Skip to main content

Advertisement

SpringerLink
Log in

P-glycoprotein-mediated multidrug resistance in normal and neoplastic hematopoietic cells

  • Review Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Summary

The multidrug transporter, P-glycoprotein (P-gp), is expressed by CD34-positive bone marrow cells, which include hematopoietic stem cells, and in other cells in the bone marrow and peripheral blood, including some lymphoid cells. Multidrug resistance mediated by P-gp appears to be a major impediment to successful treatment of acute myeloid leukemias and multiple myelomas. However, the impact of P-gp expression on prognosis has to be confirmed in several other hematopoietic neoplasms. The role of P-gp in normal and malignant hematopoiesis and clinical attempts to circumvent multidrug resistance in hematopoietic malignancies are reviewed. The recent transduction of the MDR1 gene into murine hematopoietic cells, which protects them from toxic effects of chemotherapy, suggests that MDR1 gene therapy may help prevent myelosuppression following chemotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ambudkar SV, Lelong IH, Zhang J, Cardarelli CO, Gottesman MM, Pastan I (1992) Partial purification and reconstitution of the human multidrug-resistance pump: characterization of the drug-stimulatable ATP hydrolysis. Proc Natl Acad Sci USA 89:8472–8476

    PubMed  Google Scholar 

  2. Anderson MP, Gregory RJ, Thompson S, Souza DW, Paul S, Mulligan RC, Smith AE, Welsh MJ (1991) Demonstration that CFTR is a chloride channel by alteration of its anion selectivity. Science 253:202–205

    PubMed  Google Scholar 

  3. Bear CE, Li CH, Kartner N, Ramjeesingh M, Riordan JR (1992) Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator. Cell 68:809–818

    PubMed  Google Scholar 

  4. Biedler JL (1991) Genetic aspects of multidrug resistance. Cancer [Suppl] 70:1799–1809

    Google Scholar 

  5. Black SM, Wolf CR (1991) The role of glutathione-dependent enzymes in drug resistance. Pharmacol Ther 51:139–154

    PubMed  Google Scholar 

  6. Bradley G, Juranka PF, Ling V (1988) Mechanism of multidrug resistance. Biochem Biophys Acta 948:87–128

    PubMed  Google Scholar 

  7. Brown JM (1990) Tumor hypoxia, drug resistance, and metastases. J Natl Cancer Inst 82:338–339

    PubMed  Google Scholar 

  8. Campos L, Guyotat D, Archimbaud E, Calmard-Oriol P, Tsuruo T, Troncy, Treille D, Fiere (1992) Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood 79:473–476

    PubMed  Google Scholar 

  9. Chabner B, Wilson W (1991) Reversal of multidrug resistance. J Clin Oncol 9:17–24

    PubMed  Google Scholar 

  10. Chabner BA, Bates S, Fojo T, Bryant. G, Herdt G, Wittes R, Wilson WH (1992) Drug resistance in malignant lymphoma: experience with EPOCH chemotherapy. Ann Oncol 3:63

    Google Scholar 

  11. Chan HSL, Thorner PS, Haddad G, Ling V (1990) Immunohistochemical detection of P-gylcoprotein: prognostic correlation in soft tissue sarcomas of childhood. J Clin Oncol 8:689–704

    PubMed  Google Scholar 

  12. Chaudhary PM, Roninson IB (1991) Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 66:85–94

    PubMed  Google Scholar 

  13. Chaudhary PM, Roninson IB (1993) Induction of multidrug resistance in human cells by transient exposure to different chemotherapeutic drugs. J Natl Cancer Inst 85:632–639

    PubMed  Google Scholar 

  14. Chaudhary PM, Mechetner EB, Roninson IB (1992) Expression and activity of the multidrug resistance P-glycoprotein in human peripheral blood lymphocytes. Blood 80:2729–2934

    PubMed  Google Scholar 

  15. Chauffert B, Martin M, Hammann A, Michel MF, Martin F (1986) Amiodarone-induced enhancement of doxorubicin and 4′-deoxydoxorubicin cytotoxicity to rat colon cancer cells in vitro and in vivo. Cancer Res 46:825–830

    PubMed  Google Scholar 

  16. Chen C-J, Chin CE, Ueda K, Clark DP, Pastan I, Gottesman MM, Roninson IB (1986) Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell 47:381–389

    PubMed  Google Scholar 

  17. Chen C-J, Clark D, Ueda K, Pastan I, Gottesman MM, Roninson IB (1990) Genomic organization of the human multidrug-resistance (MDR1) gene and origin of P-glycoproteins. J Biol Chem 265:506–514

    PubMed  Google Scholar 

  18. Cherif A, Farquhar D (1992) N-(5,5-diacetoxypent-1-yl)doxorubicin: a new intensely potent doxorubicin analogue. J Med Chem 35:3208–3214

    PubMed  Google Scholar 

  19. Chin K-V, Chauhan SS, Pastan I, Gottesman MM (1990) Regulation of mdr RNA levels in response to cytotoxic drugs in rodent cells. Cell Growth Diff 1:361–365

    PubMed  Google Scholar 

  20. Chin K-V, Tanaka S, Darlington G, Pastan I, Gottesman MM (1990) Heat shock and arsenite increase expression of the multidrug-resistance (MDR1) gene in human renal carcinoma cells. J Biol Chem 265:221–226

    PubMed  Google Scholar 

  21. Chitnis M, Hedge U, Chavan S, Juvekar A, Advani S (1991) Expression of the multidrug transporter P-glycoprotein and in vitro chemosensitivity: correlation with in vivo response to chemotherapy in acute myeloid leukemia. Sel Cancer Ther 7:165–173

    PubMed  Google Scholar 

  22. Cordon-Cardo C, O'Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain-barrier sites. Proc Natl Acad Sci USA 86:695–698

    PubMed  Google Scholar 

  23. Cornelissen JJ, Sonneveld P, Schoester M, Raaijmakers HGP, Nieuwenhuis HK, Dekker AW, Lokhorst HM (1994) MDR-1 expression and response to vincristine, doxorubicin, and dexamethasone chemotherapy in multiple myeloma refractory to alkylating agents. J Clin Oncol 12:115–119

