LOGIN TO YOUR ACCOUNT

Username
Password
Remember Me
Or use your Academic/Social account:

CREATE AN ACCOUNT

Or use your Academic/Social account:

Congratulations!

You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.

Important!

Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message

CREATE AN ACCOUNT

Name:
Username:
Password:
Verify Password:
E-mail:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Publisher: Elsevier
Languages: English
Types: Article
Subjects:

Classified by OpenAIRE into

mesheuropmc: hemic and lymphatic diseases, neoplasms

Objective: To investigate the interaction of imatinib mesylate (IM) with the clinically relevant adenosine triphosphate-binding cassette efflux transporter MDR1 (ABCB1) in cells from patients with chronic myeloid leukemia (CML) and to explore whether inhibition of this transporter would improve IM's efficacy in the elimination of CML CD34+ cells by increasing cell-associated drug accumulation.

\ud \ud

Materials and Methods: Cells from newly diagnosed chronic-phase CML patients were harvested by leukapheresis and enriched to >95% CD34+. Expression of the transporter gene MDR1 was performed by quantitative reverse transcription polymerase chain reaction. Interaction of IM with MDR1 was analyzed by substrate (rhodamine 123) displacement assay. Cell-associated levels of IM in CML CD34+ cells were measured by high-pressure liquid chromatography. Intracellular phospho-CrkL levels, apoptosis in total CML CD34+ cells and high-resolution tracking of cell division were assayed by flow cytometry.

\ud \ud

Results: Measurements of cell-associated IM uptake showed significantly lower drug levels in CD34+ cells, particularly the CD38- subpopulation, as compared to IM-sensitive K562 cells. MDR1 was expressed at low level and dye efflux studies demonstrated very little MDR1 activity in CML CD34+ cells. Furthermore, combination treatment of primitive CML cells with IM and the MDR1 inhibitor PSC833 did not result in elevated cell-associated IM levels. Although we observed slightly enhanced cytostasis with IM when combined with PSC833, this was independent of BCR-ABL inhibition because no associated decrease in phospho-CrkL was observed.

\ud \ud

Conclusions: Our findings demonstrate that inhibition of MDR1 neither enhances the effect of IM against BCR-ABL activity, nor significantly potentiates IM's efficiency in eliminating primitive CML cells.

