Multi-drug resistance in chronic lymphocytic leukemia

We evaluated 45 chronic lymphocyte leukemia (CLL) patients for the presence of multi-drug resistance (MDR) by the ex vivo techniques: 1) a functional assay utilizing doxorubicin (dox) retention with modulation; 2) a cytotoxic ity assay (MTT) with modulation; 3) and four monoclonal antibodies. Ex vivo tests were correlated with disease stage and prior treatment, and were rep eated as patients became resistant to alkylating agents, fludarabine and VA D chemotherapy (infusion of vincristine, dox, and oral dexamethasone). The majority of patients (64.4%) were in early stage and were untreated (62.2%) . P-glycoprotein (p-gp 170) was detected most frequently by the monoclonal antibody MRK-16 (48%) and by functional modulation of dox retention by PSC- 833 (40.6%) and by functional modulation of the MTT assay with vincristine (0.29) and dox (0.39) with PSC-833 at 1.0 mu g/mL. Functional modulation of dox retention with PSC-833 was significantly associated with stage, but no t with either the MTT assay or any of the monoclonal antibodies. None of th e tests correlated with prior chlorambucil treatment. Correlation of dox re tention with the monoclonal antibodies was mild to moderate and became stro nger following chlorambucil treatment. Three patients who became resistant to VAD were found to express p-gp 170. We conclude that MDR can frequently be detected in patients with CLL. Furthermore, the expression of p-gp 170 i ncreases with advancing stage, but not prior alkylating agent therapy. The functional expression of p-gp 170 increases with advancing stage and prior treatment and correlates well with monoclonal antibody detection (especiall y MRK-16). Patients who become resistant to VAD more frequently express p-g p 170 by a variety of techniques. PSC-833 is a more potent modulator of MDR than cyclosporin-a (CsA) ex vivo, and correlates better with stage of dise ase.