trelstar and nitrosobis(2-oxopropyl)amine

LH-RH analogs cause some inhibition of growth of pancreatic cancers. Syrian golden hamsters bearing chemically induced pancreatic cancers were treated with [D-Trp6]LH-RH for 3 d before sacrifice. LH-RH receptors were localized by electron-microscopic immunohistochemistry in the tumor cells of both treated and untreated hamsters. [D-Trp6]LH-RH treatment resulted in a marked increase in the concentration of LH-RH receptors in the nuclei. The dissociation constants (Kd) and the maximal binding capacity of the LH-RH receptors (Bmax), measured by radioreceptor assay, were higher in the nuclei of the pancreatic tumor cells of hamsters treated with [D-Trp6]LH-RH than in the untreated controls. Pancreatic cells of tumor-free hamsters did not show immunostaining for LH-RH receptors. A possible correlation between the increase in the concentration of the LH-RH receptors in the nuclei and the tumor growth-inhibiting activity of [D-Trp6]LH-RH is suggested.

Topics: Animals; Carcinogens; Cell Nucleus; Cricetinae; Female; Immunohistochemistry; Mesocricetus; Microscopy, Immunoelectron; Nitrosamines; Pancreatic Neoplasms; Radioligand Assay; Receptors, LHRH; Triptorelin Pamoate

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

Antitumoral effects of the agonist of luteinizing hormone-releasing hormone (D-Trp-6-LH-RH) and the somatostatin analog RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2) on chemically induced ductal pancreatic adenocarcinomas were studied. The tumors were induced in female Syrian golden hamsters by weekly s.c. injections of N-nitrosobis(2-oxopropyl)amine at a dose of 10 mg/kg b.w. for 6 weeks. 18 weeks after the last injection, the peptides in controlled-release microcapsule formulations were administered s.c. The animals received the following therapies: Group 1 (N = 15), vehicle only; Group 2 (N = 13), D-Trp-6-LH-RH microcapsules releasing 25 micrograms/day injected s.c. once a month; Group 3 (N = 14), RC-160 microcapsules, liberating 25 micrograms/day administered s.c. every 15 days; Group 4 (N = 14), the combination of D-Trp-6-LH-RH plus RC-160 microcapsules. The experiment was terminated on the 80th day when all hamsters in the control group were dead, but in the treated Groups 2, 3, and 4, we observed 71, 77, and 86% of survival rate, respectively. In addition to the prolongation of survival, the combination treatment resulted in a significant decrease in the tumorous pancreatic weight, increase in the body weight of the animals, reduction in ascites from 100 to 8.3% and regressive histological changes in 67% of the specimens. Our findings suggest that somatostatin analogues and D-Trp-6-LH-RH could be considered for the development of hormonal therapy for pancreatic cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capsules; Cricetinae; Female; Gonadotropin-Releasing Hormone; Mesocricetus; Neoplasm Metastasis; Nitrosamines; Organ Size; Pancreatic Neoplasms; Somatostatin; Triptorelin Pamoate

The effect of treatment with D-Trp-6-LH-RH, an agonist of luteinizing hormone-releasing hormone (LHRH), and somatostatin analog RC-160 was studied in male Syrian hamsters with N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic carcinoma. The peptides were administered periodically in long-acting microcapsule formulations designed to release controlled doses and maintain continuous blood levels of these analogs. The treatment lasted 60 d. Eighteen wk after administration of BOP, 80% of the animals developed ductal pancreatic adenocarcinomas, typically in multinodular form. Treatment with D-Trp-6-LH-RH resulted in a significant decrease in the tumorous pancreatic weight, and, in 35% of the specimens, changes indicative of histological regression were seen. Similarly, regressive alterations in the tumorous epithelium could be observed in 28% of the tumors in the RC-160 treated group. This regression was not accompanied by accumulation of lymphoid cells and only the epithelial components of the tumors were involved. These data indicate that the analogs D-Trp-6-LH-RH and RC-160 exert antitumoral effects on the experimentally-induced pancreatic cancer. It is unlikely that immunological mechanisms are involved in this response. These inhibitory effects on tumor growth could be mediated by creating a state of sex hormone deprivation of D-Trp-6-LH-RH and by inhibition of the release and/or action of gastrointestinal hormones and growth factors by the somatostatin analog RC-160.

