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

Abstract

Summary 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-1 45 prostate cancers treated with 40 ,ug day-' 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 1 19 ± 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 gg of MZ-4-71 day-' 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-I 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-Il production. GH-RH antagonists could be considered for further development for the therapy of prostate cancer, especially after the relapse.

Luteinising hormone-releasing hormone analogue reverses the cell adhesion profile of EGFR overexpressing DU-145 human prostate carcinoma subline

“…In addition, it has been shown that LHRH agonists directly inhibit cell proliferation of DU-145 and LNCaP prostate cancer cell lines (Dondi et al, 1994Limonta et al, 2001). In line with these observations, the LHRH analogue Cetrorelix has been shown to have direct antiproliferative actions on DU-145 cells (Jungwirth et al, 1997b). As a consequence of this exposure, LHRH analogues have caused decreased levels of EGFR expression (Moretti et al, 1996;El-Bahrawy and Pignatelli, 1998;Lamharzi et al, 1998).…”

Human renal cell carcinoma expresses distinct binding sites for growth hormone-releasing hormone

“…The mechanisms that mediate the antitumor effect of GHRH antagonists in vivo include the suppression of the pituitary GH͞he-patic IGF-I axis and inhibition of the autocrine͞paracrine production of IGF-I and -II in tumors (3, 7-11, 14, 16-19). It was also shown that GHRH antagonists inhibit cell proliferation, suppress the production of IGF-II, and decrease the telomerase activity in various human cancer cell lines cultured in vitro (8,9,11,13,14,18,40). Some evidence also suggests that GHRH antagonists can suppress tumor growth by mechanisms that are IGF-independent (12,14).…”

“…GHRH antagonists (4-6) inhibit the growth of various human neoplasms such as prostatic, ovarian, mammary, renal, pancreatic, and colorectal cancers, osteosarcomas, small-cell lung cancer (SCLC) and non-SCLC, and malignant gliomas (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The mechanisms that mediate the antitumor effect of GHRH antagonists in vivo include the suppression of the pituitary GH͞he-patic IGF-I axis and inhibition of the autocrine͞paracrine production of IGF-I and -II in tumors (3, 7-11, 14, 16-19).…”

“…The reduction in the levels of serum IGF-I could inhibit the proliferation of various cancers dependent on IGF-I, in view of involvement of this growth factor and of IGF-II, which is GH independent, in malignant transformation of cells, tumor progression, and metastasis (1)(2)(3). GHRH antagonists were shown to effectively inhibit the in vivo growth of various experimental human cancers, including osteosarcomas, mammary, ovarian and prostatic cancers, renal adenocarcinomas, small-cell lung cancer (SCLC) and non-SCLC, pancreatic and colorectal carcinomas, and malignant gliomas (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The proliferation of some of these human cancers in vitro was also suppressed by GHRH antagonists (7-10, 12-14, 16-18).…”

Expression of a splice variant of the receptor for GHRH in 3T3 fibroblasts activates cell proliferation responses to GHRH analogs

“…GHRH antagonists strongly suppress the growth of various experimental cancers such as osteosarcomas (ref. 2 and R. Braczkowski, A.V.S., A. Plonowski, J.L.V., K. Groot, M. Krupa, and P. Armatis, unpublished observations), renal cell carcinomas (3,4), prostatic cancers (5,6), small cell lung carcinomas (SCLC) and non-SCLC (7,8), malignant glioblastomas (9), and pancreatic (10), colorectal (11), breast (12)(13)(14), and ovarian tumors (15). Treatment with GHRH antagonists can produce a marked reduction in the serum levels of IGF-I in the tumor-bearing animals, consistent with the notion that the antitumor action of the antagonistic analogs of GHRH is exerted in part through an indirect mechanism involving the inhibition of GHRH͞GH͞IGF-I axis (16,17).…”