抗剂；2) 生长抑素直接抗增殖作用的实验研究 组织中不同胰腺癌细胞系的类似物 可以通过抑制生长因子来调节的培养 如IGF-1和EGF；3)对各种药物的效果进行评估 胃肠激素(促胰液素、胃泌素和CCK)和生长因子，如 EGF对小鼠胰腺外分泌肿瘤生长的促进作用 体内和体外。4)生物化学研究，如蛋白质 胰腺肿瘤中的磷酸化及其对肿瘤的评估 生长抑素、CCK、胃泌素IGF-1和EGF的膜受体。 5)含细胞抑制自由基的生长抑素类似物的合成 如马法兰、氮杂环丙啶、丝裂霉素C等及其在临床中的评价 胰腺癌作为靶向荷尔蒙携带者的模型 化疗药物；6)详细的组织学评价 所有肿瘤；方法1-6也将在人的结肠上试验 腺癌细胞系，如Colo 320，由于其机制 抑制可能是类似的。该项目的目标将是 开发激素敏感型胰腺癌的治疗方法 癌症和结肠癌基于各种生长抑素类似物和 黄体生成素-促性腺激素类似物单独给药或联合给药并评估 生长抑素类似物与细胞抑制自由基对肿瘤的作用 抑制这些肿瘤的生长。

Analogs of hypothalamic hormones somatostatin and luteinizing hormone-releasing hormone (LH-RH) given alone or in combination will be tested in rat and hamster models of transplanted acinar and ductal pancreatic carcinomas and in nude mice or rats bearing human pancreatic cancer cell lines e.g. SW-1990, COLO 357, PANC-1, RWP- 1, and 2, CAPAN-2 and Mia PaCa-2. Hamsters with nitrosamine (B.O.P.)-induced pancreatic tumors will also be used. Our studies will include: 1) the investigation of pancreatic tumor growth inhibition induced by: (a) new somatostatin analogs of the D-Phe- Cys-Tyr-D- Trp-Lys_Val-Cys-Trp-NH2 (RC-160) class and microcapsule formulations of these analogs in poly(D,L-lactide-co-glycolide) (pLGA) for continuous delivery for 30 days. More than 300 of these somatostatin analogs were synthesized and some, such as RC-160 and RC-121, are superactive and show antitumor activity, (b) microcapsules of the agonist D-Trp-6-LH-RH in pLGA, (c) combinations of microcapsules of somatostatin analogs with D-Trp- 6-LH-RH, (d) combination regimens of somatostatin analogs or D-Trp- 6- LH-RH microcapsules with chemotherapeutic agents, e.g. Ifosfamide, Mitomycin C and Cisplatin; e) microcapsules of N-Ac-D- p-C1-Phe-1,2, D-Trp-3,D-Arg-6,D-Ala-10-LH-RH (Antagonist I), or another antagonist in combination with other agents; 2) investigation of direct antiproliferative effect of somatostatin analogs on various pancreatic carcinoma cell lines in tissue cultures which could be mediated by inhibition of growth factors such as IGF-1 and EGF; 3) an evaluation of the effect of various G.I. hormones (secretin, gastrin, and CCK) and growth factors e.g. EGF on the promotion of growth of pancreatic exocrine tumors in vivo and in vitro. 4) Biochemical studies such as the protein phosphorylation in pancreatic tumors and the evaluation of tumor membrane receptors for somatostatin, CCK, gastrin IGF-1 and EGF. 5) Synthesis of somatostatin analogs containing cytostatic radicals such as Melphalan, Aziridine, Mitomycin C and their evaluation in models of pancreatic cancer as targeted hormonal carriers for chemotherapeutic agents; 6) Detailed histological evaluations of all tumors; 7) Approaches 1-6 will be also tried on a human colon adenocarcinoma line e.g. COLO 320, since the mechanism of suppression may be similar. The aim of this project will be to develop a method for the treatment of hormone-sensitive pancreatic cancer and colon cancer based on various somatostatin analogs and LH-RH analogs given alone or in combination and to evaluate the usefulness of somatostatin analogs with cytostatic radicals for the inhibition of these tumors.