Preferential Potentiation of Paclitaxel and Doxorubicin Cytotoxicity in Drug-Resistant Breast Tumor Cells by Tesmilifene.

5421 A phase III study of anthracycline-naive women with metastatic breast cancer by the National Cancer Institute of Canada Clinical Trials Group (MA.19) revealed that treatment of patients with doxorubicin in combination with N,N-Diethyl-2-[4-(Penylmethyl)Phenoxy]Ethanamine (tesmilifene) was superior to doxorubicin alone in terms of overall survival (P=0.021), with no difference seen in response rate or progression free survival (J. Clin. Oncol. 22: 269-276, 2004). One possible explanation for this observation may be that tesmilifene specifically increases the cytotoxicity of chemotherapy drugs only in rare drug-resistant cells, thus inhibiting the development of drug-resistant tumors over time. To assess this hypothesis, we examined in a clonogenic assay the effect of tesmilifene (at concentrations ranging from 0.1 to 6 μM) on the ability of doxorubicin or paclitaxel to kill wildtype MCF-7 breast tumor cells and isogenic MCF-7 cells resistant to doxorubicin or paclitaxel (MCF-7 DOX and MCF-7 TAX cells, respectively). Consistent with the above hypothesis, tesmilifene decreased the concentration at which 50% of MCF-7 TAX cells were killed by paclitaxel (the IC 50 ) in a dose-dependent manner by as much as 4-fold (at 6 μM tesmilifene), while having little effect or increasing the IC 50 for paclitaxel in wildtype MCF-7 cells, even at the highest concentration of tesmilifene. Cross resistance to doxorubicin in MCF-7 TAX cells was also reduced in a dose-dependent manner by as much as 4-fold by tesmilifene, while only slightly increasing the IC 50 for doxorubicin in wildtype MCF-7 cells at the highest concentration of tesmilifene. The IC 50 for doxorubicin was decreased by as much as 2.5-fold upon the addition of tesmilifene to MCF-7 DOX cells (also in a dose-dependent manner), with little change in the IC 50 for doxorubicin in wildtype cells. Since our MCF-7 TAX cell line overexpresses P-glycoprotein (P-gp), while our MCF-7 DOX cell line does not, it would appear that the effect of DPPE on the cytotoxicity of chemotherapy drugs in drug-resistant cells is not P-gp-specific, although this may be enhanced in P-gp-expressing cell lines. While accumulation of paclitaxel or doxorubicin was reduced in MCF-7 TAX and MCF-7 DOX cells, respectively, tesmilifene (at a 3 μM concentration) had no effect on the uptake of paclitaxel or doxorubicin into MCF-7, MCF-7 TAX , and MCF-7 DOX cells. Taken together, our data demonstrate that tesmilifene augments the cytotoxicity of paclitaxel and doxorubicin but only in drug-resistant cells through a mechanism unrelated to drug accumulation defects inherent in these cell lines.