HYPOTHALAMIC HORMONES IN PANCREATIC CANCER

下丘脑激素生长抑素和促黄体生成素类似物 促性腺激素释放激素（LH-RH）单独或联合给药 将在移植腺泡的大鼠和仓鼠模型中进行测试， 胰腺导管癌和荷人胰腺癌的裸鼠或大鼠 胰腺癌细胞系，例如SW-1990、C0L0 357、PANC-1、RWP-1、 1和2，CAPAN-2和Mia PaCa-2。 亚硝胺仓鼠 （B.O.P.）─也将使用诱导的胰腺肿瘤。 我们的研究 将包括：1）胰腺肿瘤生长的研究 抑制诱导：（a）新的生长抑素类似物的D-Phe- 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-共-乙交酯）中的制剂 （pLGA）连续递送30天。 其中超过300个 合成了一些生长抑素类似物，如RC-160和 RC-121具有超活性并显示抗肿瘤活性，（B） 在pLGA中的激动剂D-Trp-6-LH-RH的微胶囊，（c） 生长抑素类似物微胶囊与D-Trp- 6-LH-RH，（d）生长抑素类似物或D-Trp- 6-LH-RH微胶囊与化疗剂，例如 异环磷酰胺、丝裂霉素C和顺铂; p-C1-Phe-1，2，D-Trp-3，D-Arg-6，D-Ala-10-LH-RH（拮抗剂I），或 另一种拮抗剂与其他药剂组合; 2） 生长抑素直接抗增殖作用研究 在组织中的各种胰腺癌细胞系上的类似物 可通过抑制生长因子介导的培养物 如IGF-1和EGF; 3）评估各种 G.I.激素（促胰液素、胃泌素和CCK）和生长因子，例如 EGF对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 胰腺肿瘤中磷酸化的表达及其对肿瘤生物学行为的评价 生长抑素、CCK、胃泌素IGF-1和EGF的膜受体。 5)含细胞生长抑制自由基的生长抑素类似物的合成 例如美法仑、氮丙啶、丝裂霉素C，以及它们在 作为靶向激素载体的胰腺癌模型， 化疗药物; 6）详细的组织学评价， 7）方法1 - 6也将在人结肠上进行试验 腺癌细胞系，例如COLO 320，因为 抑制可以是类似的。 该项目的目的是 开发一种治疗胰腺癌敏感性胰腺炎的方法， 基于各种生长抑素类似物的癌症和结肠癌， LH-RH类似物单独或联合给药，并评价其对人的免疫功能的影响。 具有细胞抑制自由基的生长抑素类似物对于 抑制这些肿瘤。

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.