Abstract
Lung resistance-related protein (LRP) and P-glycoprotein (P-gp) are associated with multidrug resistance. P-gp overexpression reduces intracellular anticancer drug concentrations and is correlated with low remission rates. However, whether the presence of LRP influences the response to induction chemotherapy remains controversial. Therefore, we investigated the relationship of LRP and P-gp overexpression with the response to induction chemotherapy. Univariate analysis revealed that there was a significant difference between complete remission rates for acute myelogenous leukemia patients depending on their blast cell expressions, between LRP positive versus negative, P-gp positive versus negative, and LRP/P-gp double positive versus other groups. Crude odds ratios (ORs) for complete remission were 0.390, 0.360, and 0.307 for LRP positive, for P-gp positive, and LRP/P-gp double positive patients, respectively. After controlling the confounding variables by stepwise multivariate logistical regression analysis, the presence of LRP/P-gp double positivity and P-gp positivity were found to be independent prognostic factors; adjusted ORs were 0.233 and 0.393, respectively. Furthermore, the monoclonal antibody against LRP significantly increased daunorubicin acumulation (P=0.004) in the nuclei of leukemic blast cells with LRP positivity in more than 10% of the cells. An LRP reversing agent, PAK-104P, was found to increase the daunorubicin content with marginal significance (P=0.060). The present results suggest that not only the presence of P-gp, but also LRP in leukemic blast cells is a risk factor for resistance to induction chemotherapy. Inhibiting LRP function, similar to the inhibition of P-gp function, will be necessary to improve the effectiveness of induction chemotherapy.
Highlights
The clinical outcome of acute myelogenous leukemia (AML) has improved with advancements in chemotherapy, treatment isKey words: lung resistance-related protein, P-glycoprotein, reversing agent, acute myelogenous leukemia.Gabriel
Ninety-six de novo AML patients and 8 patients with overt leukemia transformed from myelodysplastic syndrome (MDS) were treated with idarubicin and arabinosylcytosine according to the Japan Adult Leukemia Study Group (JALSG) AML95 and MDS protocols
The remaining 3 de novo AML patients and 3 patients with overt leukemia transformed from MDS were treated according to the CAG protocol
Summary
The clinical outcome of acute myelogenous leukemia (AML) has improved with advancements in chemotherapy, treatment is. After presence of LRP has on daunorubicin (DNR) risk category included patients with abnormalcontrolling the confounding variables by step- content in the nuclei of leukemic blast cells. Sis, the presence of LRP/P-gp double positivity the response to induction chemotherapy in without either a del(9q) or a complex karyand P-gp positivity were found to be independ- AML patients. Article transformed from MDS were treated with Isolation of nuclei ters such as age, subtype (i.e. AML and MDS), behenoylcytarabine, DNR, and 6-mercaptopurine according to the Japan Adult Leukemia Study Group (JALSG) AML92 protocol.. Relapse was defined as the presence of more than 5% blasts in marrow ly aspirates or development of extra-medullary leukemia in patients with previously docun mented CR after one course of induction o chemotherapy according to National Cancer. The nuclei were suspended in aqueous counting scintillant (Amersham Biosciences, Buckinghamshire, UK), and the radioactivity in the nuclei of 1×104 cells was determined by a liquid scintillation counter system (LSC-700; Aloka, Tokyo, Japan)
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