Inhibitory effect of antagonists of bombesin and growth hormone-releasing hormone on orthotopic and intraosseous growth and invasiveness of PC-3 human prostate cancer in nude mice.
OBJECTIVE
To determine whether antagonists of growth hormone-releasing hormone (GHRH) and bombesin/gastrin-releasing peptide (BN/GRP) can inhibit the orthotopic and metastatic growth of PC-3 human androgen-independent prostate cancers.


METHODS
The effects of administration of GHRH antagonist MZ-J-7-118, BN/GRP antagonist RC-3940-II, and their combination on the growth and metastatic spread of PC-3 tumors implanted orthotopically into nude mice were evaluated. The efficacy of this treatment on PC-3 tumors implanted intratibially and s.c. was also determined.


RESULTS
Treatment with MZ-J-7-118, RC-3940-II, or their combination significantly inhibited the growth of PC-3 tumors implanted orthotopically, intraosseously, and s.c. The combination of the two antagonists had the greatest effect, inhibiting orthotopic tumor growth by 77%, intratibially implanted tumors by 86%, and s.c. tumors by 86%. The therapy with BN/GRP and GHRH antagonists, especially in combination, also reduced the local tumor spread and distant metastases in animals bearing orthotopic tumors. Combination therapy was likewise the most effective in reducing the incidence and severity of tibial osteolytic lesions and pathologic fractures in intraosseously implanted tumors. High-affinity binding sites for BN/GRP and GHRH were found in s.c. and orthotopic PC-3 tumor samples. MZ-J-7-118, RC-3940-II, and the combination of both compounds inhibited in vitro growth of PC-3 cells.


CONCLUSIONS
Our findings show the efficacy of BN/GRP antagonists and GHRH antagonists for the treatment of advanced prostate cancer in preclinical metastatic models. As BN/GRP antagonists are already in clinical trials and GHRH antagonists are effective in androgen-independent prostate cancer models, these analogues could be considered for the management of advanced prostate carcinoma.
Stangelberger
Anton
A
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.
Schally
Andrew V
AV
Varga
Jozsef L
JL
Zarandi
Marta
M
Szepeshazi
Karoly
K
Armatis
Patricia
P
Halmos
Gabor
G
D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002986:Clinical Trials as Topic; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D017337:Sermorelin / Q000494:pharmacology*; D013997:Time Factors
C501461:MZ-J-7-118; D010446:Peptide Fragments; D010455:Peptides; C096400:bombesin(6-14), Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone; D001839:Bombesin