MODULATION OF MULTIDRUG-RESISTANT TUMORS BY DEXVERAPAMIL

Clinical resistance of malignant tumors against cytostatic agents is a major obstacle to effective chemotherapy. A cell surface molecule (P-170) which acts as a pump has been identified as the underlying mechanism of the so-called multidrug resistance (MDR). Several compounds have been identified which can effectively block the action of P-170 and are able to render resistant tumor cells chemosensitive. Unfortunately, most modulators display intolerable side effects at therapeutic doses and are therefore not useful clinically. Preclinical studies show that dexverapamil (D-VPM), an optical isomer of the MDR modulator verapamil (Isoptin(R)), is able to effectively block the function of P-170. Cardiovascular effects are significantly reduced as compared to racemic verapamil, permitting dose escalations to plasma levels which modulate MDR in vitro assays. Promising clinical responses were observed in lymphoma patients, especially in the non-Hodgkin population. These encouraging trials deserve thorough succession studies.