Antagonists of growth hormone releasing hormone (GHRH) and of bombesin/gastrin releasing peptide (BN/GRP) suppress the expression of VEGF, bFGF, and receptors of the EGF/HER family in PC-3 and DU-145 human androgen-independent prostate cancers.

Abstract

BACKGROUND:

Antagonists of growth hormone releasing hormone (GHRH) as well as antagonists of bombesin/gastrin releasing peptide (BN/GRP) inhibit the growth of various malignancies (cancers) including prostate cancer.

METHODS:

We investigated the effects of GHRH antagonists MZ-J-7-118 and RC-J-29-18, BN/GRP antagonists RC-3940-II and RC-3940-Et and the combination of MZ-J-7-118 and RC-3940-II on the growth of PC-3 and DU-145 human androgen independent prostate cancers xenografted s.c. into nude mice. To elucidate the mechanisms of action of these analogs, growth factors like IGF-II (insulin-like growth factor-II), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and epidermal growth factor receptor/human epidermal growth factor receptor (EGF-R/HER) family were measured in tumors as well as IGF-I in serum.

RESULTS:

Antagonists of GHRH and BN/GRP alone or in combination significantly inhibited growth of PC-3 and DU-145 tumors, the greatest inhibition of tumor volume being achieved by combination of MZ-J-7-118 (5 microg/day) and RC-3940-II (10 microg/day). BN/GRP and GHRH antagonists and their combination also decreased the expression of VEGF significantly in PC-3 and non-significantly in DU-145, as measured by radioimmunoassay for VEGF protein and RT-PCR for mRNA levels of VEGF. GHRH and BN/GRP antagonists reduced bFGF concentrations and the maximal binding capacity of EGF receptors, and their mRNA levels in PC-3 and DU-145 tumors. mRNA levels for HER-2 and -3 were also diminished in PC-3 tumors by GHRH and BN/GRP antagonists. No changes in HER-4 were found after treatment. Serum IGF-I and tumoral IGF-II levels were not affected by the analogs.

CONCLUSIONS:

BN/GRP and GHRH antagonists inhibit growth of PC-3 and DU-145 prostate cancers by suppressing the expression of tumoral growth factors such as VEGF and bFGF as well as the receptors for EGF and related HER-2 and -3. Additive effects on tumor inhibition (TI) in vivo, but not on VEGF, bFGF, or members of the EGF/HER receptor family, can be achieved by the joint administration of both classes of analogs.

• Authors: Anton Stangelberger, Andrew V Schally, Jozsef L Varga, Brian D Hammann, Kate Groot, Gabor Halmos, Ren-Zhi Cai, Marta Zarandi
• Journal: The Prostate (Prostate) Vol. 64 Issue 3 Pg. 303-15 (Aug 01 2005) ISSN: 0270-4137 [Print] United States
• PMID: 15754342 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2005 Wiley-Liss, Inc.

Chemical References

• MZ-J-7-118
• Peptide Fragments
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• bombesin(6-14), Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-
• Fibroblast Growth Factor 2
• Gastrin-Releasing Peptide
• Sermorelin
• Growth Hormone-Releasing Hormone
• ERBB4 protein, human
• ErbB Receptors
• Erbb4 protein, mouse
• Receptor, ErbB-2
• Receptor, ErbB-3
• Receptor, ErbB-4
• Bombesin

Topics

• Animals
• Bombesin (analogs & derivatives, antagonists & inhibitors, pharmacology)
• Cell Division (drug effects)
• Cell Line, Tumor
• ErbB Receptors (genetics)
• Fibroblast Growth Factor 2 (genetics, metabolism)
• Gastrin-Releasing Peptide (antagonists & inhibitors)
• Growth Hormone-Releasing Hormone (antagonists & inhibitors)
• Humans
• Male
• Mice
• Mice, Nude
• Peptide Fragments (pharmacology)
• Prostatic Neoplasms (drug therapy, metabolism, physiopathology)
• RNA, Messenger (analysis)
• Receptor, ErbB-2 (genetics)
• Receptor, ErbB-3 (genetics)
• Receptor, ErbB-4
• Sermorelin (pharmacology)
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Xenograft Model Antitumor Assays