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.