Functional consequence of MDR1 expression on imatinib intracellular concentrations

Widmer, Nicolas; Colombo, Sara; Buclin, Thierry; Décosterd, Laurent A.

doi:10.1182/blood-2003-03-0993

Cited by 71 publications

(42 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Third, we show that imatinib is a substrate for ABCB1, which confirms the findings of Dai et al 16 and Mahon et al 18 Additionally, Widmer et al 35 and Illmer et al 36 have recently shown that ABCB1-expressing cells have lower intracellular concentrations of imatinib, which is again supported by our data in 2 cell lines, one of which was transfected with ABCB1 and has been used as a model to demonstrate the transport of many other drugs 37 (Figures 1, 4). Our data have been produced using radiolabeled imatinib, which has thus far not been used in other studies of this type.…”

Section: Discussionsupporting

confidence: 80%

Active transport of imatinib into and out of cells: implications for drug resistance

Thomas

Wang

Clark

et al. 2004

Blood

590

453

View full text Add to dashboard Cite

Imatinib is a tyrosine kinase inhibitor that is effective in the treatment of chronic myeloid leukemia (CML). Not all patients achieve cytogenetic response. Some patients even lose the initial cytogenetic response. In this study, we investigated the active cellular transport of imatinib to gain a better understanding of the possible mechanisms of imatinib resistance. We used the leukemic cell line CCRF-CEM and its drug-resistant subline VBL 100 to measure the uptake of carbon 14 ( 14 C)-labeled imatinib. Imatinib uptake was temperature dependent, indicative of an active uptake process. Additionally, incubations with transport inhibitors showed that verapamil, amantadine, and procainamide, inhibitors of the human organic cation transporter 1 (hOCT1), significantly decreased imatinib uptake into CEM cells, whereas the inhibition of hOCT2 or hOCT3 had no effect, indicating that influx into the cells is an active process likely to be mediated by hOCT1. Studies using transfected MDCK cell lines revealed an active efflux component attributable to MDR1 (ABCB1). Both hOCT1 and MDR1 were expressed in CML primary cells and cell lines. The results indicate that active transport processes mediate the influx and efflux of imatinib. Differential expression of influx (hOCT1) and efflux (MDR1) transporters may be a critical determinant of intracellular drug levels and, hence, resistance to imatinib.

show abstract

Section: Discussionsupporting

confidence: 80%

Active transport of imatinib into and out of cells: implications for drug resistance

Thomas

Wang

Clark

et al. 2004

Blood

590

453

View full text Add to dashboard Cite

show abstract

“…Additionally, drug-transporter proteins in the placenta may impede transfer. 16,17 In contrast, high concentrations of imatinib and CGP74588 were detected in breast milk. However, a single measurement of a drug concentration in breast milk may not reflect a breast-fed infant's actual exposure as this varies with time.…”

Section: Commentmentioning

confidence: 92%

Imatinib mesylate and metabolite concentrations in maternal blood, umbilical cord blood, placenta and breast milk

et al. 2007

View full text Add to dashboard Cite

Treatment of maternal chronic myeloid leukemia with imatinib mesylate is avoided because of potential fetal effects. Two women with progression of disease during pregnancy required imatinib therapy. Concentrations of imatinib in maternal blood, placenta, umbilical cord blood and breast milk were 886, 2452, 0 to 157, and 596 ng/ml, respectively. Concentrations of the active metabolite CGP74588 in maternal blood, placenta, umbilical cord blood and breast milk were 338, 1462, 0 and 1513 ng/ml, respectively. As Imatinib and CGP74588 cross the mature placenta poorly, use of the drug after the first trimester may be reasonable under some circumstances. Imatinib and CGP74588 are found in breast milk, and therefore avoidance of breastfeeding is advisable.

show abstract

“…These are more restrictive -suboptimal response: minCyR at 3 months, PCyR at 6 months, no MMR at 12 months; failure: noCyR at Table 3. Analysis of resistance to IMA treatment [13][14][15][16][17][18][19][20][21][22][23][24] .…”

Section: Discussionmentioning

confidence: 99%

A significant proportion of patients with chronic myeloid leukemia and suboptimal response according to European Leukemia Net criteria have excellent prognosis without treatment change

Rosenberger¹,

Faber²,

Divoká³

et al. 2013

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

View full text Add to dashboard Cite

Background. The Recommendations of the European Leukemia Net (ELN) have become an essential tool in the management and prognosis of patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). However, the definition of suboptimal response remains under discussion. Methods. We used conventional cytogenetics for the detection of clonal changes in Ph-positive and negative clones. RT-PCR and sequencing were carried out on peripheral blood leukocytes to detect the type of BCR-ABL1 transcript. The BCR-ABL1 mutational status was assessed using sequencing of RT-PCR products. High performance capillary electrophoresis for determination of imatinib (IMA) plasma concentration was used. Results. A retrospective study of 110 patients diagnosed with chronic-phase (CP) CML treated with IMA or 2 nd generation TKIs in the years 2000-2009 focused on analysis of patients with suboptimal response according to ELN criteria. 40 patients were administered IMA as first-line therapy and 70 had been pretreated with interferon-alpha (IFN-α) with or without Ara-C and/or hydroxyurea (HU) for a median 12 months (range, 1-92 months). After adjusting for the ELN criteria, major molecular response (MMR) was achieved after median 34 and 39 months in 66.7% and 41.7% of patients after the first and second-line IMA therapy with suboptimal response defined as lack of achievement of MMR at the 18 th month of treatment, respectively. In comparison to patients with optimal response, patients with suboptimal response did not show significant differences in overall survival (OS) or progression-free survival (PFS). Cytogenetic assays demonstrated additional chromosome abnormalities (ACAs): chromosome 8 trisomy in a Ph-negative clone during the IMA treatment (in 1 case) and der(9q) in Ph-positive clone (in 2 cases); in patients receiving first-line IMA only chromosome 8 trisomy was observed which was associated with myelodysplastic syndrome -this was the only case where hematopoietic stem cell transplantation (HSCT) was performed. During the treatment with IMA in both subgroups no regulatory mutations in the ABL kinase domain were confirmed. Conclusion. We believe that the category of suboptimal response should be redefined or withdrawn from the ELN 2009 recommendations for management of CML patients treated with TKIs. Patients with suboptimal response who have no additional risks (additional cytogenetic abnormalities or BCR-ABL1 regulatory mutations) may remain on IMA treatment while patients with these risks should be switched to the 2 nd generation TKIs.

show abstract

Functional consequence of MDR1 expression on imatinib intracellular concentrations

Cited by 71 publications

References 9 publications

Active transport of imatinib into and out of cells: implications for drug resistance

Active transport of imatinib into and out of cells: implications for drug resistance

Imatinib mesylate and metabolite concentrations in maternal blood, umbilical cord blood, placenta and breast milk

A significant proportion of patients with chronic myeloid leukemia and suboptimal response according to European Leukemia Net criteria have excellent prognosis without treatment change

Contact Info

Product

Resources

About