    PubMed  Google Scholar 

  24. Cornwell MM, Gottesman MM, Pastan I (1986) Increased vinblastine binding to membrane vesciles from multidrug-resistant KB cells. J Biol Chem 261:7921–7928

    PubMed  Google Scholar 

  25. Currier SJ, Ueda K, Willingham MC, Pastan I, Gottesman MM (1989) Deletion and insertion mutants of the multidrug transporter. J Biol Chem 264:14376–14381

    PubMed  Google Scholar 

  26. Dalton WS, Grogan TM, Metzer PS, Scheper RJ, Durie BGM, Taylor CW, Miller TP, Salmon SE (1989) Drug resistance in multiple myeloma and non-Hodgin's lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy. J Clin Oncol 7:415–424

    PubMed  Google Scholar 

  27. Dalton WS, Grogan TM, Rybski JA, Scheper RJ, Richter L, Kailey J, Broxterman HJ, Pinedo HM, Salmon SE (1989) Immunohistochemical detection and quantitation of P-glycoprotein in multiple-drug-resistant human myeloma cells: association with level of drug resistance and accumulation. Blood 73:747–752

    PubMed  Google Scholar 

  28. Danø K (1973) Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells. Biochem Biophys Acta 1130:466–483

    Google Scholar 

  29. De Isabella P, Capranico G, Zunino F (1991) The role of topoisomerase II in drug resistance. Life Sci 48:2195–2205

    PubMed  Google Scholar 

  30. De la Flor-Weiss E, Richardson C, Ward M, Himmelstein A, Smith L, Podda S, Gottesman MM, Pastan I, Bank A (1992) Transfer and expression of the human multidrug resistance gene in mouse erythroleukemia cells. Blood 80:3106–3111

    PubMed  Google Scholar 

  31. Drach D, Zhao S, Drach J, Mahadevia R, Gattringer C, Huber H, Andreeff M (1992) Subpopulations of normal and peripheral blood and bone marrow cells express a functional multidrug-resistant phenotype. Blood 80:2729–2734

    PubMed  Google Scholar 

  32. Efferth T, Löhrke H, Volm M (1989) Reciprocal correlation between expression of P-glycoprotein 170 and accumulation of rhodamine 123 in human tumors. Anticancer Res 9:1633–1638

    PubMed  Google Scholar 

  33. Eijdems EW, Borst P, Jongsma AP, de Jong S, de Vries EG, van Groenigen M, Versantvoort CH, Nieuwint AW, Baas F (1992) Genetic transfer of non-P-glycoprotein-mediated multidrug resistance (MDR) in somatic cell fusion: dissection of a compound MDR phenotype. Proc Natl Acad Sci USA 89:3498–3502

    PubMed  Google Scholar 

  34. Epstein J, Xiao HQ, Oba BK (1989) P-glycoprotein expression in plasma-cell myeloma is associated with resistance to VAD. Blood 74:913–917

    PubMed  Google Scholar 

  35. Ferguson L, Baguley BC (1993) Multidrug resistance and mutagenesis. Mutat Res 285:79–90

    PubMed  Google Scholar 

  36. FitzGerald D, Willingham MC, Cardarelli CO, Hamada H, Tsuruo T, Gottesman MM, Pastan I (1987) A monoclonal antibodyPseudomonas toxin conjugate that specifically kills multidrug-resistant cells. Proc Natl Acad Sci USA 84:4288–4292

    PubMed  Google Scholar 

  37. Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM, Pastan I (1987) Expression of a multidrug resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 86:695–698

    Google Scholar 

  38. Friedlander ML, Bell DR, Leary J, Davey RA (1989) Comparison of western blot analysis and immunocytochemical detection of P-glycoprotein in multidrug-resistant cells. J Clin Pathol 42:719–722

    PubMed  Google Scholar 

  39. Futscher BW, Campbell K, Dalton WS (1992) Collateral sensitivity to nitrosoureas in multidrug-resistant cells selected with verapamil. Cancer Res 52:5013–5017

    PubMed  Google Scholar 

  40. Galski H, Sullivan M, Willingham MC, Chin K-V, Gottesman MM, Pastan I, Merlino GT (1989) Expression of a human multidrug resistance cDNA (MDR1) in the bone marrow of transgenic mice: resistance to daunomycin-induced leukopenia. Mol Cell Biol 9:4357–4363

    PubMed  Google Scholar 

  41. Gaveriaux C, Boersch D, Boelsterli JJ, Bollinger P, Eberle MK, Heistand P, Payne T, Traber R, Wenger F, Loor R (1989) Overcoming multi-drug resistance in Chinese hamster ovary cells in vitro by cyclosporin A (Sandimmune) and nonimmunosuppressive derivatives. Br J Cancer 60:867–871

    PubMed  Google Scholar 

  42. Gekeler V, Frese G, Noller A, Handgretinger R, Willisch A, Schmidt H, Muller CP, Dopfner R, Klingebiel T, Diddens H, Probst H, Niethammer D (1992) Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase pi gene expression in primary and relapsed-state adult and childhood leukaemias. Br J Cancer 66:507–517

    PubMed  Google Scholar 

  43. Gerlach JH, Endicott JA, Juranka PF, Henderson G, Sarangi F, Deuchards KL, Ling V (1986) Homology between P-glycoprotein and a bacterial haemolysin transport protein suggests a model for multidrug resistance. Nature 324:485–489

    PubMed  Google Scholar 

  44. Germann UA (1993) Molecular analysis of the multidrug transporter. Cytotechnology 12:33–62

    PubMed  Google Scholar 

  45. Germann UA, Pastan I, Gottesman MM (1993) P-glycoproteins: mediators of multidrug resistance. Semin Cell Biol 4:63–76

    PubMed  Google Scholar 

  46. Gill DR, Hyde SC, Higgins CF, Valverde MA, Mintenig GM, Sepulveda FV (1992) Separation of drug transport and chloride channel functions of the human multidrug resistance P-glycoprotein. Cell 71:23–32

