Inhibitory effects of analogs of luteinizing hormone-releasing hormone and somatostatin on pancreatic cancers in hamsters. Events that accompany tumor regression.
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.
Szende
B
B
Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, New Orleans, LA 70146.
Srkalovic
G
G
Schally
A V
AV
Lapis
K
K
Groot
K
K
D000595:Amino Acid Sequence; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D006224:Cricetinae; D003593:Cytoplasm / Q000648:ultrastructure; D003692:Delayed-Action Preparations; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis; D013006:Growth Hormone / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood; D008264:Macrophages / Q000648:ultrastructure; D008647:Mesocricetus; D008969:Molecular Sequence Data; D009336:Necrosis; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000032:analysis; D017451:Receptors, Somatomedin; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis; D017329:Triptorelin Pamoate
D003692:Delayed-Action Preparations; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D017329:Triptorelin Pamoate; C051458:vapreotide; D007987:Gonadotropin-Releasing Hormone; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D007986:Luteinizing Hormone; D013006:Growth Hormone