trelstar and Pancreatic-Neoplasms

Between 1987 and 1989 we treated 18 patients with advanced pancreatic adenocarcinoma with a long acting LH-RH analogue: triptorelin. Seventeen patients were evaluated. We obtained no objective responses. The median survival time was 4.5 months. The treatment was well tolerated without any major secondary effects. The absence of dosage of hormonal receptors did not allow the selection of hormone sensitive patients. The future study of hormone therapy will analyse the pancreatic hormonal receptors.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Pancreatic Neoplasms; Triptorelin Pamoate

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

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

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Drug Evaluation; Female; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Pancreatic Neoplasms; Triptorelin Pamoate

Analogues of somatostatin (SS) and luteinizing hormone-releasing hormone (LH-RH) activate tyrosine phosphatases in MIA PaCa-2 human pancreatic cancer cell line membranes and inhibit growth. We compared the substrates phosphorylated by epidermal growth factor (EGF) to those dephosphorylated by the SS analogue RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2) and [D-Trp6]LH-RH in cancer cell lines such as MIA PaCa-2 (human pancreatic cancer), HCPC (hamster cheek pouch carcinoma), A-549 (human lung cancer), HT-29 (human colon cancer), and R3230AC (breast cancer). EGF phosphorylated proteins of 170, 65, and 60 kDa and analogues of SS and LH-RH promoted the dephosphorylation of these proteins in MIA PaCa-2 and HCPC cell lines. The EGF receptor is 170 kDa. pp60src (60 kDa) is known to be a substrate for EGF receptor. The LH-RH receptor is also 60 kDa. The effects of RC-160 and [D-Trp6]LH-RH were quantitatively different. Examinations of HT-29, A-549, and R3230AC cancer cell lines revealed no phosphorylation by EGF or dephosphorylation by RC-160 and [D-Trp6]LH-RH. In addition to the 170-, 65-, and 60-kDa proteins, 35-kDa proteins were also phosphorylated in some cancer cell lines. This work demonstrates that analogues of SS and LH-RH can reverse the effects of EGF biochemically as well as functionally.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Autoradiography; Breast Neoplasms; Cell Line; Colonic Neoplasms; Epidermal Growth Factor; Gonadotropin-Releasing Hormone; Humans; Kinetics; Lung Neoplasms; Membrane Proteins; Molecular Sequence Data; Pancreatic Neoplasms; Phosphorus Radioisotopes; Phosphorylation; Protein Kinases; Protein-Tyrosine Kinases; Somatostatin; Triptorelin Pamoate; Tyrosine

Pancreatic cancers overexpress tyrosine kinase and luteinizing hormone-releasing hormone (LH-RH) receptor (LH-RHR)-mediated tyrosine phosphatase. LH-RHR is a 60-kDa protein. One of the substrates of epidermal growth factor (EGF)-stimulated tyrosine kinase activity and LH-RH- and somatostatin-stimulated tyrosine phosphatase activity is also a 60-kDa protein. This suggests the possibility that LH-RHR regulation by tyrosine phosphatase and tyrosine kinase is mediated by (de)phosphorylation of existing LH-RHR. To test this hypothesis, membranes of MIA PaCa-2 cells, a human dedifferentiated pancreatic cancer cell line, were incubated without hormone (control) or with 0.1 microM EGF or somatostatin analogue RC-160 for 1 hr at 4 degrees C to phosphorylate the 60-kDa protein. Competition binding experiments with I125-labeled [D-Trp6]LH-RH by displacement with a nonradioactive ligand showed that the LH-RH binding in 69% of the points was increased by EGF and 85% was decreased by RC-160 compared with controls (n = 61; both significant, P less than 0.001). The specific binding was altered, increasing 50-150% after preincubation with EGF and decreasing 60-70% after RC-160. No change was seen in the binding affinity constant after pretreatment with EGF or RC-160. This shows that phosphorylation regulates binding of LH-RH and may explain the up-regulation by EGF and down-regulation by RC-160 and by LH-RH of the LH-RH response.

