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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
Author(s) -
Heinrich Elmar,
Schally Andrew V.,
Buchholz Stefan,
Rick Ferenc G.,
Halmos Gabor,
Mile Melinda,
Groot Kate,
Hohla Florian,
Zarandi Marta,
Varga Jozsef L.
Publication year - 2008
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20843
Subject(s) - endocrinology , antagonist , medicine , growth hormone–releasing hormone , receptor , prostate cancer , growth inhibition , prostate , hormone , growth factor , hormone antagonist , in vivo , cancer , biology , cell growth , growth hormone , microbiology and biotechnology , genetics
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 µg/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 µg/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 µg/day. The suppression of IGF‐II protein levels in tumors was seen at all doses of MZ‐J‐7‐138, but only 10 µg dose induced a significant inhibition. MZ‐J‐7‐138 also reduced VEGF protein levels, the inhibition being significant at doses of 5 and 10 µg. 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. Prostate © 2008 Wiley‐Liss, Inc.