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.
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