LUTEINIZING-HORMONE-RELEASING HORMONE (LH-RH) ANTAGONIST CETRORELIX INHIBITS GROWTH OF DU-145 HUMAN ANDROGEN-INDEPENDENT PROSTATE CARCINOMAIN NUDE-MICE AND SUPPRESSES THE LEVELS AND MESSENGER-RNA EXPRESSION OF IGF-II IN TUMORS

In previous studies, we showed that LH-RH antagonist Cetrorelix inhibi ts the growth of DU-145 and PC-3 human androgen-independent prostate c ancers in nude mice. To investigate the mechanisms involved, we treate d male nude mice bearing xenografts of DU-145 human androgen-independe nt prostate cancer with Cetrorelix at a dose of 100 mu g/animal subcut aneously (s.c.) once a day. Tumor growth, serum and tumor levels of IG F-I and -II as well as the mRNA expression of IGF-I and -II in tumors were evaluated. After 8 weeks of treatment, final volume and weight of DU-145 tumors in mice treated with Cetrorelix were significantly decr eased compared with controls and serum IGF-1 showed a significant redu ction. Therapy with Cetrorelix also reduced by 84% the levels of IGF-I I in DU-145 tumor tissue compared with controls, but did not affect th e concentration of IGF-I. RT-PCR analyses revealed a high expression o f mRNA for IGF-II, but not for IGF-I in DU-145 tumors. Treatment with Cetrorelix decreased the expression of IGF-II mRNA by 78% (p < 0.01) a s compared with controls. Our study indicates that LH-RH antagonist Ce trorelix may inhibit the growth of DU-145 human androgen-independent p rostate cancers by decreasing the production and mRNA expression of IG F-II by the tumor tissue. This also suggests that LH-RH antagonist Cet rorelix could interfere with the signal transduction pathways involvin g IGF-II, leading to tumor growth inhibition. (C) 1998 Elsevier Scienc e BN. All rights reserved.