Inhibition of growth of human ovarian cancer in nude mice by luteinizing hormone-releasing hormone antagonist Cetrorelix (SB-75 )

Abstract

To report on the in vitro and in vivo inhibitory effects of LH-releasing hormone (LH-RH) antagonist Cetrorelix (SB-75; Asta Medica, Frankfurt-Main, Germany) against a panel of human ovarian carcinomas. the effect of SB-75 was measured using a standardized chemosensitivity assay in the following ovarian cancer cell lines: UCI 101; UCI 107; PA-1; NIH: OVCAR 3; UCLA: 222; A2780, parental; A2780-CR, cisplatin resistant; A2780-DR, doxorubicin resistant; and the human breast cancer cell line, MCF-7. Results were expressed as percent growth inhibition determined by crystal violet photometric analysis. In vivo studies: the antiproliferative effect of this agent was examined using UCI-107, a primary epithelial ovarian carcinoma cell line, in a nude mouse model. On day 0, 10 x 10(6) UCI 107 cells were implanted subcutaneously into 20 intact female athymic nude mice (5 to 6 weeks old). On day 8, the mice were randomly divided into two groups of 10; control mice were implanted with miniosmotic pumps filled with a vehicle solution consisting of 5.2% mannitol in saline; and treated animals received pumps filled to deliver continuous administration of SB-75 at 60 micrograms per mouse per day. direct inhibition of cell proliferation by SB-75 was not observed at concentrations ranging from 1 nM to 100 microM (exposure lasting three to four cell doublings) with the exception of MCF-7, which demonstrated a 33% inhibition at the latter concentration. In vivo studies: on day 16, caliper measurements were taken from subcutaneous tumor nodules in SB-75-treated and untreated mice and a significant difference of 270% in mean tumor volume was observed. End point was determined, on day 30, when control tumor volume approached 10,000 mm3. At that time the difference in mean tumor volumes increased to 600%, indicating a substantial antiproliferative effect had been achieved in the SB-75-treated group. Our in vitro findings show direct inhibition by SB-75 on proliferation of human breast cancer cells. This direct inhibition in vitro was not observed in our ovarian cancer cell lines. However, in vivo SB-75 caused a significant inhibition of growth of human epithelial ovarian cancer. This may be a result of inhibition of the pituitary gonadal axis and gonadotropin secretion. Our results warrant further investigation.