Antagonists of bombesin/gastrin-releasing peptides as adjuncts to agonists of luteinizing hormone-releasing hormone in the treatment of experimental prostate cancer.
BACKGROUND
Palliative methods for treatment of advanced prostatic carcinoma, including those based on luteinizing hormone-releasing hormone (LH-RH) agonists, cannot prevent the ultimate growth of hormone-independent cells, and the duration of disease remission in patients with prostate cancer is limited. New therapeutic approaches combining androgen ablation therapy with other compounds must be explored. Various studies suggest that bombesin or gastrin-releasing peptide (GRP) act as autocrine growth factors and may play a role in the initiation and progression of some cancers, including those of the prostate.


METHODS
The effects of treatment with bombesin/gastrin-releasing peptide (GRP) receptor antagonist [D-Tpi6, Leu13 psi(CH2NH)Leu14]BN(6-14)(RC-3095), an agonist of LH-RH [D-Lys6]-LH-RH and their combination were investigated in the androgen-dependent Dunning R-3327H rat prostate cancer model. Both analogs were administered by continuous subcutaneous infusion from osmotic minipumps for 7 weeks.


RESULTS
Tumor volumes and weights were significantly reduced by treatment with RC-3095, compared with those of controls. In rats that received [D-Lys6]-LH-RH, there was a greater decrease in tumor weight and volume than that produced by RC-3095, and the weights of testes, ventral prostate, and seminal vesicles also were reduced. The combination of RC-3095 and [D-Lys6]-LH-RH had the greatest inhibitory effect on tumor growth. Histologic parameters demonstrated a significant increase of the ratio of apoptotic to mitotic indices in the groups treated with [D-Lys6]-LH-RH or the combination. Serum LH and testosterone levels were greatly depressed by [D-Lys6]-LH-RH or the combination. Specific high-affinity binding sites for bombesin/GRP, epidermal growth factor (EGF), and insulin-like growth Factor I (IGF-I) were found on the tumor membranes. The concentration of receptors for EGF was significantly reduced by treatment with the bombesin/GRP antagonist RC-3095.


CONCLUSIONS
Combination therapy of LH-RH analogs with bombesin antagonists such as RC-3095 might be considered for improvement of hormonal therapy of prostate cancer.
Pinski
J
J
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70146.
Halmos
G
G
Szepeshazi
K
K
Schally
A V
AV
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001839:Bombesin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D003238:Connective Tissue / Q000187:drug effects / Q000473:pathology; D066246:ErbB Receptors / Q000187:drug effects; D019886:Gastrin-Releasing Peptide; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D008297:Male; D008938:Mitosis; D010446:Peptide Fragments / Q000008:administration & dosage / Q000627:therapeutic use; D010455:Peptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D017526:Receptor, IGF Type 1 / Q000187:drug effects; D018004:Receptors, Bombesin / Q000187:drug effects; D013739:Testosterone / Q000097:blood; D013997:Time Factors
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D010455:Peptides; D018004:Receptors, Bombesin; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; C035029:LHRH, Lys(6)-; D019886:Gastrin-Releasing Peptide; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D001839:Bombesin