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Inhibition of in vivo proliferation of androgen-independent prostate cancers by an antagonist of growth hormone-releasing hormone.

Abstract
Tumour-inhibitory effects of a new antagonist of growth hormone-releasing hormone (GH-RH), MZ-4-71, were evaluated in nude mice bearing androgen-independent human prostate cancer cell lines DU-145 and PC-3 and in Copenhagen rats implanted with Dunning R-3327 AT-1 prostatic adenocarcinoma. After 6 weeks of therapy, the tumour volume in nude mice with DU-145 prostate cancers treated with 40 microg day(-1) MZ-4-71 was significantly decreased to 37 +/- 13 mm3 (P < 0.01) compared with controls that measured 194 +/- 35 mm3. A similar inhibition of tumour growth was obtained in nude mice bearing PC-3 cancers, in which the treatment with MZ-4-71 for 4 weeks diminished the tumour volume to 119 +/- 35 mm3 compared with 397 +/- 115 mm3 for control animals. Therapy with MZ-4-71 also significantly decreased weights of PC-3 and DU-145 tumours and increased tumour doubling time. Serum levels of GH and IGF-I were significantly decreased in animals treated with GH-RH antagonist. In PC-3 tumour tissue, the levels of IGF-I and IGF-II were reduced to non-detectable values after therapy with MZ-4-71. The growth of Dunning R-3327 AT-1 tumours in rats was also significantly inhibited after 3 weeks of treatment with 100 microg of MZ-4-71 day(-1) i.p. as shown by a reduction in tumour volume and weight (both P-values < 0.05). Specific high-affinity binding sites for IGF-I were found on the membranes of DU-145, PC-3 and Dunning R-3327 AT-1 tumours. Our results indicate that GH-RH antagonist MZ-4-71 suppresses growth of PC-3, DU-145 and Dunning AT-1 androgen-independent prostate cancers, through diminution of GH release and the resulting decrease in the secretion of hepatic IGF-I, or through mechanisms involving a lowering of tumour IGF-I levels and possibly an inhibition of tumour IGF-I and IGF-II production. GH-RH antagonists could be considered for further development for the therapy of prostate cancer, especially after the relapse.
AuthorsA Jungwirth, A V Schally, J Pinski, G Halmos, K Groot, P Armatis, M Vadillo-Buenfil
JournalBritish journal of cancer (Br J Cancer) Vol. 75 Issue 11 Pg. 1585-92 ( 1997) ISSN: 0007-0920 [Print] England
PMID9184172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Hormone Antagonists
  • MZ 4-71
  • Sermorelin
  • Growth Hormone
  • Growth Hormone-Releasing Hormone
  • Receptor, IGF Type 1
Topics
  • Animals
  • Cell Division (drug effects)
  • Growth Hormone (blood)
  • Growth Hormone-Releasing Hormone (antagonists & inhibitors)
  • Hormone Antagonists (therapeutic use)
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Prostatic Neoplasms (drug therapy, pathology)
  • Rats
  • Receptor, IGF Type 1 (analysis)
  • Sermorelin (analogs & derivatives, therapeutic use)
  • Tumor Cells, Cultured

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