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Drug resistance to chemotherapy is an important factor of treatment failure in acute myeloid leukemia (AML). One type of resistance, the multidrug resistance (MDR), can develop after exposure to certain natural chemotherapeutic agents such as vinca alkaloids, anthracyclines, actinomycin D, and epipodophyllotoxins (Biedler & Riehm 1970). MDR is associated with overexpression of a 170 kDa membrane glycoprotein (P170), which is encoded by the mdr1 gene located on the long arm of chromosome 7 (Bradley et al. 1988). Membrane transport studies have shown that calcium channel blocking agents such as verapamil (VER) inhibit drug efflux by direct binding to P170 causing increased intracellular drug accumulation (Willingham et al. 1986; Safa et al. 1987). Recent clinical studies have indicated that MDR is induced by treatment with anthracyclines and vinca alkaloids in several hematologic malignancies (te Boekhorst et al. 1993). Thus, the expression of mdr1 is detected in about 50% of patients with pretreated AML, in contrast to only 20% of patients with de novo AML (Marie et al. 1991). Patients with mdr1 gene expression had a significantly shorter overall survival compared with the mdr1-negative group (Pirker et al. 1991). |