Topics: Cell Line; Gonadotropin-Releasing Hormone; Humans; Kinetics; Pancreatic Neoplasms; Phosphorylation; Protein-Tyrosine Kinases; Receptors, LHRH; Somatostatin; Triptorelin Pamoate

Syrian golden hamsters bearing N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic carcinomas were treated for 2 months with the delayed delivery systems of the agonist D-Trp-6-LH-RH (microcapsules releasing 25 micrograms/day for 30 days), the somatostatin analog RC-160 (the microcapsules liberating 48.2 micrograms/day for 30 days), or with the combination of these two analogues. The increase in the dose of RC-160 was possible in view of the lack of toxicity of this analog. This higher dose of RC-160 exerted a greater suppressive effect on pancreatic cancers than the regimens previously used (5-25 micrograms/day). RC-160, D-Trp-6-LH-RH, and their combination reduced the number of pancreatic carcinomas and significantly inhibited tumor growth as compared with the controls. The combination had the strongest tumor-inhibitory effect and reduced tumor weight by 85% as compared with controls. Both the light and electron microscopic analysis of the tumors showed that the inhibitory effect was due to the enhancement of apoptosis (programmed cell death) of tumor cells. Insulin-like growth factor (IGF-I) receptors were detected immunohistochemically in the untreated tumors and their number decreased after the treatment with the analogues. Binding of D-Trp-6-LH-RH and RC-160 to tumor cells was shown immunohistochemically and receptors to these analogues and IGF-I were also determined biochemically by radioligand titration. Treatment with D-Trp-6-LH-RH and RC-160 decreased the binding capacity of receptors for D-Trp-6-LH-RH and IGF-I, producing down-regulation of these receptors. This suggests that pancreatic tumor cells with receptors to these peptides are sensitive to the treatment. This work reinforces the view that the combination of high doses of somatostatin analog RC-160 with LH-RH agonists or antagonists should be considered for the development of a new hormonal therapy for ductal pancreatic cancers.

Topics: Amino Acid Sequence; Animals; Antineoplastic Combined Chemotherapy Protocols; Cricetinae; Cytoplasm; Delayed-Action Preparations; Female; Gonadotropin-Releasing Hormone; Growth Hormone; Insulin-Like Growth Factor I; Luteinizing Hormone; Macrophages; Mesocricetus; Molecular Sequence Data; Necrosis; Pancreatic Neoplasms; Receptors, Cell Surface; Receptors, Somatomedin; Somatostatin; 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

Carcinoma of the exocrine pancreas seems to be sex-hormone sensitive. Administration of agonistic analogs of luteinizing hormone--releasing hormone (LH-RH) creates a state of sex-hormone deficiency. Therapy with D-Trp-6-LH-RH was evaluated in 17 patients with unresectable and biopsy-proven adenocarcinoma of the pancreas (stage IV). Nine patients were male and 8 female, and the median age at diagnosis was 60 years. The majority of patients underwent a gastro-intestinal and biliary bypass. The therapy with D-Trp-6-LH-RH was started 3-31 days after bypass surgery. The analog was given at the dose of 1 mg/day subcutaneously for the first 7 days. Subsequently, the dose was reduced to 100 micrograms/day. One month after the start of the therapy the gonadotropin levels were in subnormal range. This therapy led to clinical improvement, better quality of life and an increase in survival time. The median survival time for all the groups was 7.2 months (men 7.4 months and women 6.9 months). LH-RH agonists appear to decrease pancreatic cancer growth by eliminating the stimulatory effect of sex steroids, and by direct effects on tumors. Further improvement in the clinical response in patients with inoperable pancreatic carcinoma might be possibly obtained by the combination of LH--RH agonists with modern somatostatin analogs.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Pancreatic Neoplasms; Time Factors; Triptorelin Pamoate

Female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amine (BOP)-induced ductal pancreatic cancers were treated with long-acting microcapsular preparations of the 6-D-tryptophan analog of luteinizing hormone-releasing hormone [( D-Trp6]LH-RH), releasing 25 micrograms/day; the somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160), liberating 15 micrograms/day; and the combination of these two peptides. Therapy with analogs was initiated 24 weeks after initial administration of BOP. These treatments resulted in significantly better survival of all animals as compared to BOP controls; body weights of surviving peptide-treated animals were significantly higher than those of the BOP controls. All 15 BOP-control animals had pancreatic cancers. In the group treated with RC-160 four hamsters were free of tumors, whereas therapy with [D-Trp6]LH-RH resulted in seven tumor-free animals, and combination of RC-160 and [D-Trp6]LH-RH resulted in eight tumor-free animals from groups of 15. Only preblastomatous lesions were found in these animals. Average tumor weight of animals in all peptide-treated groups, sacrificed 60 days after beginning the peptide treatment, was significantly lower than that of BOP controls. No significant differences were seen between the various peptide-treated groups. Histologically, analog-treated tumors of hamsters showed striking regressive changes characteristic of programmed cell death (apoptosis). This apoptosis presumably resulted from hormonal effects on tumor cells from prolonged treatment with these analogs of hypothalamic hormones. Our present data confirm the beneficial effect of long-acting microcapsules of [D-Trp6]LH-RH and RC-160 on pancreatic carcinoma and suggest a mode of action for these peptides. The feasibility of applying this treatment with analogs of hypothalamic hormones to human pancreatic carcinoma can be envisioned from these studies.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Survival; Cricetinae; Female; Gonadotropin-Releasing Hormone; Mesocricetus; Pancreatic Neoplasms; Somatostatin; 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