    PubMed  Google Scholar 

  47. Goasguen JE, Dossot J-M, Fardel O, Lee Mee F, Le Gall E, Leblay R, LePrise PY, Chaperon J, Fauchet R (1993) Expression of the multidrug resistance-associated P-glycoprotein (P-170) in 59 cases of de novo acute lymphoblastic leukemia: prognostic implications. Blood 81:2394–2398

    PubMed  Google Scholar 

  48. Goldstein L, Galski H, Fojo A, Willingham M, Lai S-I, Gadzar A, Priker R, Green A, Crist W, Brodeur GM, Lieber M, Cossman J, Gottesman MM, Pastan I (1989) Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst 81:116–124

    PubMed  Google Scholar 

  49. Gosland MP, Lum BL, Sikic BI (1989) Reversal by cefoper-azone of resistance to etoposide, doxorubicin, and vinblastine in multidrug-resistant human sarcoma cells. Cancer Res 49:6901–6905

    PubMed  Google Scholar 

  50. Gottesman MM, Pastan I (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 62:385–427

    PubMed  Google Scholar 

  51. Grogan TM, Spier CM, Salmon SE, Matzner M, Rybski J, Weinstein RS, Scheper RJ, Dalton WS (1993) P-glycoprotein expression in human plasma cell myeloma: correlation with prior chemotherpay. Blood 81:490–495

    PubMed  Google Scholar 

  52. Grogl M, Martin RK, Oduola AM, Milhous WK, Kyle DE (1991) Characteristics of multidrug resistance inPlasmodium andLeishmania: detection of P-glycoprotein-like components. Am J Trop Med Hyg 45:98–111

    PubMed  Google Scholar 

  53. Gros P, Croop J, Housman DE (1986) Mammalian multi-drug-resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 47:371–380

    PubMed  Google Scholar 

  54. Gros P, Raymond M, Bell J, Housman DE (1988) Cloning and characterization of a second member of the mouse mdr gene familiy. Mol Cell Biol 10:1652–1663

    Google Scholar 

  55. Gruber A, Vitols S, Norgren S, Arenstrom I, Peterson C, Bjorkholm M, Reizenstein P, Luthman H (1992) Quantitative determination of mdr1 gene expression in leukaemic cells from patients with acute leukaemia. Br J Cancer 66:266–272

    PubMed  Google Scholar 

  56. Grunicke H, Hofmann J (1992) Cytotoxic and cytostatic effects of antitumor agents induced at the plasma membrane level. Pharmacol Ther 55:1–30

    PubMed  Google Scholar 

  57. Hamada H, Tsuruo T (1988) Purification of the 170- to 180-kilodalton membrane glycoprotein associated with multidrug resistance: 170- to 180-kilodalton membrane glycoprotein is an ATPase. J Biol Chem 263:1454–1458

    PubMed  Google Scholar 

  58. Hanania EG, Deisseroth AB (1994) Serial transplantation shows that early hematopoietic precursor cells are transduced by MDR-1 retroviral vector in a mouse gene therapy model. Cancer Gene Therapy 1:21–25

    PubMed  Google Scholar 

  59. Harris AL, Hochhauser D (1992) Mechanisms of multidrug resistance in cancer treatment. Acta Oncol 31:205–213

    PubMed  Google Scholar 

  60. Hegewisch-Becker S, Fliegner M, Tsuruo T, Zander A, Zeller W, Hossfeld DK (1993) P-glycoprotein expression in normal and reactive bone marrows. Br J Cancer 67:430–435

    PubMed  Google Scholar 

  61. Hegewisch-Becker S, Szudra A, Hossfeld DK (1993) Exposure to lipophilic industrial solvents leads to increased P-glycoprotein expression in peripheral blood cells. Br J Haematol 85:220–222

    PubMed  Google Scholar 

  62. Herzog CE, Trepel JB, Mickley LA, Bates SE, Fojo AT (1992) Various methods of analysis of mdr-1/P-glycoprotein in human colon cancer cell lines. J Natl Cancer Inst 84:711–716

    PubMed  Google Scholar 

  63. Hesdorfer C, Ward M, Markowitz D, Bank A (1990) Efficient gene transfer in live mice using a unique retroviral packaging line. DNA Cell Biol 9:717–723

    PubMed  Google Scholar 

  64. Hofsli E, Nissen-Meyer J (1989) Reversal of drug resistance by erythromycin: erythromycin increases the accumulation of actinomycin D and doxorubicin in multidrug-resistant cells. Int J Cancer 44:149–154

    PubMed  Google Scholar 

  65. Holmes J, Jacobs A, Carter G, Janowska-Wieczorek A, Padua RA (1989) Multidrug resistance in haematopoietic lines cell, myelodysplastic syndromes and acute myeloblastic leukaemia. Br J Haematol 72:40–44

    PubMed  Google Scholar 

  66. Holzmayer TA, Hilsenbeck S, von Hoff DD, Roninson IB (1992) Clinical correlates of MDR1 (P-glycoprotein) gene expression in ovarian and small-cell lung carcinomas. J Natl Cancer Inst 84:1486–1491

    PubMed  Google Scholar 

  67. Homolya L, Hollo Z, Germann UA, Pastan I, Gottesman MM, Sarkadi B (1993) Fluorescent cellular indicators are extruded by the multidrug resistance protein. J Biol Chem 268:21493–21496

    PubMed  Google Scholar 

  68. Horio M, Gottesman MM, Pastan I (1988) ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells. Proc Natl Acad Sci USA 85:3580–3584

    PubMed  Google Scholar 

  69. Hu XF, Martin TJ, Bell DR, de Luise M, Zalcberg JR (1990) Combined use of cyclosporin A and verapamil in modulating multidrug resistance in human leukemia cell lines. Cancer Res 50:2953–2957

    PubMed  Google Scholar 

  70. Hyde SC, Emsly P, Hartshorn MJ, Mimmack MM, Gileadi V, Pearce SR, Gallagher MP, Gill DR, Hubbard RE, Higgins CF (1990) Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug-resistance and bacterial transport. Nature 346:312–313

