Antineoplastic enhancer - tesmilifene
Despite huge advances in treatment, breast cancer remains the second biggest cancer killer of women, with a million new cases diagnosed worldwide every year. As many breast cancers are dependent on a low level of oestrogen circulating to thrive, if this is removed tumours will shrink. Thus drug treatment of breast cancer is heavily reliant on antioestrogenic agents that block the mitogenic effects of the hormone, with tamoxifen having proved particularly successful.
However, as well as acting as a competitive antagonist for 17b-oestradiol at the oestrogen receptor, tamoxifen also acts as a partial oestrogen agonist. While some of the effects this causes are beneficial, such as lipid lowering activity, it also increases the incidence of endometrial cancer. Hence an antioestrogen antagonist with cytotoxic effects but without the partial oestrogen receptor agonism would be an advantage. This means aiming for a different target from the oestrogen receptor.
AEBS is a membranous protein complex that binds triphenylethylenic antioestrogens with high affinity. YM BioSciences discovered that the compound tesmilifene acts specifically at this site, and has no affinity for the oestrogen receptor.1 As a result, it is being investigated as a potential agent for use in the treatment of breast cancer, and also prostate cancer, another hormone-dependent malignancy.
In a Phase II study in 23 women with meta-
static breast cancer, the subjects were given 6mg/kg tesmilifene intravenously every three weeks for up to seven cycles, in conjunction with standard doxorubicin therapy. The response rate observed was higher than historical cases where doxorubicin was administered alone.2 A further Phase II trial in 42 women showed similar results, with toxicities similar to
historical cases.3
These results led to a Phase III trial being carried out in 305 patients with metastatic or recurrent breast cancer.4 Again, they were given tesmilifene in addition to doxorubicin, this time in a comparative study with women given doxorubicin alone. Interim analysis failed to detect a difference in response rate of more than 5%, so the trial was closed to additional accrual and tesmilifene dosing stopped. Follow-up studies showed no significant difference in response rate or duration, or progression-free survival. However, tesmilifene dosed patients did display a statistically superior overall survival rate, and further trials are thus warranted.