Multiple Drug Resistance Mediated by P-Glycoprotein is not a Major Factor in a Slow Response to Therapy in Childhood All

Abstract

In childhood acute lymphoblastic leukemia (ALL), early response to treatment is an important prognostic factor and drug resistance is a major cause of poor outcome. One of the most investigated resistance mechanisms is P-glycoprotein (P-gp)-mediated multiple drug resistance (MDR). We analyzed P-gp using flow cytometry with monoclonal antibody JSB1 in a series of 118 children with ALL, 103 at diagnosis and 15 at relapse. Increased P-gp expression was found in 55 (53%) patients at diagnosis and in 11 (73%) at relapse. We also analyzed the bone marrow aspirate slides for early response to treatment in a central review. No correlation was found between P-gp and early response. Patients with T-ALL had higher P-gp levels than the others, 5.3% versus 1.0% (P = .002). We conclude that P-gp-mediated multiple drug resistance is not a factor in a slow response to ALL induction therapy.

Further elucidation of mechanism of resistance to vincristine in myeloid cells: role of hypochlorous acid in degradation of vincristine by myeloperoxidase

“…18 In our study, blast cells from two patients with high VCR LC 50 and increased MDR function also had HOCl production indicating the presence of multiple factors contributing to VCR resistance in AML blasts. Moreover, VCR-induced apoptosis indexes observed in MPO-negative cell lines were quite close to HL-60, even lower, suggesting the involvement of different mechanisms in VCR resistance.…”

Novel mechanisms of drug resistance in leukemia

“…12 In contrast to AML, the consensus among studies of acute lymphoblastic leukemia is less as to the prognostic significance of Pgp expression, with some studies reporting Pgp as an adverse prognostic factor 13,14 and others not. [15][16][17][18] A number of agents have been identified that can inhibit Pgp drug efflux. 2 The older, first-generation drugs used in this context include extant drugs found to be substrates for Pgp, including verapamil, cyclosporin A, tamoxifen, and the phenothiazines.…”

Expression of P-glycoprotein, Cyclin D1 and Ki-67 in Acute Lymphoblastic Leukemia: Relation with Induction Chemotherapy and Overall Survival

“…Although some studies showed that PGP expression may be related to poor prognosis [15,16], we and others [17,18] give no indication that PGP is clinically important in ALL (relatively young population). This discrepancy may be explained by the relatively short time (15.6 months) for which our patients were observed considering the long term possibility of the occurrence of a relapse in ALL.…”