    PubMed  Google Scholar 

  71. Inaba M, Kobayashi H, Sakurai Y, Johnson RK (1979) Active efflux of daunorubicin and adriamycin in sensitive and resistant sublines of P388 leukemia. Cancer Res 39:2200–2203

    PubMed  Google Scholar 

  72. Ishida Y, Shimada Y, Shimoyama M (1990) Synergistic effect of cyclosporin A and verapamil in overcoming vincristine resistance of multidrug-resistant cultured human leukemia cells. Jpn J Cancer Res 81:834–841

    PubMed  Google Scholar 

  73. Juliano RL, Ling V (1973) A surface glycoprotein modulating drug permeability in Chinese hamster ovary mutants. Biochim Biophys Acta 455:152–162

    Google Scholar 

  74. Keller RP, Altermatt HJ, Nooter K, Poschmann G, Laissue JA, Bollinger P, Hiestand PC (1992) SDZ PSC 833, a nonimmunosuppressive cyclosporine: its potency in overcoming P-glycoprotein-mediated multidrug resistance of murine leukemia. Int J Cancer 50:593–597

    PubMed  Google Scholar 

  75. Kessel D (1989) Exploring multidrug resistance using rhodamine 123. Cancer Commun 3:145–149

    Google Scholar 

  76. Kiehntopf K, Brach MA, Licht T, Kirschning C, Wedel E, Herrmann F (1993) Ribozyme-mediated cleavage of MDR-1 mRNA, a possible approach to reverse multiple-drug resistance in cancer chemotherapy. Blood 82:117

    Google Scholar 

  77. Kobayashi H, Dorai T, Holland JF, Ohnuma T (1993) Cleavage of human MDR1 by a hammerhead ribozyme. FEBS Lett 319:71–74

    PubMed  Google Scholar 

  78. Kulkarni SS, Wang Z, Spitzer G, Taha M, Hamada H, Tsuruo T, Dicke KA (1989) Elimination of drug-resistant myeloma tumor cell lines by monoclonal anti-P-glycoprotein antibody and rabbit complement. Blood 74:2244–2251

    PubMed  Google Scholar 

  79. Kuwazuru Y, Hanada S, Furukawa T, Yoshimura A, Sumizawa T, Utsunomiya A, Ishibashi K, Saito T, Uozumi M, Maruyama K (1990) Expression of P-glycoprotein in adult T-cell leukemia cells. Blood 76:2065–2071

    PubMed  Google Scholar 

  80. Kawazuru Y, Yoshimura A, Hanada S, Ichikawa M, Saito T, Uozumi K, Utsunomyia A, Arima T, Akiyama S (1990) Expression of the multidrug transporter, P-glycoprotein, in chronic myelogenous leukaemia cells in blast crisis. Br J Haematol 74:24–29

    PubMed  Google Scholar 

  81. Kuwazuru Y, Yoshimura A, Hanada S, Utsunomiya A, Makino TT, Ishibashi K, Kodama M, Iwahashi M, Arima T, Akiyama S (1990) Expression of the multidrug transporter, P-glycoprotein, in acute leukemia cells and correlation to clinical drug resistance. Cancer 66:868–873

    PubMed  Google Scholar 

  82. Lai S-L, Goldstein L, Gottesman MM, Pastan I, Tsai C-M, Johnson BE, Mulshine JL, Ihde DC, Kayser K, Gadzar AF (1989) MDR1 gene expression in lung cancer. J Natl Cancer Inst 81:1144–1150

    PubMed  Google Scholar 

  83. Lehnert M, Dalton WS, Roe D, Emerson S, Salmon SE (1991) Synergistic inhibition by verapamil and quinine of Pglycoprotein-mediated multidrug resistance in a human myeloma cell line model. Blood 77:348–354

    PubMed  Google Scholar 

  84. Lelong IH, Padmanabhan R, Lovelace E, Pastan I, Gottesman MM (1992) ATP and GTP as alternative energy sources for vinblastine transport by P-170 in KB-V1 plasma membrane vesicles. FEBS Lett 304:256–260

    PubMed  Google Scholar 

  85. Li CL, Johnson GR (1992) Rhodamine 123 reveals heterogeneity within murine Lin-, Sca-1 + hemopoietic stem cells. J Exp Med 175:1443–1447

    PubMed  Google Scholar 

  86. Licht T, Fiebig HH, Bross KJ, Herrmann F, Berger DP, Shoemaker R, Mertelsmann R (1991) Induction of multipledrug anti-neoplastic chemotherapy in vitro. Int J Cancer 49:630–637

    PubMed  Google Scholar 

  87. Licht T, Bross KJ, Fiebig HH, Schötta K, Berger DP, Dreher C, Löhr GW, Herrmann F (1992) Expression of the proliferation-associated Ki-67 antigen, of transferrin receptors, and of DNA-polymerase alpha in human tumor lines: implications for in vitro chemoresistance. J Cancer Res Clin Oncol 118:116–122

    PubMed  Google Scholar 

  88. Licht T, Fiebig HH, Dreher C, Bross KJ, Herrmann F (1992) Modulation of multidrug resistance by tumor necrosis factor-alpha and verapamil. Proc Am Assoc Cancer Res 33:477

    Google Scholar 

  89. Lincke CR, Smit JJM, van der Velde-Koetrs T, Borst P (1991) Structure of the human MDR3 gene and physical mapping of the human MDR locus. J Biol Chem 266:5303–5310

    PubMed  Google Scholar 

  90. Linsenmeyer ME, Jefferson S, Wolf M, Matthews JP, Board PG, Woodcock DM (1992) Levels of expression of the mdr1 gene and glutathione S-transferase genes 2 and 3 and response to chemotherapy in multiple myeloma. Br J Cancer 65:471–475

    PubMed  Google Scholar 

  91. List AF, Spier CM, Cline A, Doll DC, Garewal H, Morgan R, Sandberg AA (1991) Expression of the multidrug-resistance gene product (P-glycoprotein) in myelodysplasia is associated with a stem cell phenotype. Br J Hematol 78:28–34