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Capsules; Gonadotropin-Releasing Hormone; Humans; Injections, Intramuscular; Male; Mammary Neoplasms, Experimental; Neoplasms, Hormone-Dependent; Octreotide; Pancreatic Neoplasms; Prostatic Neoplasms; Rats; Somatostatin; Triptorelin Pamoate

Pancreatic ductal adenocarcinoma was induced in female Syrian golden hamsters by injecting N-nitrosobis(2-oxopropyl)amine (BOP) once a week at a dose of 10 mg per kg of body weight for 18 weeks. Hamsters were then treated with somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) or with [6-D-tryptophan]luteinizing hormone-releasing hormone [( D-Trp6]LH-RH) delayed delivery systems. Microcapsules of somatostatin analog RC-160, designed to release a dose of 5 micrograms/day, were injected twice a month and microcapsules of [D-Trp6]LH-RH, calculated to liberate 25 micrograms per day, once a month. After 18 weeks of BOP administration, the hamsters were divided into three groups of 10-20 animals each. Group I consisted of untreated controls, group II was injected with RC-160, and group III was injected with [D-Trp6]LH-RH. A striking decrease in tumor weight and volume was obtained in animals treated with [D-Trp6]LH-RH or with the somatostatin analog RC-160. After 45 days of treatment with either analog, the survival rate was significantly higher in groups II and III (70%), as compared with the control group (35%). The studies, done by light microscopy, high-resolution microscopy, and electron microscopy, showed a decrease in the total number of cancer cells and changes in the epithelium, connective tissue, and cellular organelles in groups II and III treated with the hypothalamic analogs as compared to controls. These results in female hamsters with induced ductal pancreatic tumors confirm and extend our findings, obtained in male animals with transplanted tumors, that [D-Trp6]LH-RH and somatostatin analogs inhibit the growth of pancreatic cancers.

Topics: Adenocarcinoma; Animals; Cricetinae; Female; Gonadotropin-Releasing Hormone; Mesocricetus; Microscopy, Electron; Mortality; Nitrosamines; Pancreatic Neoplasms; Somatostatin; Triptorelin Pamoate

Topics: Adenocarcinoma; Adult; Aged; Female; Gonadotropin-Releasing Hormone; Humans; Male; Pancreatic Neoplasms; Triptorelin Pamoate

Using animal models of acinar and ductal pancreatic cancer, we investigated the effect of analogs of hypothalamic hormones on tumor growth. In Wistar/Lewis rats bearing the acinar pancreatic tumor DNCP-322, chronic administration of [L-5-Br-Trp8]somatostatin-14 significantly decreased tumor weights and volume. Somatostatin-28 and the cyclic hexapeptide analog of somatostatin cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe) failed to influence the growth of this tumor. The agonistic analog of luteinizing hormone-releasing hormone [D-Trp6]LH-RH also significantly decreased tumor weight and volume in this model and reduced testosterone levels and the weights of the ventral prostate and tests. In Syrian hamsters bearing ductal type of pancreatic carcinoma, chronic administration of [L-5-Br-Trp8]somatostatin diminished tumor weights and volume. The percentage change in tumor volume was significantly decreased when compared to control animals. In one experiment, cyclic hexapeptide of somatostatin also inhibited growth of this tumor. [D-Trp6]LH-RH, given twice daily or injected in the form of microcapsules for constant controlled release, significantly decreased tumor weight and volume and suppressed serum testosterone levels. Hamsters castrated 4 days after transplantation of the pancreatic tumors showed a significant decrease in weight and volume of these tumors. This suggests that pancreatic cancers may, at least in part, be sex hormone sensitive. [D-Trp6]LH-RH may decrease the growth of pancreatic carcinomas by suppressing androgens. Somatostatin analogs reduce the growth of pancreatic ductal and acinar cancers, probably by inhibiting the release or stimulatory action of gastrointestinal hormones on tumor cells (or both). Inhibition of animal models of pancreatic tumors by chronic administration of somatostatin analogs and [D-Trp6]LH-RH suggests that these compounds should be considered for the development of a new hormonal therapy for cancer of the pancreas.

Topics: Animals; Castration; Cell Line; Cricetinae; Drug Evaluation, Preclinical; Gonadotropin-Releasing Hormone; Luteolytic Agents; Male; Mesocricetus; Pancreatic Neoplasms; Protein Precursors; Rats; Rats, Inbred Strains; Somatostatin; Somatostatin-28; Structure-Activity Relationship; Triptorelin Pamoate