Endocrine Abstracts

2-Methoxyoestradiol (2-MeOE2) is a human endogenous metabolite of oestradiol which is known to inhibit the proliferation of breast cancer cells. Sulphamoylation of 2-MeOE2 greatly enhances its ability to inhibit breast cancer cell proliferation and induce apoptosis. To establish whether 2-MeOE2 and its mono- and bis-sulphamoylated derivatives would also be an effective treatment for other endocrine cancers, we have investigated their effects, and those of 2-ethyloestradiol (2-EtE2) and its sulphamoylated derivatives, on prostate and ovarian cancer cells in vitro.
Proliferation of cells was measured using an MTS assay. The cell lines tested included an androgen receptor-positive cell line, LNCaP, and an androgen receptor-negative cell line, PC3. The ovarian A2780 cell line was studied along with two of its drug-resistant derivatives, A2780ADR and A2780cis. Of the unsubstituted 2-oestradiol derivatives, 2-MeOE2 was far more potent than 2-EtE2 in all cell lines tested, with an IC50 value of less than 10 micromolar. However, the sulphamoylated derivatives of both compounds were much more potent with IC50 values below 1.5 micromolar in all cell lines. FACS analysis showed that the cells were arrested in the G2/M phase of the cell cycle, and analysis after removal of the treatments suggested that the effects were irreversible. The cells appeared apoptotic becoming detached and rounded with increased intracellular phosphorylation of BCL-2.
The A2780 and A2780cis cell lines were most sensitive to all compounds, but the A2780ADR cell line was the least sensitive. Both prostate lines showed intermediate sensitivities to the treatments. This may be due to expression of multidrug resistance proteins by some of the cell lines and is currently being investigated.
These studies indicate that the sulphamated oestrogen derivatives are potent anti-tumour agents which may be effective against androgen receptor positive and negative endocrine cancers, and against those which are resistant to established chemotherapeutic treatments.