    Google Scholar 

  92. List AF, Spier C, Greer J, Wolff S, Hutter J, Dorr R, Salmon S, Futscher B, Baier M, Dalton W (1993) Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia. J Clin Oncol 11:1652–1660

    PubMed  Google Scholar 

  93. Ludescher C, Hilbe W, Eisterer W, Preuss E, Huber C, Gotwald M, Hofmann J, Thaler J (1993) Activity of P-glycoprotein in B-cell chronic lymphocytic leukemia determined by a flow cytometric assay. J Natl Cancer Inst 85:1751–1758

    PubMed  Google Scholar 

  94. Luk CK, Veinot-Drebot L, Tjan E, Tannock IF (1990) Effect of transient hypoxia on sensitivity to doxorubicin in human and murine cell lines. J Natl Cancer Inst 82:684–692

    PubMed  Google Scholar 

  95. Lum BL, Fisher GA, Brophy NA, Yahanda AM, Adler KM, Kaubisch S, Halsey J, Sikic BI (1993) Clinical trials of modulation of multidrug resistance. Cancer [Suppl] 72:3502–3514

    Google Scholar 

  96. Marie JP, Zittoun R, Sikic BI (1991) Multidrug resistance (mdr1) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity. Blood 78:586–592

    PubMed  Google Scholar 

  97. Marie JP, Brophy NA, Ehsan MN, Aihara Y, Mohamed NA, Cornbleet J, Chao NJ, Sikic BI (1992) Expression of multidrug-resistance gene mdr1 mRNA in a subset of normal bone marrow cells. Br J Haematol 81:145–152

    PubMed  Google Scholar 

  98. Marie JP, Helou C, Thevenin D, Delmer A, Zittoun R (1992) In vitro effect of P-glycoprotein (P-gp) modulators on drug sensitivity of leukemic progenitors (CFU-L) in acute myelogenous leukemia (AML). Exp Hematol 20:565–568

    PubMed  Google Scholar 

  99. McGrath JP, Varshavsky A (1989) The yeast STE6 gene encodes a homologue of the mammalian multidrug resistance P-glycoprotein. Nature 340:400–4

    PubMed  Google Scholar 

  100. McLachlin JR, Eglitis MA, Ueda K, Kantoff PW, Pastan I, Anderson WF, Gottesman MM (1990) Expression of a human complementary DNA for the human multidrug-resistance gene in murine hematopoietic precursor cells with the use of retroviral gene transfer. J Natl Cancer Inst 82:1260–1263

    PubMed  Google Scholar 

  101. Mechetner EB, Roninson IB (1992) Efficient inibition of P-glycoprotein-mediated multidrug resistance with a monoclonal antibody. Proc Natl Acad Sci USA 89:5824–5828

    PubMed  Google Scholar 

  102. Meister A (1988) Glutathione metabolism and its selective modification. J Biol Chem 263:17205–17208

    PubMed  Google Scholar 

  103. Mickisch GH, Licht T, Merlino GT, Gottesman MM, Pastan I (1991) Chemotherapy and chemosensitization of transgenic mice which express the human multidrug-resistance gene in bone marrow: efficacy, potency and toxicity. Cancer Res 51:5417–5424

    PubMed  Google Scholar 

  104. Mickisch GH, Aksentijevich I, Schoenlein PV, Goldstein LJ, Galski H, Staehle C, Sachs DH, Pastan I, Gottesman MM (1992) Transplantation of bone marrow cells from transgenic mice expressing the human MDR1 gene results in long-term protection against the myelosuppressive effect of chemotherapy in mice. Blood 79:212–218

    Google Scholar 

  105. Mickisch GH, Rahman A, Pastan I, Gottesman MM (1992) Increased effectiveness of liposome-encapsulated doxorubicin in multidrug-resistant transgenic mice compared with free doxorubicin. J Natl Cancer Inst 84:804–805

    PubMed  Google Scholar 

  106. Mickisch GH, Pai LH, Siegsmund M, Campain J, Gottesman MM, Pastan I (1993) Pseudomonas exotoxin conjugated to monoclonal antibody MRK16 specifically kills multidrug-resistant cells in cultured renal carcinomas and in MDR-transgenic mice. J Urol 149:174–178

    PubMed  Google Scholar 

  107. Miller TP, Grogan TM, Dalton WS, Spier R, Scheper CMJ, Salmon SE (1991) P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with che-motherapy plus high-dose verapamil. J Clin Oncol 9:17–24

    PubMed  Google Scholar 

  108. Miwa H, Kenkichi K, Nishii K, Morita N, Takakura N, Ohishi K, Mahmid N, Kageyama S, Fukumoto M, Shirakawa S (1993) Expression of MDR1 gene in acute leukemia cells: association with CD7+ acute myeloblastic leukemia/acute lymphoblastic leukemia. Blood 82:3445–3451

    PubMed  Google Scholar 

  109. Neyfakh AA (1988) Use of fluorescent dyes as molecular probes for the study of multidrug resistance. Exp Cell Res 174:168–176

    PubMed  Google Scholar 

  110. Neyfakh AA, Serpinskaya AS, Chervonsky AV, Aposov SG, Kazarov AR (1989) Multidrug-resistance phenotype of a subpopulation of T-lymphocytes without drug selection. Exp Cell Res 185:496–505

    PubMed  Google Scholar 

  111. Niehans GA, Jaszcz W, Brunetto V, Perri RT, Gajl-Peczalska K, Wick MR, Tsuruo T, Bloomfield CD (1992) Immunohistochemical identification of P-glycoprotein in previously untreated, diffuse large cell and immunoblastic lymphomas. Cancer Res 52:3768–3775

    PubMed  Google Scholar 

  112. Noonan KE, Beck C, Holzmayer TA, Chin JE, Wunder JS, Andrulis IL, Gadzar AF, Willman CL, Griffith B, van Hoff DD, Roninson IB (1990) Quantitative analysis of mdr1 (multridrug resistance) gene expression in human tumors by polymerase chain reaction. Proc Natl Acad Sci USA 87:7160–7164