Topics: Animals; Antineoplastic Agents; Capsules; Cricetinae; Epithelium; Gonadotropin-Releasing Hormone; Male; Mesocricetus; Nitrosamines; Pancreas; Pancreatic Neoplasms; Somatostatin; Triptorelin Pamoate

Characteristics of binding sites (dissociation constant: Kd and maximal binding capacity: Bmax) for [D-Trp6]-luteinizing hormone-releasing hormone [( D-Trp6]-LH-RH]), somatostatin (SS-14) and epidermal growth factor (EGF) were evaluated in membrane fractions of N-Nitrosobis (2-oxopropyl) amine (BOP)-induced pancreatic adenocarcinoma of hamsters. Intact, normal hamster pancreata did not show any binding sites for [D-Trp6]-LH-RH, but specific [D-Trp6]-LH-RH binding sites with low affinity and high capacity were found after pancreatic cancer was induced with BOP. Membrane binding sites for SS-14 and EGF, with high affinity and low capacity were present, both in normal and cancerous pancreata. Normal hamster pancreatic tissue had significantly higher levels of SS-14 binding sites and lower concentration of EGF binding sites as compared to pancreatic carcinoma. In vivo treatment of hamsters bearing pancreatic cancers with microcapsules of agonist [D-Trp6]-LH-RH and the somatostatin analog RC-160 alone, or in combination, caused histopathological regression of tumors and concomitantly decreased the Kd and Bmax of [D-Trp6]-LH-RH, and increased the Bmax of the SS-14 binding sites. These findings represent the first demonstration of binding sites for [D-Trp6]-LH-RH in pancreatic cancers. Our results also suggest that tumor inhibitory effects of [D-Trp6]-LH-RH and RC-160 in pancreatic cancer could be mediated not only indirectly through suppression of sex-steroids, gastrointestinal hormones and growth factors, but also directly by an action on specific binding sites located on the tumor membranes.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cricetinae; ErbB Receptors; Female; Gonadotropin-Releasing Hormone; Mesocricetus; Nitrosamines; Pancreatic Neoplasms; Receptors, LHRH; Receptors, Neurotransmitter; Receptors, Somatostatin; Somatostatin; Triptorelin Pamoate

Membrane receptors for [D-Trp6]-luteinizing hormone-releasing hormone [( D-Trp6]-LH-RH), somatostatin (SS-14), and epidermal growth factor (EGF) were investigated in experimental N-nitrosobis-(2-oxopropyl)-amine (BOP)-induced pancreatic cancers of hamsters and in specimens of normal human pancreas and human pancreatic cancer obtained from autopsies. Membrane receptors for [D-Trp6]-LH-RH were absent in the pancreas of normal hamsters, but appeared after the carcinoma was induced with BOP. Binding capacity of SS-14 receptors was lower in membranes of BOP-induced pancreatic cancers than in the normal pancreas. In the BOP-induced pancreatic cancers, the receptors were also characterized following in vivo treatment of hamsters with microcapsules of the agonist [D-Trp6]-LH-RH, somatostatin analog RC-160, and the combination of both peptides, which resulted in significant tumor inhibition. Therapy with [D-Trp6]-LH-RH and RC-160, alone or in combination, decreased the binding capacity of receptors for [D-Trp6]-LH-RH, but increased Bmax for SS-14. There were no significant changes in characteristics of the EGF receptor following these therapies. Membranes from human pancreatic cancers showed binding sites for [D-Trp6]-LH-RH, but no binding was detected in normal human pancreas. The presence of receptors for LH-RH in pancreatic tumors of hamster and humans raises the intriguing possibility that LH-RH could be involved in complex interactions that contribute to the appearance of pancreatic cancer. The binding capacity of receptors for SS-14 in human pancreatic cancer membranes was lower, while Bmax for EGF was higher, as compared to normal pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Autopsy; Carcinogens; Cricetinae; ErbB Receptors; Female; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Mesocricetus; Nitrosamines; Pancreatic Neoplasms; Receptors, LHRH; Receptors, Somatotropin; Somatostatin; Triptorelin Pamoate