Chemotherapy resistance in breast cancer.

Chemotherapy resistance is a major problem in the management of patients with breast cancer. Clinical resistance of solid tumors such as breast cancer is likely to be multifactorial and heterogeneous. Usually, patients refractory to chemotherapy exhibit resistance to multiple cytotoxic agents of different structure (and often function). A comparable experimental phenomenon has been termed multidnug resistance or MDR. MDR can be caused by various molecular mechanisms. One of these mechanisms is overexpression of MDR1/P-glycoprotein, which cna be expected in around 30-40% of primary and 50% of metastatic breast cancers. Preliminary evidence suggests that P-glycoprotein-positivity is associated with poor treatment outcome in both primary and advanced breast cancer. Studies of MDR reversal in metastatic breast cancer have generally yielded negative results. Recently, however, we found dexverapamil to be able to induce partial remissions to epirubicin in 4/23 patients (17%) with metastatic breast cancer refractory to the same dose and schedule of epirubicin alone. Dexverapamil did not increase the toxicity or the area under the plasma concentration-time curve of epirubicin. More carefully designed and conducted studies are needed to conclusively determine the clinical relevance of various resistance mechanisms in breast cancer and whether chemosensitizers such as dexverapamil or cyclosporins are able to enhance chemotherapy efficacy in this tumor.