Inhibition of proliferation of PC-3 human prostate cancer by antagonists of growth hormone-releasing hormone: lack of correlation with the levels of serum IGF-I and expression of tumoral IGF-II and vascular endothelial growth factor.

Abstract

BACKGROUND:

Antagonists of growth hormone-releasing hormone (GHRH) such as JV-1-38 can inhibit androgen-independent prostate cancer directly by several mechanisms and/or indirectly by suppressing growth hormone/insulin-like growth factor-I (GH/IGF-I) axis. To shed more light on the mechanisms involved, the effects of JV-1-38 on PC-3 human prostate cancer were compared with those of somatostatin analog RC-160 in vivo and in vitro.

METHODS:

Nude mice bearing PC-3 tumors received JV-1-38 (20 microg), RC-160 (50 microg) or a combination of JV-1-38 and RC-160. The concentration of IGF-I in serum and the expression of mRNA for IGF-II and vascular endothelial growth factor (VEGF) in tumor tissue were investigated.

RESULTS:

In vivo, the final volume of PC-3 tumors treated with JV-1-38 was significantly lowered by 49% (P < 0.01), whereas RC-160 exerted only 30% inhibition (NS), compared with controls. Combined use of both compounds augmented tumor inhibition to 63% (P < 0.001). Serum IGF-I levels were decreased only in mice treated with RC-160. JV-1-38 suppressed mRNA for IGF-II in PC-3 tumors by 42%, whereas RC-160 alone or in combination with JV-1-38 caused a 65% reduction. JV-1-38 and RC-160 used as single drugs decreased the expression of VEGF by 50%, and their combination caused a 63% reduction. In vitro, JV-1-38 inhibited the proliferation of PC-3 cells by 39%. This effect could be partially reversed by addition of IGF-I to the serum-free medium. RC-160 alone did not affect the PC-3 cell growth in vitro, but in combination with JV-1-38 it augmented the antiproliferative effect of the GH-RH antagonist to 72%. Exposure to JV-1-38 in vitro reduced the expression of mRNA for IGF-II in PC-3 cells by 55% but did not change VEGF mRNA levels, whereas RC-160 had no effect.

CONCLUSIONS:

The antiproliferative effect of JV-1-38 was not associated with the suppression of serum IGF-I and was only partially correlated with the expression of IGF-II and VEGF in PC-3 tumors, suggesting that other mechanisms play a role in the antitumor action of GHRH antagonists. Nevertheless, the stronger inhibition of tumor growth after combined treatment with JV-1-38 and RC-160 indicates that the interference with multiple local stimulatory factors leads to an enhanced inhibition of prostate cancer.

• Authors: Artur Plonowski, Andrew V Schally, Markus Letsch, Magdalena Krupa, Francine Hebert, Rebeca Busto, Kate Groot, Jozsef L Varga
• Journal: The Prostate (Prostate) Vol. 52 Issue 3 Pg. 173-82 (Aug 01 2002) ISSN: 0270-4137 [Print] United States
• PMID: 12111694 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright 2002 Wiley-Liss, Inc.

Chemical References

• Antineoplastic Agents
• Drug Combinations
• Endothelial Growth Factors
• JV 1-38
• Lymphokines
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• vapreotide
• Somatostatin
• Insulin-Like Growth Factor I
• Insulin-Like Growth Factor II
• Growth Hormone-Releasing Hormone

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Division
• Drug Combinations
• Endothelial Growth Factors (genetics, metabolism)
• Growth Hormone-Releasing Hormone (analogs & derivatives, antagonists & inhibitors, pharmacology)
• Humans
• Insulin-Like Growth Factor I (genetics, metabolism)
• Insulin-Like Growth Factor II (genetics, metabolism)
• Lymphokines (genetics, metabolism)
• Male
• Mice
• Mice, Nude
• Prostatic Neoplasms (metabolism, pathology)
• RNA, Messenger (metabolism)
• Somatostatin (analogs & derivatives, pharmacology)
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors