The anti-proliferative and anti-angiogenic properties of the endogenous oestrogen metabolite,
2-methoxyoestradiol (2-MeOE2), are enhanced in a series of sulphamoylated derivatives of 2-MeOE2. To investigate possible mechanisms of resistance to these compounds, a cell line, A2780.140, eightfold less sensitive to the 3,17-O,O-bis-sulphamoylated derivative,
STX140, was derived from the A2780
ovarian cancer cell line by dose escalation. Other cell lines tested did not develop
STX140 resistance. RT-PCR and immunoblot analysis demonstrated that
breast cancer resistance
protein (BCRP) expression is dramatically increased in A2780.140 cells. The cells are cross-resistant to the most structurally similar bis-sulphamates, and to BCRP substrates,
mitoxantrone and
doxorubicin; but they remain sensitive to
taxol, an MDR1 substrate, and to all other sulphamates tested. Sensitivity can be restored using a BCRP inhibitor, and this pattern of resistance is also seen in a BCRP-expressing MCF-7-derived cell line, MCF-7.MR. In mice bearing wild-type (wt) and BCRP-expressing tumours on either flank, both
STX140 and
mitoxantrone inhibited the growth of the MCF-7wt xenografts, but only
STX140 inhibited growth of the MCF-7.MR tumours. In conclusion,
STX140, a promising orally bioavailable anti-
cancer agent in pre-clinical development, is highly efficacious in BCRP-expressing xenografts. This is despite an increase in BCRP expression in A2780 cells in vitro after chronic dosing with
STX140.