Three of four patients with chronic myelogenous leukemia in blast crisis were found to express the multidrug resistance (MDR1) gene in their blast cells.
MDR1 RNA levels were usually elevated in untreated, intrinsically drug-resistant tumors, including those derived from the colon, kidney, adrenal gland, liver, and pancreas, as well as in carcinoid tumors, chronic myelogenous leukemia in blast crisis, and cell lines of non-small cell carcinoma of the lung (NSCLC) with neuroendocrine properties.
Expression of mdr1 was found in samples from patients with acute nonlymphocytic leukemia (13 of 17), chronic myelocytic leukemia (CML, chronic phase, 10 of 10; blast crisis, three of four), acute lymphocytic leukemia (ALL, eight of 11), B-cell chronic lymphocytic leukemia (B-CLL, 17 of 17), hairy cell leukemia (HCL, one of two), and T-cell prolymphocytic leukemia (one of one), but not in B-cell prolymphocytic leukemia (B-PLL, 0 of seven).
These studies support the idea that expression of the MDR1 gene contributes to drug resistance in ANLL, and may play a role in some instances in the drug-resistance of CML in blastic crisis.
We have developed a preclinical model of MDR/CML uncomplicated by other mechanisms of drug resistance to evaluate the effects of MDR1 overexpression on cytodestructive and differentiation therapy and the ability of sensitizers to restore chemosensitivity in this disease.
A chronic myeloid leukemia (CML) in blast crisis, however, showed combined increases in mdr1 (about 20-fold) and mrp (about four fold) gene expression after intense but unsuccessful chemotherapy over a 6-month period.
We have previously generated chronic myeloid leukemia (CML) cell lines resistant to the tyrosine kinase inhibitor imatinib mesylate (STI571), and one line (LAMA84-r) showed overexpression not only of the Bcr-Abl protein but also of Pgp.
Our previous studies have shown that overexpression of MDR1 and cyclooygenase-2 (COX-2) resulted in resistance development to imatinib in chronic myelogenous leukemia (CML) K562 (IR-K562) cells.
To investigate the interplay between these three modes of resistance, three CML blast crisis cell lines (K562, its ABCB1-overexpressing variant K562 Dox, and KU812) were cultured in gradually increasing concentrations of imatinib to 2 μM, or dasatinib to 200 nM.
The strong correlation between survivin and Pgp expression in late (p=0.018), but not in early (p=0.5) chronic phase of CML, suggests that this association may play a biological role in late CML phase and may offer an important target for the development of new therapies.
In conclusion, the present study suggests that single nucleotide polymorphisms of the influx transporter SLCO1B3 and the efflux transporter ABCB1 were functionally associated with individual variability of imatinib pharmacokinetics in Japanese patients with chronic myeloid leukemia.
LQB-118 treatment resulted in an important reduction of cell viability in cell lines derived from CML, both the vincristine-sensitive K562 cell line, and the resistant K562-Lucena (a cell line overexpressing P-glycoprotein).
Using flow cytometry, Pgp expression was more frequently observed in early chronic (P = 0.00) and in advanced (P = 0.02) CML phases when it was compared to MRP1 expression.
We aimed to determine plasma imatinib concentration, intracellular imatinib concentration, human organic cation transporter 1 (hOCT1) and adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) mRNA expression in bone marrow cells of CML patients in order to evaluate the potential usefulness of these measures as markers of imatinib efficacy and understand their clinical relationships.
Using MTT, Annexin V/flow cytometry, immunocytochemistry, subcellular fractionation, and Western blotting assays we analyzed the effect of imatinib in two blast phase of chronic myeloid leukemia (CML) cell lines: K562 P-glycoprotein (Pgp)-negative, and Lucena, Pgp-positive.