INHIBITION OF IN-VIVO PROLIFERATION OF ANDROGEN-INDEPENDENT PROSTATE CANCERS BY AN ANTAGONIST OF GROWTH HORMONE-RELEASING HORMONE

Tumour-inhibitory effects of a new antagonist of growth hormone-releas ing hormone (GH-RH), MZ-4-71, were evaluated in nude mice bearing andr ogen-independent human prostate cancer cell lines DU-145 and PC-3 and in Copenhagen rats implanted with Dunning R-3327 AT-1 prostatic adenoc arcinoma. After 6 weeks of therapy the tumour Volume in nude mice with DU-145 prostate cancers treated with 40 mu g day(-1) MZ-4-71 was sign ificantly decreased to 37 +/- 13 mm(3) (P < 0.01) compared with contro ls that measured 194 +/- 35 mm(3). A similar inhibition of tumour grow th was obtained in nude mice bearing PC-3 cancers, in which the treatm ent with MZ-4-71 for 4 weeks diminished the tumour volume to 119 +/- 3 5 mm(3) compared with 397 +/- 115 mm(3) for control animals. Therapy w ith MZ-4-71 also significantly decreased weights of PC-3 and DU-145 tu mours 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-l and IGF-II were reduced t o non-detectable values after therapy with MZ-4-71. The growth of Dunn ing R-3327 AT-1 tumours in rats was also significantly inhibited after 3 weeks of treatment with 100 mu g of MZ-4-71 day(-1) i.p. as shown b y a reduction in tumour volume and weight (both P-values < 0.05). Spec ific 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 D unning AT-I androgen-independent prostate cancers, through diminution of GH release and the resulting decrease in the secretion of hepatic I GF-I, or through mechanisms involving a lowering of tumour IGF-I level s and possibly an inhibition of tumour IGF-I and IGF-II production. GH -RH antagonists could be considered for further development for the th erapy of prostate cancer, especially after the relapse.