    PubMed  Google Scholar 

  113. Nooter K, Sonneveld P, Janssen A, Oostrum R, Boersma T, Herweijer H, Valerio D, Hagemeijer A, Baas F (1990) Expression of the mdr3 gene in prolymphocytic leukemia: association with cyclosporin-A-induced increase in drug accumulation. Int J Cancer 45:626–631

    PubMed  Google Scholar 

  114. Okada S, Nakauchi H, Nagayoshi K, Nishikawa S, Nishikawa S-I, Miura Y, Suda T (1991) Enrichment and characterization of murine hematopoietic stem cells that express the c-kit molecule. Blood 78:1706–1712

    PubMed  Google Scholar 

  115. Okochi E, Iwashashi T, Ariyoshi K, Watanabe H, Kodama F, Maruta I, Tsuruo T, Ono K (1993) A novel MRK16-magnet affinity cell-sorting system applicable to diagnosis and prognosis of MDR in hematological malignancies. Proc Am Assoc Cancer Res 34:309

    Google Scholar 

  116. Padmanabhan R, Tsuruo T, Kane SE, Willingham MC, Howard BH, Gottesman MM, Pastan I (1991) Magnetic-affinity cell sorting of human multidrug-resistant cells. J Natl Cancer Inst 83:565–569

    PubMed  Google Scholar 

  117. Pastan I, Gottesman MM (1987) Mutliple-drug resistance in human cancer. N Engl J Med 316:1388–1393

    PubMed  Google Scholar 

  118. Pastan I, Gottesman MM, Ueda K, Lovelace E, Rutherford AV, Willingham MC (1988) A retrovirus carrying an MDR1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells. Proc Natl Acad Sci USA 85:4486–4490

    PubMed  Google Scholar 

  119. Pieters R, Hongo T, Loonen AH, Huismans DR, Broxterman HJ, Hahlen K, Veerman AJ (1992) Different types of non-P-glycoprotein-mediated multiple-drug resistance in children with relapsed acute lymphoblastic leukemia. Br J Cancer 65:691–697

    PubMed  Google Scholar 

  120. Pileri SA, Sabattini E, Falini B, Tazzari PL, Gherlinzoni F, Michieli MG, Damiani D, Zucchini L, Gobbi M, Tsuruo T, Baccarinini M (1991) Immunohistochemical detection of the multidrug transport protein P170 in human normal tissues and malignant lymphomas. Histopathology 19:131–140

    PubMed  Google Scholar 

  121. Pirker R, Keilhauer G, Raschak M, Lechner C, Ludwig H (1990) Reversal of multi-drug resistance in human KB cell lines by structural analogs of verapamil. Int J Cancer 45:916–919

    PubMed  Google Scholar 

  122. Pirker R, Wallner J, Geissler K, Linkesch W, Haas OA, Bettelheim P, Hopfner M, Scherrer R, Valent P, Havelec L, Ludwig H, Lechner K (1991) MDR1 gene expression and treatment outcome in acute myceloid leukemia. J Natl Cancer Inst 83:708–712

    PubMed  Google Scholar 

  123. Pirker P, Wallner J, Gotzl M, Gsur A, Geissler K, Havelec L, Knapp W, Haas O, Linkesch W, Lechner K (1992) MDR1 RNA expression is an independent prognostic factor in acute myeloid leukemia. Blood 80:557–559

    PubMed  Google Scholar 

  124. Podda S, Ward M, Himelstein A, Richardson C, de la Flor-Weiss E, Smith L, Gottesman MM, Pastan I, Bank A (1992) Transfer and expression of the human multiple-drug resistance gene into live mice. Proc Natl Acad Sci USA 89:9676–9680

    PubMed  Google Scholar 

  125. Raderer M, Scheithauser W (1993) Clinical trials of agents that reverse multidrug resistance. Cancer 72:3553–3663

    PubMed  Google Scholar 

  126. Raymond M, Gros P (1989) Mammalian multidrug-resistance gene: correlation of exon organization with structural domains and duplication of an ancestral gene. Proc Natl Acad Sci USA 86:6488–6492

    PubMed  Google Scholar 

  127. Ramu A, Pollard HB, Rosario LM (1989) Doxorubicin resistance in P388 leukemia-evidence for reduced drug influx. Int J Cancer 44:539–547

    PubMed  Google Scholar 

  128. Rochlitz CF, de Kant E, Neubauer A, Heide I, Böhmer R, Oertel J, Huhn D, Herrmann R (1992) PCR-determined expression of the MDR1 gene in chronic lymphocytic leukemia. Ann Hematol 65:241–246

    PubMed  Google Scholar 

  129. Rodriguez C, Commes T, Robert J, Rossi JF (1993) Expression of P-glycoprotein and anionic glutathione-S-transferase in non-Hodgkin's lymphoma. Leuk Res 17:149–156

    PubMed  Google Scholar 

  130. Salmon SE, Grogan TM, Miller T, Scheper R, Dalton WS (1989) Prediction of doxorubicin resistance in vitro in myeloma, lymphoma, and breast cancer by P-glycoprotein staining. J Natl Cancer Inst 81:696–701

    PubMed  Google Scholar 

  131. Salmon SE, Soehnlen B, Dalton WS, Meltzer P, Scuderi P (1989) Effects of tumor necrosis factor on sensitive and multidrug-resistant human leukemia and myeloma cell lines. Blood 74:1723–1727

    PubMed  Google Scholar 

  132. Salmon SE, Dalton WS, Grogan TM, Plezia P, Lehnert M, Roe DJ, Miller TP (1991) Mutlidrug-resistant myeloma: laboratory and clinical effects of verapamil as a chemosensitizer. Blood 78:44–50

    PubMed  Google Scholar 

  133. Sato H, Gottesman MM, Goldstein LJ, Pastan I, Block AM, Sandberg AA, Preisler HD (1990) Expression of the multidrug-resistance gene in myeloid leukemias. Leuk Res 14:11–22

    PubMed  Google Scholar 

  134. Savas B, Cole SPC, Akoglu TF, Pross HE (1992) P-glycoprotein-mediated multidrug-resistance and cytotoxic effector cells. Nat Immun Cell Growth Regul 11:177–192

