Advertisement

Pathology & Oncology Research

, Volume 4, Issue 4, pp 251–257 | Cite as

Diagnostics of multidrug resistance in cancer

  • Gergely SzakÁCs 
  • Katalin Jakab 
  • Ferenc Antal 
  • Balázs Sarkadi 
Seminar

Abstract

Multidrug resistance (MDR), caused by the overexpression of two membrane proteins, MDR1-Pgp and/or MRP, is a major obstacle in the chemotherapy of cancer. The proper laboratory diagnosis of clinical multidrug resistance is still an unresolved question, and this uncertainty, in a vicious cycle, does not allow the correct evaluation of the clinical relevance of the MDR phenomenon. Moreover, inefficient MDR diagnostics hinders the de velopment of effective resistance-modulation strategies. In this review, after describing the basic features of the MDR drug pump proteins, the currently employed diagnostic methods are discussed. We suggest that a quantitative, functional method developed in our laboratory may provide a major help in the laboratory assessment of cancer MDR.

Key words

P-glycoprotein MDR1 MRP multidrug transporters diagnostic methods 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Endicott JA, Ling VZ: The biochemistry of P-glycoprotein mediated multidrug resistance. Annu Rev Biochem 58:137–171, 1989.PubMedCrossRefGoogle Scholar
  2. 2.
    Goldstein LJ, Pastan I, Gottesman MM: Multidrug resistance in human cancer. Critical Reviews in Oncology/Hematology 12:243–253, 1992.PubMedCrossRefGoogle Scholar
  3. 3.
    Gottesman MM, Pastan I: Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 62:385–427, 1993.PubMedCrossRefGoogle Scholar
  4. 4.
    Broxterman HJ, Giaccone G, Lankelma J: Multidrug resistance proteins and other drug transport-related resistance to natural product agents. Current Op Oncol 7:532–540, 1995CrossRefGoogle Scholar
  5. 5.
    Sarkadi B, Müller M, Holló Zs; The Multidrug transporters -proteins of an ancient immune system. Immunology Letters 54:215–219, 1996.PubMedCrossRefGoogle Scholar
  6. 6.
    Gottesman MM, Pastan I: The multidrug transporter, a double-edged sword. J Biol Chem 263:12163–12166, 1988.PubMedGoogle Scholar
  7. 7.
    Cole SPC, Bhardwaj G, Gerlach JH, et al: Overexpression of a novel transporter gene in a multidrug resistant human lung cancer cell line. Science 258:1650–1654, 1992.PubMedCrossRefGoogle Scholar
  8. 8.
    Leier I, Jedlitschky G, Buchholz U, et al: MRP gene encodes an ATP-dependent export pump for Leukotriene C4 and structuraly related conjugates. J Biol Chem 269:27807–278010, 1994.PubMedGoogle Scholar
  9. 9.
    Zaman GJR, Versantvoort CHM, Smit JJM, et al: Analysis of the expression of MRP, the gene for a new putative transmembrane drug transporter, in human multidrug resistant lung cancer cell lines. Cancer Res 53:1747–1750, 1993.PubMedGoogle Scholar
  10. 10.
    Kartenbeck J, Leuschner U, Mayer R, et al: Absence of the Canalicular Isoform of the MRP Gene-Encoded Conjugate Export Pump From the Hepatocytes in Dubin-Johnson Syndrome. Hepatology 23:1061–1066, 1966.Google Scholar
  11. 11.
    Schinkel AH, Smit JJ, van Teilingen O, et al: Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491–502, 1994.PubMedCrossRefGoogle Scholar
  12. 12.
    Schinkel AH, Mayer U, Wagenaar E, et al: P: Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc. Natl. Acad. Sci. USA 94:4028–4033, 1997.PubMedCrossRefGoogle Scholar
  13. 13.
    Filipits M, Suchomel RW, Zöcherbauer S, et al: Clinical relevance of drug resistance genes in malignant diseases. Leukemia 10, Suppl: S10-S17, 1996.PubMedGoogle Scholar
  14. 14.
