INHIBITORY EFFECTS OF ANALOGS OF LUTEINIZING-HORMONE-RELEASING HORMONE ON THE GROWTH OF THE ANDROGEN-INDEPENDENT DUNNING R-3327-AT-1 RAT PROSTATE-CANCER

The effects of treatment with the luteinizing hormone-releasing hormone (LH-RH) antagonist SB-75 and agonist [D-Trp(6)] LH-RH were investigated in Copenhagen rats bearing the anaplastic, androgen-independent Dunning R-3327-AT-1 prostatic adenocarcinoma implanted orthotopically into the ventral lobes of prostate glands. The LH-RH antagonist SB-75 and the LH-RH agonist [D-Trp(6)] LH-RH were administered from osmotic minipumps and the survival time of animals bearing this cancer was evaluated. Treatment with SB-75 and [D-Trp(6)] LH-RH significantly prolonged the mean survival time of rats by 4.1 days and 4.5 days, respectively. In cell cultures, proliferation of the AT-1 cell line was strongly inhibited by the antagonist SB-75, but only a moderate suppression of tumor cell growth in vitro was observed with the agonist [D-Trp(6)] LH-RH. Receptor assays on Dunning R-3327-AT-1 tumor membranes showed high-affinity binding sites for LH-RH, epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Receptors for EGF were significantly down-regulated by treatment with SB-75. Therapy with SB-75 also decreased EGF levels in tumor tissue to non-detectable levels, as measured by specific RIA. Our results demonstrate that the LH-RH antagonist SB-75 and agonist [D-Trp(6)] LH-RH inhibit the growth of androgen-independent Dunning R-3327-AT-1 prostatic cancer in vivo and in vitro. (C) 1994 Wiley-Liss, Inc.