    Google Scholar 

  135. Schinkel AH, Borst P (1991) Multidrug resistance mediated by P-glycoproteins. Semin Cancer Biol 2:213–226

    PubMed  Google Scholar 

  136. Schinkel AH, Roelofs MEM, Borst P (1991) Characterization of human MDR3 P-glycoprotein and its recognition by P-glycoprotein-specific monoclonal antibodies. Cancer Res 51:2628–2635

    PubMed  Google Scholar 

  137. Schinkel AH, Arceci RJ, Smit JJM, Wagenaar E, Baas F, Dollé M, Tsuruo T, Mechetner EB, Roninson IB, Borst P (1993) Binding properties of monoclonal antibodies recognizing external epitopes of the humam, MDR1 P-glycoprotein. Int J Cancer 55:478–484

    PubMed  Google Scholar 

  138. Schinkel AH, Smit JJM, van Telling O, Beijnen JH, Wagenaar E, van Deemter L, Mol CAAM, van der Valk MA, Robanus-Maandag EC, te Riele HPJ, Berns AJM, Borst P (1994) Disruption of the mouse mdr 1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491–502

    PubMed  Google Scholar 

  139. Shalinsky DR, Jekunen AP, Alcaraz JE, Christen RD, Kim S, Khatibi S, Howell SB (1993) Regulation of initial vinblastine influx by P-glycoprotein. Br J Cancer 67:30–36

    PubMed  Google Scholar 

  140. Siegsmund MJ, Cardarelli C, Aksentijevich I, Sugimoto Y, Pastan I, Gottesman MM (1994) Ketoconazole effectively reverses multidrug resistance in highly resistant KB cells. J Urol 151:485–491

    PubMed  Google Scholar 

  141. Sirotnak FM, Yang CH, Mines LS, Oribe E, Biedler JL (1986) Markedly altered membrane transport and intracellular binding of vincristine in multidrug-resistant Chinese hamster cells selected for resistance to Vinca alkaloids. J Cell Physiol 126:266–274

    PubMed  Google Scholar 

  142. Shustik C, Groulx N, Gros P (1991) Analysis of multidrugresistance (MDR-1) gene expression in chronic lymphocytic leukaemia. Br J Hematol 79:50–56

    Google Scholar 

  143. Smit EF, de Vries EG, Timmer-Bosscha H, de Leij LF, Oosterhius JW, Scheper RJ, Weening JJ, Postmus PE, Mulder HH (1992) In vitro response of human small-cell lung-cancer cell lines to chemotherapeutic drugs; no correlation with clinical data. Int J Cancer 51:72–78

    PubMed  Google Scholar 

  144. Smit JJ, Schinkel AH, Oude Elferink RPJ, Groen AK, Wagenaar E, van Deemter L, Mol CAAM, Ottenhoff R, van der Lugt NMT, van Room MA, van der Valk MA, Offerhaus GJA, Berns AJM, Borst P (1993) Homozygous disruption of the murine mrd2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75:451–462

    PubMed  Google Scholar 

  145. Sonneveld P, Durie BDM, Lokhorst HM, Marie JP, Solbu G, Suciu S, Zittoun R, Löwenberg B, Nooter K for the Leukemia Group of the EORTC and the HOVON (1992) Modulation of multidrug-resistant multiple myeloma by cyclosporine. Lancet 340:255–259

    PubMed  Google Scholar 

  146. Sonneveld P, Nooter K, Burghouts JT, Herweijer H, Adriaansen HJ, van Dongen JJ (1992) High expression of the mdr3 multidrug-resistance gene in advanced-stage chronic lymphocytic leukemia. Blood 79:1496–1500

    PubMed  Google Scholar 

  147. Sonneveld P, van Dongen JJ, Hagemeijer A, van Lom K, Nooter K, Schoester M, Adriaansen HJ, Tsuruo T, de Leeuw K (1993) High expression of the multidrug resistance P-glycoprotein in high-risk myelodysplasia is associated with immature phenotype. Leukemia 7:963–969

    PubMed  Google Scholar 

  148. Sorrentino BP, Brandt SJ, Bodine D, Gottesman MM, Pastan I, Cline A, Nienhuis AW (1992) Selection of drug-resistant bone marrow cells in vivo after retroviral transfer of human MDR1. Science 257:99–103

    PubMed  Google Scholar 

  149. Sparrow RL, Hall FJ, Siregar H, van der Weyden MB (1993) Common expression of the multidrug resistance marker P-glycoprotein in B-CCL chronic lymphocytic leukaemia and corrleation with in vitro drug resistance. Leuk Res 17:941–947

    PubMed  Google Scholar 

  150. Stein WD, Cardarelli C, Pastan I, Gottesman MM (1994) Kinetic evidence suggesting that the multidrug transporter differentially handles influx and efflux of its substrates. Mol Pharmacol 45:763–772

    PubMed  Google Scholar 

  151. Sugawara I, Kataoka I, Morishita Y, Hamada H, Tsuruo T, Itoyama S, Mori S (1988) Tissue distribution of P-glycoprotein encoded by a multidrug-resistant gene as revealed by a monoclonal antibody, MRK 16. Cancer Res 48:1926–1929

    PubMed  Google Scholar 

  152. te Boekhorst PAW, de Leeuw K, Schoester M, Wittebol S, Nooter K, Hagemeijer A, Löwenberg B, Sonneveld P (1993) Predominance of functional multidrug resistance (mdr-1) phenotype in CD34+ acute myeloid leukemia cells. Blood 85:3157–3162

    Google Scholar 

  153. Thiebault F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1987) Cellular localization of the multi-drug-resistance gene product in normal human tissues. J Natl Acad Sci USA 84:7735–7738

    Google Scholar 

  154. Thiebault F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1989) Immunocytochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and cross-reactivity of one antibody with a muscle protein. J Histochem Cytochem 37:159–164

    PubMed  Google Scholar 

  155. Thierry AR, Dritschilo A, Rahman A (1992) Effect of lipo-somes on P-glycoprotein function in multidrug-resistant cells. Biochem Biophys Res Commun 187:1098–105

