Drug resistance in chemotherapy for breast cancer.

Recent developments with chemotherapy for breast cancer have improved patient survival. However, there continue to be nonresponders to conventional anticancer agents. Multidrug resistance (MDR) is caused by the expression of P-glycoprotein (P-gp) on the cell membrane. The expression of P-gp is encoded by MDR1 mRNA in tumors and is associated with clinical drug resistance. Since P-gp appears to be involved in both acquired and congenital MDR in human cancers, P-gp could be an important target for improving the efficacy of chemotherapy. Recently, we have focused on a therapeutic approach to reduce drug resistance in chemotherapy for breast cancer. Dofequidar fumarate (Dof) is a novel, orally active quinoline derivative that reverses multidrug resistance. In preclinical studies, the inhibition of doxorubicin-resistant cancer cell lines was observed in the presence of Dof + doxorubicin. We conducted clinical trials including Dof + cyclophosphamide (C), doxorubicin (A), and fluorouracil therapy (F) for patients with advanced or recurrent breast cancer. We compared the efficacy and tolerability of Dof + CAF with CAF alone. In this randomized, placebo-controlled trial, all patients were treated with six cycles of CAF therapy. Patients received Dof (900 mg p.o.) 30 min before doxorubicin. The primary endpoint was overall response rate (partial or complete response). In total, 221 patients were evaluable. The overall response rate was 42.6% for CAF alone versus 53.1% for Dof + CAF. Although the response rate improved by more than 10% with the combination of Dof + CAF, it was not statistically significant. Initially, we were expecting more than 20% improvement in the overall response rate. However, Dof significantly improved progression-free survival in patients who were premenopausal (P=0.046), who had received no prior therapy (P<0.01), or patients with advanced (stage IV) primary tumors (P=0.017). In addition, treatment with Dof did not affect the plasma concentration of doxorubicin in patients. These clinical studies indicate that Dof was well tolerated and displayed promising efficacy in patients who had not received prior therapy. The antiestrogens, tamoxifen, and toremifene, may moderate P-gp-related drug resistance in vitro. Toremifene demonstrated a synergistic effect in combination with paclitaxel on various human breast cancer cell lines. Furthermore, a synergistic effect was observed on a multidrug-resistant cell line. This synergistic effect was more potent when paclitaxel was combined with toremifene than with tamoxifen. Clinical benefits in some patients with recurrent breast cancer were reported.