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Despite of many advances in the treatment of acute leukemia, one of the remaining obstacles is still the development of resistance to certain structurally unrelated cytotoxic agents [9]. A major factor responsible for the multidrug resistance (MDR) phenotype is the decreased drug accumulation in tumour cells, associated with the overexpression of a 170-kilodalton transmembrane glycoprotein (P-170), that acts as an energy-dependent drug-efflux pump [5,8]. Mdrl messenger RNA coding for P-170 has been shown to be present in several human tumours and also in some normal tissues [4]. A variety of agents such as calcium antagonists and calmodulin inhibitors are able to overcome MDR by inhibiting the transport function of the P-170 glycoprotein. This inhibition leads to an increase in intracellular drug concentration and thus to a partial or complete restoring of normal cell sensitivity [7,15,16]. We tested R-verapamil and the dihydropyridine derivative B8509-035 for their MDR reversing capacities. In comparison with niguldipine and Sverapamil these optical antipodes show lowest effects on blood pressure, but are equally efficient in resistance modulation [13]. |
