Endocrine Abstracts

Ovarian cancer is the leading cause of death from all gynaecological malignancies. The observation that decreased levels of the natural oestrogen-17beta metabolite, 2-methoxyoestradiol (2-MeOE2) may create a predisposition to oestrogen dependent cancer, has led to considerable interest in the potential use of oestrogen derivatives for the prevention and treatment of hormone dependent cancers. The sulphamoylated oestrone derivative 2-methoxyoestrone-3-O-sulphamate (2-MeOEMATE) has previously been shown to induce G2/M cell cycle arrest and apoptosis in breast cancer cells in vitro. The present study was undertaken to evaluate and compare the effects of an oestrogen derivative 2-MeOE2-6-oxime, with those of a number of 2-substituted oestrogen sulphamates on the growth of wild type and drug-resistant ovarian cancer cells.

This study provides evidence for the potent effects of sulphamoylated compounds on a number of ovarian drug resistant cell lines and demonstrates that similar effectiveness can be achieved by the compound, 2-MeOE2-6-oxime. 2-MeOE2-6-oxime more potently inhibited the growth of wild type and drug resistant ovarian cells when compared with 2-MeOE2, which is currently in phase II trials for breast cancer. 2-MeOE2-6-oxime (1 micromolar) inhibited cell growth by 63.4%, whereas 2-MeOE2 achieved a mere 7.9% inhibition at the same concentration, using a microwell plate proliferation assay.

Exposure of wild type and drug resistant ovarian cells to 2-MeOE2-6-oxime caused them to round up and detach, suggesting this compound may induce apoptosis. FACscan analysis revealed that 2-MeOE2-6-oxime caused cells to arrest in the G2/M phase, detectable after just 24 hours in the wild type and cisplatin resistant cell lines. Such morphological and cell cycle effects indicates that 2-MeOE2-6-oxime has a similar mechanism of action to Taxol and other anti-microtubule agents.

Such observations indicate that sulphamoylated derivatives and 2-MeOE2-6-oxime may be useful as first and second line therapies in patients who have already been exposed to several chemotherapeutic agents.