The combination of antagonists of LHRH with antagonists of GHRH improves inhibition of androgen sensitive MDA-PCa-2b and LuCaP-35 prostate cancers.
BACKGROUND
Antagonists of growth hormone-releasing hormone (GHRH) could extend the duration of response of androgen sensitive prostate cancers to androgen deprivation.


METHODS
We investigated the effect of new GHRH antagonists MZ-J-7-118 and MZ-J-7-138 and luteinizing hormone-releasing hormone (LHRH) antagonist Cetrorelix or castration on androgen sensitive MDA-PCa-2b and LuCaP-35 prostate cancer models xenografted into nude mice. Animals bearing androgen-independent LuCaP-35V prostatic cancer model were also treated with MZ-J-7-118.


RESULTS
Receptors for LHRH and GHRH were present in MDA-PCA-2b, LuCaP-35, and LuCaP-35V tumors. GHRH antagonists increased the inhibitory effect of surgical castration and LHRH antagonists on androgen sensitive MDA-PCa-2b and LuCaP-35 tumors. The time to relapse of androgen-dependent LuCaP-35 tumors was extended by GHRH antagonists. Growth of androgen-independent LuCaP-35V xenografts was also significantly inhibited by MZ-J-7-118. In MDA-PCa-2b tumors treatment with MZ-J-7-118 caused a significant decrease of VEGF and Cetrorelix or its combination with MZ-J-7-118 reduced EGF. The B(max) of EGF receptors was significantly reduced by Cetrorelix, MZ-J-7-118 and their combination.


CONCLUSIONS
Our findings suggest that the use of a combination of antagonists of GHRH and LHRH could improve the therapy for androgen sensitive prostate cancer. Antagonists of GHRH could be also considered for treatment of androgen-independent prostate cancers.
Stangelberger
Anton
A
Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, Louisiana, USA.
Schally
Andrew V
AV
Zarandi
Marta
M
Heinrich
Elmar
E
Groot
Kate
K
Havt
Alexandre
A
Kanashiro
Celia A
CA
Varga
Jozsef L
JL
Halmos
Gabor
G
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000188:drug therapy*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy*; D017337:Sermorelin / Q000008:administration & dosage / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D006727:Hormone Antagonists; C501461:MZ-J-7-118; D042461:Vascular Endothelial Growth Factor A; D007987:Gonadotropin-Releasing Hormone; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone; D017430:Prostate-Specific Antigen; C062876:cetrorelix