INHIBITION OF GROWTH OF ANDROGEN-INDEPENDENT DU-145 PROSTATE-CANCER IN-VIVO BY LUTEINIZING-HORMONE-RELEASING HORMONE ANTAGONIST CETRORELIX AND BOMBESIN ANTAGONISTS RC-3940-II AND RC-3950-II

The aim of this study was to test the antagonist of LH-RH (CetroreLix) , agonist [D-Trp(6)]LH-RH (triptorelin) and new bombesin antagonists R C-3940-II and RC-3950-II for their effect on the growth of an androgen -independent prostate cancer cell line, DU-145, xenografted into nude mice. Xenografts were grown in male nude mice, and after 4 weeks, the animals were treated either with saline (control) or with one of the a nalogues. One group of mice was given a combination of Cetrorelix and RC-3950-II. Treatment was given for 4 weeks. Tumour and body weights, and tumour volumes were measured. At sacrifice, tumours were dissected for histological examination and receptor studies. Serum was collecte d for measurement of hormone levels. The final tumour volume in contro l animals injected with saline was 577 +/- 155 mm(3) and that of anima ls treated with Cetrorelix only 121.4 +/- 45 mm(3) (P < 0.01). Bombesi n antagonists RC-3940-II and RC-3950-II also significantly reduced DU- 145 tumour volume in nude mice to 84.9 +/- 19.9 and 96.8 +/- 28 mm(3), respectively. Agonist [D-Trp(6)]LH-RH did not significantly inhibit t umour growth. Serum levels of LH were decreased to 0.08 +/- 0.02 ng/ml (P < 0.05) in the Cetrorelix treated group as compared to 1.02 +/- 0. 1 ng/ml for the controls, and testosterone levels were reduced to cast ration levels (0.01 +/- 0.01 ng/ml). Specific receptors for EGF and LH -RH in DU-145 tumours were significantly downregulated after treatment with Cetrorelix, RC-3940-II and RC-3950-II. Although LH-RH could be a local regulator of growth of prostate cancer, the fall in LH-RH recep tors is not fully understood and the inhibitory effects of Cetrorelix and bombesin antagonists on DU-145 tumour growth might be attributed a t least in part to a downregulation of EHF receptors. Since Cetrorelix and bombesin antagonists inhibit growth of androgen-independent DU-14 5 prostate cancers, these compounds could be considered for the therap y of advanced prostate cancer in men, especially after relapse. (C) 19 97 Elsevier Science Ltd.