title: 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.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70146, USA.
authors.forename: A
authors.initials: A
authors.lastname: Jungwirth
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
authors.forename: J
authors.initials: J
authors.lastname: Pinski
authors.forename: G
authors.initials: G
authors.lastname: Halmos
authors.forename: K
authors.initials: K
authors.lastname: Groot
authors.forename: P
authors.initials: P
authors.lastname: Armatis
authors.forename: M
authors.initials: M
authors.lastname: Vadillo-Buenfil
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D013006:Growth Hormone / Q000097:blood; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006727:Hormone Antagonists / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000032:analysis; D017337:Sermorelin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D006727:Hormone Antagonists; C095215:MZ 4-71; D017337:Sermorelin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D017526:Receptor, IGF Type 1