  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.
    • 3. Roumiantsev S, Shah NP, Gorre ME, et al. Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop. Proc Natl Acad Sci USA. 2002;99:10700-10705.
    • 4. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876- 880.
    • 5. Swords R, Quinn J, Fay M, O'Donnell R, Goldman J, Murphy PT. CML clonal evolution with resistance to single agent imatinib therapy. Clin Lab Haematol. 2005;27:347-349.
    • 6. Willis SG, Lange T, Demehri S, et al. High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood. 2005;106:2128-2137.
    • 7. Quintás-Cardama A, Kantarjian H, Cortes J. Targeting ABL and SRC kinases in chronic myeloid leukemia: experience with dasatinib. Future Oncol. 2006;2:655-665.
    • 8. Melo JV, Chuah C. Resistance to imatinib mesylate in chronic myeloid leukaemia. Cancer Lett. 2007;249:121-132.
    • 9. Azam M, Latek RR, Daley GQ. Mechanisms of autoinhibition and STI571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cel.l 2003;112:831-843.
    • 10. Corbin AS, La Rosee P, Stoffregen EP, Druker BJ, Deininger MW. Several BcrAbl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood. 2003;101:4611-4614.
    • 11. Kantarjian H, Talpaz M, O'Brien S, Garcia-Manero G, Verstovsek S, Giles F et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosomepositive chronic phase chronic myeloid leukemia. Blood. 2004;103:2873-2878.
    • 12. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354:2531-2541.
    • 13. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006;354:2542-2551.
    • 14. White DL, Saunders VA, Dang P, et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood. 2007;110:4064- 4072.
    • 15. White DL, Saunders VA, Dang P, et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood. 2006;108:697-704.
    • 16. Hegedus T, Orfi L, Seprodi A, Varadi A, Sarkadi B & Keri G. Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1. Biochim Biophys Acta. 2002;1587:318−325.
    • 17. Shukla S, Sauna ZE, Ambudkar SV. Evidence for the interaction of imatinib at the transport-substrate sites of the multidrug-resistance linked ABC drug transporters ABCB1 (P-glycoprotein) and ABCG2. Leukemia. 2008;22:445-447.
    • 18. Hamada A, Miyano H, Watanabe H, Saito H. Interaction of imatinib mesilate with human P-glycoprotein. J Pharmacol Exp Ther. 2003;307:824-828.
    • 19. Dai H, Marbach P, Lemaire M, Hayes M & Elmquist WF. Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J Pharmacol Exp Ther. 2003;304:1085−1092.
    • 20. Hirayama C, Watanabe H, Nakashima R, Nanbu T, Hamada A, Kuniyasu A et al. Constitutive overexpression of P-glycoprotein, rather than breast cancer resistance protein or organic cation transporter 1, contributes to acquisition of imatinibresistance in K562 Cells. Pharm Res. 2008;25:827-835.
    • 21. Illmer T, Schaich M, Platzbecker U, et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia. 2004;18:401-408.
    • 22. Mahon FX, Belloc F, Lagarde V, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003;101:2368- 2373.
    • 23. Widmer N, Rumpold H, Untergasser G, Fayet A, Buclin T, Decosterd. Resistant reversal by RNAi silencing of MDR1 in CML cells associated with increase in imatinib intracellular levels. Leukemia. 2007;21:1561-1562.
    • 24. Rumpold H, Wolf AM, Gruenewald K, Gastl G, Gunsilius E, Wolf D. RNAimediated knockdown of P-glycoprotein using a transposon-based vector system durably restores imatinib sensitivity in imatinib-resistant CML cell lines. Exp Hematol. 2005;33:767-775.
    • 25. Ferrao PT, Frost MJ, Siah SP, Ashman LK. Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro. Blood. 2003;102:4499-4503.
    • 26. Zong Y, Zhou S, Sorrentino BP. Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia. Leukemia. 2005;19:1590-1596. 28. Holyoake T, Jiang X, Eaves C, Eaves A. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood. 1999;94:2056-2064.
    • 30. Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood. 2006;107:4532- 4539.
    • 31. Graham SM, Jørgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99:319-325.
    • 32. Larson RA, Druker BJ, Guilhot F, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008;111:4022-4028.
    • 33. Jordanides NE, Jorgensen HG, Holyoake TL, Mountford JC. Functional ABCG2 is overexpressed on primary CML CD34+ cells and is inhibited by imatinib mesylate. Blood. 2006;108:1370-1373.
    • 34. Noonan KE, Beck C, Holzmayer TA, Chin JE, Wunder JS, Andrulis IL, Gazdar AF et al. Quantitative analysis of MDR1 (multidrug resistance) gene expression in 35. Galimberti S, Guerrini F, Palumbo GA, Consoli U, Fazzi R, Morabito F et al. Evaluation of BCRP and MDR-1 co-expression by quantitative molecular assessment in AML patients. Leuk Res. 2004;28:367-372 do you use this?
    • 36. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using realtime quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402- 408. do you use this?
    • 37. Guetens G, Prenen H, De Boeck G, van Oosterom A, Schöffski P, Highley M, et al. Simultaneous determination of AMN107 and Imatinib (Gleevec, Glivec, STI571) in cultured tumour cells using an isocratic high-performance liquid chromatography procedure with UV detection. J Chromatogr B Analyt Technol Biomed Life Sci 2007: 846;341-345.
    • 38. Robey RW, Honjo Y, van de Laar A, Miyake K, Regis JT, Litman T. et al. A functional assay for detection of the mitoxantrone resistance protein, MXR (ABCG2). Biochim Biophys Acta. 2001;1512:171-182.
    • 39. Hamilton A, Elrick L, Myssina S, Copland M, Jørgensen H, Melo JV, et al. BCRABL activity and its response to drugs can be determined in CD34+ CML stem cells by CrkL phosphorylation status using flow cytometry. Leukemia. 2006;20:1035-1039.
    • 40. Jiang X, Zhao Y, Smith C, Gasparetto M, Turhan A, Eaves A, et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCRABL targeted therapies. Leukemia. 2007;21:926-935.
    • 41. Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004;104:3739-3745.
    • 42. Stavrovskaya A, Turkina A, Sedyakhina N, et al. Prognostic value of pglycoprotein and leukocyte differentiation antigens in chronic myeloid leukemia. Leuk Lymph. 1998;28:469-482.
    • 43. Carter A, Dann EJ, Katz T, et al. Cells from chronic myelogenous leukaemia patients at presentation exhibit multidrug resistance not mediated by either MDR1 or MRP1. Br J Haematol. 2001;114:581-590.
    • 44. White DL, Saunders VA, Quinn SR, Manley PW, Hughes TP. Imatinib increases the intracellular concentration of nilotinib, which may explain the observed synergy between these drugs. Blood. 2007;109:3609-3610.
    • 45. Houghton PJ, Germain GS, Harwood FC, et al. Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res. 2004;64:2333-2337.
    • 46. Burger H, van Tol H, Boersma AW, et al. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood. 2004;104:2940-2942.
    • 47. Peng B, Hayes M, Resta D, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol. 2004;22: 935-942.
    • 48. Wang L, Giannoudis A, Lane S, Williamson P, Pirmohamed M, Clark RE. Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther. 2008;83:258-264.
    • 49. Szakács G, Váradi A, Ozvegy-Laczka C, Sarkadi B. The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov Today. 2008;13:379-393.
  • No related research data.
  • No similar publications.

Share - Bookmark

Download from

Cite this article