Advertisement

Annals of Hematology

, Volume 69, Issue 1, pp S19–S24 | Cite as

Drug-induced changes in the expression of MDR-associated genes: Investigations on cultured cell lines and chemotherapeutically treated leukemias

  • V. Gekeler
  • J. Beck
  • A. Noller
  • A. Wilisch
  • G. Frese
  • M. Neumann
  • R. Handgretinger
  • G. Ehninger
  • H. Probst
  • D. Niethammer
First Workshop of CSG-CR

Summary

The induced expression of multiple drug resistance (MDR)-associated genes as a direct response of tumor cells to antineoplastic drugs could be an important factor influencing the success of cancer chemotherapy. We investigated the effects of such compounds on mdr1/P-glycoprotein (P-gp) gene expression and drug sensitivities in the T-lymphoblastoid human cell line CCRF-CEM and MDR sublines. Thereby, we observed that actinomycin D or adriamycin administered at sublethal concentrations induced increases of mdr1 mRNA levels and resistance within 72 h. Furthermore, on leukemia cell samples collected before and after chemotherapy we checked by a complementary DNA polymerase chain reaction (cDNA-PCR) approach for similar alterations in the relative expression levels of the MDR-associated genes (a) mdr1/P-gp (b) mrp (MDR related protein), and (c) the topoisomerase II isoformsα andΒ. We found a concomitant increase in mdr1 and mrp gene expression combined with a decreased expression of topoisomerase IIα in the course of the second relapse of an acute lymphoblastic leukemia (ALL). This points to the emergence of at least three different MDR mechanisms in this type of leukemia unresponsive to chemotherapy. 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. Our results indicate the occurrence of induced resistance in vitro and in vivo and suggest a contribution of the newly identified ATP-binding cassette (ABC) transporter MRP in MDR.

Keywords

Acute Lymphoblastic Leukemia Chronic Myeloid Leukemia Adriamycin Actinomycin Blast Crisis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
CSG-CR

Cooperative Study Group — Cellular Resistance

References

  1. 1.
    Burt RK, Thorgeirsson SS (1988) Coinduction of mdr-1 multidrug-resistance and cytochrome p-450 genes in rat liver by xenobiotics. J Natl Cancer Inst 80:1383–1386Google Scholar
  2. 2.
    Bates SE, Lee JS, Dickstein B, Spolyar M, Fojo AT (1993) Differential modulation of P-glycoprotein transport by protein kinase inhibition. Biochemistry 32:9156–9164Google Scholar
  3. 3.
    Chaudhary PM, Roninson IB (1992) Activation of mdr1 (P-glycoprotein) gene expression in human cells by protein kinase C agonists. