Dose-dependent growth inhibition in vivo of PC-3 prostate cancer with a reduction in tumoral growth factors after therapy with GHRH antagonist MZ-J-7-138.

Abstract

BACKGROUND:

Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of various cancers and affect tumoral growth factors.

METHODS:

We investigated the effect of a new GHRH antagonist MZ-J-7-138 at doses of 1.25, 2.5, 5 and 10 microg/day s.c. on the growth of PC-3 human androgen independent prostate cancers xenografted s.c. into nude mice. Binding assays were used to investigate GHRH receptors. The levels of IGF-II and VEGF in tumors were measured by radioimmunoassays.

RESULTS:

Treatment with 2.5, 5, and 10 microg/day MZ-J-7-138 caused a significant dose-dependent growth reduction of PC-3 tumors. The greatest inhibition of 78% was obtained with 10 microg/day. The suppression of IGF-II protein levels in tumors was seen at all doses of MZ-J-7-138, but only 10 microg dose induced a significant inhibition. MZ-J-7-138 also reduced VEGF protein levels, the inhibition being significant at doses of 5 and 10 microg. Specific high affinity binding sites for GHRH were found on PC-3 tumors using (125)I-labeled GHRH antagonist JV-1-42. MZ-J-7-138 displaced radiolabeled JV-1-42 with an IC(50) of 0.32 nM indicating its high affinity to GHRH receptors. Real-time PCR analyses detected splice variant 1 (SV1) of GHRH receptor (GHRH-R) as well as pituitary type of GHRH-R and GHRH ligand.

CONCLUSION:

Our results demonstrate the efficacy of GHRH antagonist MZ-J-7-138 in suppressing growth of PC-3 prostate cancer at doses lower than previous antagonists. The reduction of levels of growth factors such as VEGF and IGF-II in tumors by GHRH antagonist was correlated with the suppression of tumor growth.

• Authors: Elmar Heinrich, Andrew V Schally, Stefan Buchholz, Ferenc G Rick, Gabor Halmos, Melinda Mile, Kate Groot, Florian Hohla, Marta Zarandi, Jozsef L Varga
• Journal: The Prostate (Prostate) Vol. 68 Issue 16 Pg. 1763-72 (Dec 01 2008) ISSN: 1097-0045 [Electronic] United States
• PMID: 18729085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• MZ-J-7-138
• RNA, Messenger
• Receptors, Neuropeptide
• Receptors, Pituitary Hormone-Regulating Hormone
• Vascular Endothelial Growth Factor A
• Insulin-Like Growth Factor II
• Sermorelin
• Growth Hormone-Releasing Hormone
• somatotropin releasing hormone receptor

Topics

• Adenocarcinoma (drug therapy, metabolism, pathology)
• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Growth Hormone-Releasing Hormone (antagonists & inhibitors)
• Humans
• Insulin-Like Growth Factor II (metabolism)
• Male
• Mice
• Mice, Nude
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• RNA, Messenger (metabolism)
• Receptors, Neuropeptide (metabolism)
• Receptors, Pituitary Hormone-Regulating Hormone (metabolism)
• Sermorelin (analogs & derivatives, pharmacology, therapeutic use)
• Vascular Endothelial Growth Factor A (metabolism)
• Xenograft Model Antitumor Assays