GROWTH HORMONE-RELEASING HORMONE ANTAGONIST MZ-5-156 INHIBITS GROWTH OF DU-145 HUMAN ANDROGEN-INDEPENDENT PROSTATE CARCINOMA IN NUDE-MICE AND SUPPRESSES THE LEVELS AND MESSENGER-RNA EXPRESSION OF INSULIN-LIKE-GROWTH-FACTOR-II IN TUMORS

Insulin-like growth factors I and II (IGF-I and -II) are potent mitoge ns for various cancers, including carcinoma of the prostate, In severa l experimental cancers, treatment with antagonists of growth hormone-r eleasing hormone (GH-RH) produces a reduction in IGP-I and -II, concom itant to inhibition of tumor growth. To investigate the mechanisms inv olved, we treated male nude mice bearing xenografts of DU-145 human an drogen-independent prostate cancer for 8 weeks with potent GH-RH antag onist MZ-5-156 at a dose of 20 mu g/animal s,c, twice a day. Tumor gro wth, serum and tumor Levels of IGF-I and -II, and the mRNA expression of IGF-I and -II in tumors,were evaluated. After 8 weeks of therapy, f inal volume and weight of DU-145 tumors in mice treated with MZ-5-156 were significantly (P < 0.01) decreased compared with controls, and se rum IGF-I showed a significant reduction, Treatment of nude mice beari ng DU-145 xenografts with MZ-5-156 also significantly (P < 0.01) dimin ished by 77% the levels of IGF-II in tumor tissue compared with contro ls, but did not affect the concentration of IGF-I, Reverse transcripti on-PCR analyses revealed a high expression of IGP-II mRNA in DU-145 tu mors. Treatment with GH-RH antagonist MZ-5-156 decreased the expressio n of IGF-II mRNA by 58% (P < 0.01) as compared with controls. Our work suggests that GH-RH antagonist MZ-5-156 may inhibit the growth of DU- 145 human androgen-independent prostate cancers through a reduction in the production and mRNA expression of IGF-II by the tumor tissue. The se findings extend our observations on the mechanism of action of GH-R H antagonists and may explain how GH-RH antagonists inhibit tumor grow th.