N,N-diethyl-2-[4-(phenylmethyl)phenoxyl]ethanamine (
tesmilifene), a
tamoxifen derivative with
antihistamine activity, greatly enhanced the survival of
doxorubicin-treated, advanced stage
breast cancer patients in a phase III trial. However, the molecular basis of
tesmilifene action is not firmly established. The effects of
tesmilifene on activity of several anticancer drugs was investigated using human
head and neck squamous cell carcinoma (
HNSCC) and
breast carcinoma cell lines as a model system. Multidrug resistant (MDR) variants of an
HNSCC cell line, HN-5a/V15e, and a
breast carcinoma cell line, MCF-7/V25a, both highly overexpressed mdr1 (ABCB1)
mRNA and the
proteins P-glycoprotein and
glutathione transferase-pi.
Drug sensitivities were measured by a vital
stain after 4 days of continuous exposure to anticancer
drug in the absence and presence of
tesmilifene at a concentration that alone had no antiproliferative effect.
Tesmilifene had minimal effect on
drug cytotoxicity against the parental cell lines. However, the same
tesmilifene treatment enhanced cytotoxicity of
docetaxel,
paclitaxel,
epirubicin,
doxorubicin, and
vinorelbine against both MDR cell lines by up to 50%. Flow cytometric measurement of
annexin V/
propidium iodide staining demonstrated that
tesmilifene increased the killing of HN-5a/V15e cells caused by
docetaxel after 24 and 48h exposure.
Tesmilifene increased accumulation of radiolabelled
vincristine in HN-5a/V15e cells, over 4h, by up to 100%. The results suggest that
tesmilifene might be effective in the treatment of
tumors that are resistant to
natural product drugs. The mechanism of enhancement appears to be related to expression of an ABC pump-dependent, MDR phenotype.