    PubMed  Google Scholar 

  156. Tiirikainen MI, Syrjälä MT, Jansson S-E, Krusius T (1992) Flow cytometric analysis of P-glycoprotein in normal and leukemic cells. Ann Hematol 65:124–130

    PubMed  Google Scholar 

  157. Tong W, Berman E, Lin S (1992) Pharmacokinetic study of high-dose tamoxifen with daunorubicin: a phase-I study with escalation of tamoxifen. Proc Am Assoc Cancer Res 33:528

    Google Scholar 

  158. Townsend A, Trowsdale J (1993) The transporters associated with antigen presentation. Semin Cell Biol 4:53–61

    PubMed  Google Scholar 

  159. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1981) Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41:1967–1972

    PubMed  Google Scholar 

  160. Tsuchida S, Kiyomi S (1992) Glutathione transferases and cancer. Crit Rev Biochem Mol Biol 27:337–384

    PubMed  Google Scholar 

  161. Umeda Y, Tsuruo T, Mori S, Arimoto S, Sugawara I (1990) High-level expression of P-glycoprotein and 85-kD protein as assessed by flow cytrometry and immunocytochemistry in leukemias and malignant lymphomas. Tokai J Exp Clin Med 15:179–187

    PubMed  Google Scholar 

  162. Valverde MA, Diaz M, Sepulveda FV, Gill DR, Hyde SC, Higgins CF (1992) Volume-regulated chloride channels associated with the human multidrug resistance P-glycoprotein. Nature 355:820–833

    Google Scholar 

  163. Van der Valk P, van Kalkien CK, Ketelaars E, Broxterman HJ, Scheffer G, Kuiper CM, Tsuruo T, Lankelma J, Meijer CJLM, Pinedo HM, Schepter RJ (1990) Distribution of multi-drug resistance-associated P-glycoprotein in normal and neoplastic tissues. Analysis with a monoclonal antibodies recognizing different epitopes of the P-glycoprotein molecule. Ann Oncol 1:56–64

    PubMed  Google Scholar 

  164. Van Kalken CK, van der Valk P, Hadisaputro MMN, Pieters R, Broxterman HJ, Kuiper CM, Scheffer GL, Veerman AJP, Meyer CJLM, Scheper RJ, Pinedo HM (1991) Differentiation-dependent expression of P-glycoprotein in the normal and neoplastic human tissue. Ann Oncol 2:55–62

    Google Scholar 

  165. Weinstein RS, Jakate SM, Dominguez JM, Lebovitz MD, Koukoulis GK, Kuszak JR, Klusens LF, Grogan TM, Saclarides TJ, Roninson IB (1991) Relationship of the expression of the multidrug-resistance gene product (P-glycoprotein) in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. Cancer Res 51:2720–2726

    PubMed  Google Scholar 

  166. Willingham MC, Cornwell MM, Cardarelli CO, Gottesman MM, Pastan I (1986) Single cell analysis of daunomycin uptake and efflux in multidrug-resistant and -sensitive KB cells: effects of verapamil and other drugs. Cancer Res 46:5941–5946

    PubMed  Google Scholar 

  167. Willingham MC, Richert ND, Cornwell MC, Tsuruo T, Hamada H, Gottesman MM, Pastan I (1987) Immunocytochemical localization of P170 at the plasma membrane of multidrug-resistant cells. J Histochem Cytochem 35:1451–1456

    PubMed  Google Scholar 

  168. Wilson CM, Serrano AE, Wasley A, Bogenschutz MP, Shankar AH, Wirth DF (1989) Amplification of a gene related to mammalian mdr genes in drug-resistantPlasmodium falciparum. Science 244:1184–1186

    PubMed  Google Scholar 

  169. Wishart GC, Plumb JA, Going JJ, McNicol AM, McArdle CS, Tsuruo T, Kaye SB (1990) P-glycoprotein expression in primary breast cancer detected by immunocytochemistry with two monoclonal antibodies. Br J Cancer 62:758–761

    PubMed  Google Scholar 

  170. Yahanda AM, Alder KM, Fisher GA, Brophy NA, Halsey J, Hardy RI, Gosland MP, Lum BL, Sicic BI (1992) Phase I trial of etoposide with cyclosporine as a modulator of multidrug resistance. J Clin Oncol 10:1624–34

    PubMed  Google Scholar 

  171. Yamamoto T, Iwasaki T, Watanabe N, Oshimi K, Naito M, Tsuruo T, Kobayashi Y (1993) Expression of multidrug resistance P-glycoprotein on peripheral blood mononucleaer cells of patients with granular lymphocyte-proliferative disorders. Blood 81:1342–1346

    PubMed  Google Scholar 

  172. Young SD, Hill RP (1990) Effects of reoxygenation on cells from hypoxic regions of solid tumors: anticancer drug sensitivity and metastatic potential. J Natl Cancer Inst 82:371–380

    PubMed  Google Scholar 

  173. Zhou DC, Marie JP, Suberville AM, Zittoun R (1992) Relevance of mdr1 gene expression in acute myeloid leukemia and comparison of different diagnostic methods. Leukemia 6:879–885

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Oncology and Applied Molecular Biology, Universitätsklinikum Rudolf Virchow, Robert-Rössle-Cancer-Center and Max-Delbrück-Center for Molecular Medicine, Lindenberger Weg 80, D-13122, Berlin, Germany

    F. Herrmann

  2. Laboratory of Molecular Biology, National Cancer Institute, NIH, DCBC, Bethesda, MD, USA

    T. Licht & I. Pastan

  3. Laboratory of Cell Biology, National Cancer Institute, NIH, DCBC, Bethesda, MD, USA

    M. Gottesman

Authors
  1. T. Licht
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. Pastan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Gottesman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. Herrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Licht, T., Pastan, I., Gottesman, M. et al. P-glycoprotein-mediated multidrug resistance in normal and neoplastic hematopoietic cells. Ann Hematol 69, 159–171 (1994). https://doi.org/10.1007/BF02215949

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02215949

Key words

Search

Navigation