MULTIDRUG-RESISTANCE IN LYMPHOMAS

Purpose: To discuss the significance of multidrug resistance (MDR) in human lymphomas and to review recent and ongoing clinical trials using MDR modulators.Design: A medical literature search was used to identi fy articles that reported results on the expression or modulation of M DR in human lymphomas. This review summarizes the various methods for detecting expression of the mdr1 gene in tumor specimens, the patterns of expression in lymphomas, and recent and upcoming clinical trials u sing modulating agents to reverse MDR. Results: There is considerable variation in the assays used to evaluate the expression of mdr1 in lym phomas. Current methodology includes reverse transcriptase polymerase chain reaction (rt-PCR) for assay of mdr1 mRNA, and immunohistochemist ry or flow cytometry for detection of the multidrug transporter, p-gly coprotein (P-gp). The preponderance of evidence suggests that mdr1 exp ression is relatively low in untreated patients (10% to 20% of lymphom as positive), but increases in patients with recurrent disease (50% to 70% positive). Some evidence suggests that mdr1 expression is a progn ostic factor for response to chemotherapy, as well as for subsequent s urvival. Verapamil and cyclosporine (CsA) have been used as competitiv e inhibitors of the multidrug transporter P-gp in early clinical trial s. Although these studies show some activity in modulating clinical MD R, both verapamil and CsA manifest considerable toxicities at doses be low those required for complete inhibition of P-gp function. Conclusio n: MDR due to the expression of the mdr1 gene is an important factor i n the course of patients with lymphomas. Continued clinical trials wit h more potent and less toxic modulators are needed to define the ultim ate benefit of modulating MDR in lymphomas.