Effective tumor growth inhibition of MX1 and MDA-MB-231 estrogen receptor negative human breast cancer xenografts by treatment with LHRH antagonist cetrorelix.

Abstract

Abstract Abstract #2137 Introduction
 Agonists of LHRH are a treatment option in premenopausal women with estrogen receptor positive breast cancer. The treatment with those agonists decreases the levels of FSH and LH in the blood and thus reduces the levels of sex hormones. Patients with estrogen receptor negative breast cancers do not benefit from therapy with LHRH agonists. Antagonists of LHRH lower LH, FSH and sex steroid levels but without the initial flare up of FSH and LH. In addition to the endocrine effects, Cetrorelix also shows a direct inhibition of cell growth in LHRH receptor (LHRH-R) positive gynecological cancer in vitro where alterations of FSH, LH and sex hormone levels are clearly excluded. In view of these findings we decided to investigate Cetrorelix on the tumor growth in two estrogen receptor negative but LHRH-R positive breast cancer cell lines.
 Materials and Methods
 The mRNA expression of LHRH-R was detected by PCR. For proliferation assays cells were treated with increasing doses of Cetrorelix acetate in 0.5% FBS supplemented RPMI 1640 media. MTS assays were performed after 72h. Fluorescence microscopy using ethidium bromide staining was performed to show cell death. In the in vivo study, nude mice were treated with Cetrorelix pamoate preparation at a dose of 3mg s.c. releasing an estimated 100mg Cetrorelix/day.
 Results
 MX1 and MDA-MB-231 estrogen receptor negative human breast cancer cell lines were positive for the expression of mRNA for LHRH-R. The cell proliferation in vitro of MX1 and MDA-MB-231 lines treated with different concentrations of Cetrorelix was significantly inhibited in a dose dependent manner. Time and dose dependent cell death was observed by fluorescence staining. Experimental treatment in vivo with Cetrorelix pamoate preparation reduced a significant inhibition of tumor growth in MX1 xenografts as compared to the Controls after 14 days and the suppression remained significant until the end of the study on day 28. MDA-MB-231 xenografts treated with Cetrorelix also showed a significant inhibition of tumor growth compared to the Control as early as day 7 and the inhibition remained significant until the end of the study on day 28.
 Conclusion
 Our results indicate a direct inhibitory effect of Cetrorelix on LHRH-R positive breast cancers. Since LHRH-R are expressed in ER negative breast cancers, these findings suggest a new approach to the treatment of LHRH-R positive breast cancer patients independent of the estrogen receptor status. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2137.