P-glycoprotein Activity Predicts Outcome in Childhood Acute Lymphoblastic Leukemia

Abstract

Treatment of children with acute lymphoblastic leukemia (ALL) is based on P-glycoprotein (P-gp)-dependent cytostatics. We assessed the P-gp function in blast cells as a possible prognostic factor and its influence on the overall survival. P-gp function was measured using the verapamil-sensitive Rhodamine efflux. Cell samples from 7 of 45 (16%) patients revealed rhodamine-efflux positive blasts. There were no relations between the presence of P-gp, clinical characteristics (age, sex, hepatomegaly, and splenomegaly) and initial laboratory parameters (immunophenotype, white blood cells count, and serum lactate dehydrogenase) in ALL. P-gp activity plays a negative role, both for a remission achieved on day 33 and for susceptibility to steroid therapy. Children bearing rhodamine-efflux positive blasts had a significantly shorter 5-year overall survival of 35%, as compared with 74% in those negative for P-gp function. Lack of any association with clinical characteristic and initial laboratory parameters suggests that presence of P-gp is an independent prognostic factor.

MRP1 and P-glycoprotein expression assays would be useful in the additional detection of treatment non-responders in CML patients without ABL1 mutation

“…MDR mediated by efflux pump hyperactivation is known to be an important resistance mechanism in acute leukemia [13,14]. By contrast, the relationship between MDR protein expression/activation and resistance to TKIs in CML has not been analyzed adequately, and the utility of the rhodamine-123 efflux assay (MDR functional assay) and MRP1/Pgp expression assays (MDR expression assay) in the prediction of treatment resistance in CML needs to be more fully evaluated.…”

Drug Efflux Transporters and Multidrug Resistance in Acute Leukemia: Therapeutic Impact and Novel Approaches to Mediation

“…P-gp expression on the surface of acute nonlymphoblastic lymphoma cells obtained at the time of diagnosis was associated with significantly lower CR rates and shorter survival times in a study of 150 patients (Campos et al, 1992). Likewise, P-gp activity identified with a rhodamine efflux assay was associated with significantly shorter OS times for pediatric ALL in one study (Brozek et al, 2009) and with responses to induction, relapse rates, and OS times for adult AML but not newly diagnosed pediatric ALL in another study (Wuchter et al, 2000). P-gp is not the only MDR transporter to be associated with poorer responses to therapy and survival rates for acute leukemia.…”

Iron containing anti-tumoral agents: unexpected apoptosis-inducing activity of a ferrocene amino acid derivative

“…We suppose that the cells developed resistance by overexpression of p-glycoprotein and Bcl-2, which are common causes of MDR. The expression of these proteins in childhood ALL correlates with the poor response to chemotherapy (Srinivas et al 2000;Brozek et al 2009, Prokop et al 2000. Using gene expression analysis, we found a 50-fold upregulation of the pro-apoptotic harakiri gene in lymphoma cells treated with the ferrocene derivative.…”