    Higgins CF: ABC transporters-from microorganisms to man. Annu Rev Cell Biol 8:67–113, 1992.PubMedCrossRefGoogle Scholar
  15. 15.
    Borst P, Kool M, Ever s R: Do cMOAT (MRP2), other MRP homologues, and LRP play a role in MDR? Seminars in Cancer Biology 8:205–213, 1997.PubMedCrossRefGoogle Scholar
  16. 16.
    Jedlitschky G, Leier I, Buchholz U, et al: ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Res 54:4833–4836, 1994.PubMedGoogle Scholar
  17. 17.
    Müller M, Meijer C, Zaman GJR, et al: Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport. Proc Natl Acad Sci USA 91:13033–13037, 1994.PubMedCrossRefGoogle Scholar
  18. 18.
    Versantvoort CHM, Broxterman, HJ, Bagrij T, et al: Regulation by gluthatione of drug transport in multidrug resistant human lung tumour cell lines overexpressing MRP. Br J Cancer 72:82–89, 1995PubMedGoogle Scholar
  19. 19.
    Sarkadi B, Müller M: Search for specific inhibitors of multidrug resistance in cancer. Seminars in Cancer Biology 8:171–182, 1997.PubMedCrossRefGoogle Scholar
  20. 20.
    Raderer M, Scheithauer W: Clinical trials of agents that reverse multidrug resistance. Cancer 72:3553–3563, 1993.PubMedCrossRefGoogle Scholar
  21. 21.
    Sikic BI, Fisher GA, Lum BL, et al: Clinical reversal of multidrug resistance. Cancer Treat Res 73:149–65, 1994.PubMedGoogle Scholar
  22. 22.
    Fisher GA, Lum BL, Sikic BI: The reversal of multidrug resistance. Cancer Treat Res 78:5–70, 1995.Google Scholar
  23. 23.
    Ford JM: Experimental reversal of P-glycoprotein-mediated multidrug resistance by pharmacological chemosensitisers. Eur J Cancer 32A:991–1001, 1996.PubMedCrossRefGoogle Scholar
  24. 24.
    Sonneveld P: Reversal of multidrug resistance in acute myeloid leukemia and other haematological malignancies. Eur J Cancer 32A: 1062–1069, 1996.PubMedCrossRefGoogle Scholar
  25. 25.
    Broxtermann HJ, Lankelma J, Pinedo HM: How to Probe Clinical Tumour Samples for P-glycoprotein and Multidrug Resistance-associated Protein. Eur J Cancer 32A:1024–1033, 1996.CrossRefGoogle Scholar
  26. 26.
    Beck WT, Grogan TM: Methods to detect P-glycoprotein and implications for other drug resistance-associated proteins. Leukemia 11:1107–1109, 1997.PubMedCrossRefGoogle Scholar
  27. 27.
    Piwnica-Worms D, Rao VV, Kronauge JF, et al: Characterization of multidrug resistance P-glycoprotein transport function with an organotechnetium cation. Biochemistry 34(38):12210–12220, 1995.PubMedCrossRefGoogle Scholar
  28. 28.
    Taki J, Sumiya H, Asada N, et al: Assessment of P-glycoprotein in patients with malignant bone and soft-tissue tumors using technetium-99m-MIBI scintigraphy. J Nucl Med 39:1179–84, 1998PubMedGoogle Scholar
  29. 29.
    Kostakoglu L, Guc D, Canpinar H, et al: P-glycoprotein expression by technetium-99m-MIBI scintigraphy in hematologie malignancy. J Nucl Med 39:1191–1197, 1998.PubMedGoogle Scholar
  30. 30.
    Noonan KE, Beck C, Holzmayer TA, et al: Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction. Proc Nat Acad Sci 87:7160–7164, 1990.PubMedCrossRefGoogle Scholar
  31. 31.
    Okochi E, Iwahashi T, Tsuoro T: Monoclonal antibodies specific for P-glycoprotein. Leukemia 11:1119–1123, 1997.PubMedCrossRefGoogle Scholar
  32. 32.
    Flens MJ, Izquierdo MA, Scheffer GL et al: Immunochemical detection of the multidrug resistance-associated protein MRP in human multidrug resistant tumor cells by monoclonal antibodies. Cancer Res 51:4557–4563, 1994.Google Scholar
  33. 33.
    Beck WT, Grogan TM, Willman CL et al: Methods to Detect P-Glycoprotein-associated Multidrug Resistance in Patients Tumors: Consensus Recommendations. Cancer Res 56:3010–3020, 1996.PubMedGoogle Scholar
