A. Jungwirth et al., INHIBITION OF IN-VIVO PROLIFERATION OF ANDROGEN-INDEPENDENT PROSTATE CANCERS BY AN ANTAGONIST OF GROWTH HORMONE-RELEASING HORMONE, British Journal of Cancer, 75(11), 1997, pp. 1585-1592
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.