cetrorelix and Pancreatic-Neoplasms

Nude mice bearing xenografts of the MIA PaCa-2 human pancreatic cancer cell line were treated with sustained-release formulations (microcapsules) of luteinizing hormone releasing hormone (LH-RH) agonist [D-Trp6]-LH-RH, somatostatin analogue RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2), or combination of both analogues. Other groups of mice received daily subcutaneous injections of LH-RH antagonist SB-75 [Ac-D-Nal(2)',D- Phe(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10-LH-RH] or bombesin antagonist RC-3095. At necropsy, in mice given microcapsules releasing 25 micrograms/day of [D-Trp6]-LH-RH, tumor weight and volume were decreased, but not significantly, as compared with control mice. Microcapsules of RC-160, releasing 25 micrograms/day, significantly reduced tumor volume, percentage change in tumor volume, and tumor weight. Combination of RC-160 and [D-Trp6]-LH-RH inhibited tumor growth to a somewhat greater extent than RC-160 alone. Bombesin antagonist RC-3095, at a dose of 25 micrograms/day, did not influence the growth of tumors. In mice receiving 100 micrograms/day of antagonist SB-75, there was a significant decrease in tumor weight and volume and a significant reduction in the weight of ovaries and uteri. Specific binding of [125I]RC-160 and [125I][D-Trp6]-LH-RH, but not [125I]Tyr4-bombesin, was found on MIA PaCa-2 cells in culture. [D-Trp6]-LH-RH, SB-75, and RC-160 inhibited the growth of MIA PaCa-2 cells in vitro. Neither bombesin nor RC-3095 influenced the growth of MIA PaCa-2 cells in cultures. The results indicate that the LH-RH antagonist SB-75 could be tried for treatment of pancreatic cancer. Our findings confirm the efficacy of somatostatin analogue RC-160 in inhibiting the growth of pancreatic cancers and suggest that the combination of RC-160 and agonist [D-Trp6]-LH-RH might possibly increase the therapeutic response.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Binding Sites; Delayed-Action Preparations; Drug Therapy, Combination; Female; Gonadotropin-Releasing Hormone; Humans; Male; Mice; Mice, Nude; Molecular Sequence Data; Neoplasm Transplantation; Pancreatic Neoplasms; Somatostatin; Transplantation, Heterologous; Triptorelin Pamoate

Ductal pancreatic cancers were induced with N-nitrosobis(2-oxopropyl)amine (BOP) in female Syrian golden hamsters. The animals were then treated for 2 months with 5-fluorouracil (5-FU) and with sustained delivery systems of the LH-RH agonist D-Trp-6-LH-RH antagonist (Ac-D-Nal(2)'-D-Phe(4Cl)2-D-Pal(3)3-D-Cit6,D-Ala10)LH- RH(SB-75) and somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160), and with some combinations thereof. In the first experiment, the treatment with D-Trp-6-LH-RH plus 5-FU resulted in 52% inhibition of tumorous pancreas weight, a smaller number of tumor nodules on histology, a marked increase of programmed cell death (apoptosis) and a reduced number of AgNOR (argyrophilic nucleolar organizer region) in tumor cells, as compared with controls. The inhibitory effects of this combination were greater than those obtained with 5-FU and D-Trp-6-LH-RH treatment alone. In the 2nd experiment, a 76% inhibition of tumorous pancreas weight, a significant decrease in the number of tumor nodules, an increased amount of stroma, enhanced apoptosis and decreased AgNORs were observed after therapy with somatostatin analog RC-160 plus 5-FU. Most of these tumor inhibition parameters were superior to those in the group treated with 5-FU alone, and in some cases slightly better than those treated with RC-160 alone. Both LH-RH antagonist SB-75 and somatostatin analog RC-160 caused a significant inhibition of tumors, and their combination had the strongest tumor inhibitory effect, with the best survival of animals, the lowest tumorous pancreas weight and the highest apoptosis index among groups. Our results suggest that the combinations of LH-RH analogs with somatostatin analogs or of either type of analog with 5-FU may be superior to single agents in the therapy of pancreatic cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinogens; Cricetinae; Drug Screening Assays, Antitumor; Female; Fluorouracil; Gonadotropin-Releasing Hormone; Mesocricetus; Nitrosamines; Organ Size; Pancreatic Neoplasms; Pyrrolidonecarboxylic Acid; Somatostatin

Groups of 15 female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers were treated for 2 mo with microcapsules of the luteinizing hormone-releasing hormone (LH-RH) antagonist [Ac-D-Nal(2)1-D-Phe(4Cl)2-D-Pal(3)3,D-Cit6,D-Ala10] LH-RH (SB-75) releasing 8 micrograms/day or with the microcapsules of the LH-RH agonist D-tryptophan-6-luteinizing hormone-releasing hormone (D-Trp-6-LH-RH) releasing 8 micrograms/day or 25 micrograms/day. Chronic treatment with SB-75 resulted in 70% inhibition of pancreatic tumor weight; D-Trp-6-LH-RH in doses of 8 micrograms/day and 25 micrograms/day produced 66% and 62% inhibition, respectively. The number of animals with pancreatic tumors was reduced by about 50% in each treated group. Tumorous ascites were found in seven control hamsters and in one hamster in each group treated with D-Trp-6-LH-RH but not in the group given SB-75. Reduction in serum luteinizing hormone levels and ovarian as well as uterine weights indicated that an inhibition of the pituitary-gonadal axis occurred during chronic SB-75 and D-Trp-6-LH-RH treatment. Membrane receptor assays showed a significant decrease of the concentration of binding sites for LH-RH in tumor cells after SB-75 or D-Trp-6-LH-RH treatment. Insulin-like growth factor I receptors, but not epidermal growth factor receptors, were down-regulated by D-Trp-6-LH-RH. SB-75 did not influence the concentration or the binding capacity of insulin-like growth factor I and epidermal growth factor receptors in the tumor cells. The inhibitory effect of chronic treatment with SB-75 and D-Trp-6-LH-RH on tumor growth was mediated by enhanced apoptosis (programmed cell death) induced by the change in hormonal environment. Apoptosis was also produced in hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers by acute treatment (3 to 6 days) with high doses of D-Trp-6-LH-RH or SB-75. In view of its potency and an immediate powerful inhibitory effect, the LH-RH antagonist SB-75 might be considered as a possible new hormonal agent for the treatment of exocrine pancreatic cancer.

Topics: Animals; Antineoplastic Agents; Cricetinae; Female; Gonadotropin-Releasing Hormone; Mesocricetus; Nitrosamines; Pancreatic Neoplasms; Receptors, Cell Surface; Receptors, LH; Receptors, Somatomedin; Remission Induction; Triptorelin Pamoate