  34. 34.
    Marie JP, Legrand O, Perrot JY, et al: Measuring Multidrug Resistance Expression in Human Malignancies: Elaboration of Consensus Recommendations. Seminars in Hematology 34, Suppl 5:63–71, 1997.PubMedGoogle Scholar
  35. 35.
    Pétriz J, García-Lopez J: Flow cytometric analysis of P-glycoprotein function using rhodamine 123. Leukemia 11:1124–1130, 1997.PubMedCrossRefGoogle Scholar
  36. 36.
    Kuttesch JF Jr: Multidrug resistance in pediatrie oncology. Invest New Drugs 14:55–67, 1996.PubMedCrossRefGoogle Scholar
  37. 37.
    Brotherick I, Shenton BK, Egan M, et al: Examination of Multidrug Resistance in Cell Lines and Primary Breast Tumours by Flow Cytometry. Eur J Cancer 32A:2334–2341, 1996.PubMedCrossRefGoogle Scholar
  38. 38.
    Mechetner EB, Schott B, Morse BS, et al: P-glycoprotein function involves conformational transitions detectable by differential immunoreactivity. Proc Nat Acad Sci 94:12908–12913, 1997.PubMedCrossRefGoogle Scholar
  39. 39.
    Chevillard S, Vielh P, Validire P, et al: French multicentric evaluation of mdr1 gene expression by RT-PCR in leukemia and solid tumours. Standardization of RT-PCR and preliminary comparisons between RT-PCR and immunohistochemistry in solid tumours. Leukemia 11:1095–1106, 1997.PubMedCrossRefGoogle Scholar
  40. 40.
    Feller N, Kuiper CM, Lankelma J, et al: Functional detection of MDR1/P170 and MRP/P190-mediated multidrug resistance in tumour cells by flow cytometry. Br J Cancer 72:543–549, 1995.PubMedGoogle Scholar
  41. 41.
    Leith CP, Chen IM, Kopecky KJ, et al: Correlation of multidrug resistance (MDR1) protein expression with functional dye/drug efflux in acute myeloid leukemia by multiparameter flow cytometry: identification of discordant MDR-/efflux+ and MDR1+/efflux- cases. Blood 86:2329–2342, 1995.PubMedGoogle Scholar
  42. 42.
    Twentyman PR, Rhodes T, Rayner S: A comparison of rhodamine 123 accumulation and efflux in cells with P-glycoprotein-mediated and MRP-associated multidrug resistance pheno-types. Eur J Cancer 30A: 1360–1369, 1994.PubMedCrossRefGoogle Scholar
  43. 43.
    Homolya L, Holló Z, Germann UA, et al: Fluorescent cellular indicators are extruded by the multidrug resistance protein. J Biol Chem 268:21493–21496, 1993.PubMedGoogle Scholar
  44. 44.
    Holló Zs, Homolya L, Davis CW,et al: Calcein accumulation as a fluorometric functional assay of the multidrug transporter. Biochim Biophys Acta 1191:384–388, 1994.PubMedCrossRefGoogle Scholar
  45. 45.
    Homolya L, Hollo Z, Müller M, et al: A new method for quantitative assessment of P-glycoprotein-related multidrug resistance in turnout cells. Br J Cancer 73:849–855, 1996.PubMedGoogle Scholar
  46. 46.
    Feller N, Broxterman HJ, W hrer DCR, et al: ATP-dependent efflux of calcein by the multidrug resistance protein (MRP): no inhibition by intracellular glutathione depletion. FEBS Lett 368:385–388, 1995.PubMedCrossRefGoogle Scholar
  47. 47.
    Holló Zs, Homolya L, Hegedűs T, et al: Transport properties of the multidrug resistance-associated protein (MRP) in human tumour cells. FEBS Lett 383:99–104, 1996.PubMedCrossRefGoogle Scholar
  48. 48.
    Holló Zs, Homolya L, Hegedűs T, et al: Parallel functional and immunological detection of human multidrug resistance Proteins, P-glycoprotein and MRP1. Anticancer Res 18:2981–2988, 1988.Google Scholar
  49. 49.
    Legrand O, Simonin G, Perrot H, et al: Pgp and MRP activities using calcein-AM are prognostic factors in adult acute myeloid leukemia patients. Blood 91:4480–8, 1998.PubMedGoogle Scholar
  50. 50.
    Legrand O, Simonin G, Zittoun R, et al: Both P-gp and MRP contribute to drug resistance in AML. Leukemia 12:1327–1328, 1998.PubMedCrossRefGoogle Scholar
  51. 51.
    Raspadori D, Lauria F, Ventura A, et al: Incidence and prognostic relevance of CD34 expression in acute myeloblastic leukemia: analysis of 141 cases. Leukemia Res 21:603–607, 1997CrossRefGoogle Scholar
  52. 52.
    Boekhorst PA, Leeuw K, Schoester M, et al: Predominance of functional multidrug resistance (MDR-1) phenotype in CD34+ acute myeloid leukemia cells. Blood 82:3157–3162,1993Google Scholar
  53. 53.
    Nuessler V, Gullis E, Pelka-Fleischer R, et al: Expression and functional activity of P-glycoprotein in adult acute myeloge-nous leukemia patients. Ann Haematol 75:17–26, 1997CrossRefGoogle Scholar
  54. 54.
    Martinez A, San Miguel JF, Valverde B, et al: Functional expression of MDR-1 in acute myeloid leukemia: correlation with the clinical-biological, immunophenotypical, and prognostic disease characteristics. Ann Haematol 75:81–86, 1997CrossRefGoogle Scholar
  55. 55.
    Del Poeta G, Stasi R, Aronica G, et al: Clinical relevance of P-glycoprotein expression in de novo acute myeloid leukemia. Blood 87:1997–2004, 1996PubMedGoogle Scholar
  56. 56.
    Lamy T, Goasguen J, Mordetet E, et al: P-Glycoprotein (P-170) and CD34 expression in adult acute myeloid leukemia (AML). Leukemia 8:1879–1883, 1994PubMedGoogle Scholar
  57. 57.
    Heuvel-Eibrink MM, Holt B, te Boekhorst PA et al: MDR1 expresssion is an independent prognostic factor for response and survival in de novo acute myeloid leukaemia. British Journal of Haematology 99: 76–83, 1997PubMedCrossRefGoogle Scholar
  58. 58.
    Wattel E, Lepelley P, Merlat A, et al: Expression of the multidrug resistance P glycoprotein in newly diagnosed adult acute lymphoblastic leukemia: absence of correlation with response to treatment. Leukemia 9:1870–1874, 1995PubMedGoogle Scholar
  59. 59.
    Schneider E, Cowan KH, Bader H, et al: Increased expression of the multidrug resistance-associated protein gene in relapsed acute leukemia. Blood 85:186–193, 1995.PubMedGoogle Scholar
  60. 60.
    Kuss BJ, Deeley RG, Cole SP, et al: The biological significance of the multidrug resistance gene MRP in inversion 16 leuke-mias. Leuk Lymphoma 20:357–364, 1996PubMedCrossRefGoogle Scholar
  61. 61.
    Salmon SE, Dalton WS, Grogan TM, et al: Multidrug-resistant myeloma: laboratory and clinical effects of verapamil as a chemosensitizer. Blood 78:44–50, 1991.PubMedGoogle Scholar
  62. 62.
    Watanabe T, Tsuge H, Oh-Hara T, et al: Comparative study on reversal efficacy of SDZ PSC 833, cyclosporin A and verapamil on multidrug resistance in vitro and in vivo. Acta Oncol 34:235–41, 1995.PubMedCrossRefGoogle Scholar
  63. 63.
    Kornblau SM, Estey E, Madden T, et al: Phase I study of Mitoxantrone plus Etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia. J Clin Oncol 15:1796–1802, 1997.PubMedGoogle Scholar
  64. 64.
    Wattel E, Solary E, Hecquet B, et al: Quinine improves the results of intensive chemotherapy in myelodysplastic syndromes expressing P glycoprotein: results of a randomized study. Br J Haematol 102:1015–1024, 1998.PubMedCrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 1998

Authors and Affiliations

  • Gergely SzakÁCs 
    • 1
    • 2
  • Katalin Jakab 
    • 1
    • 2
  • Ferenc Antal 
    • 1
    • 2
  • Balázs Sarkadi 
    • 1
    • 2
  1. 1.National Institute of Haematology and ImmunologyBudapestHungary
  2. 2.Membrane Research Group of the Hungarian Academy of SciencesBudapestHungary

Personalised recommendations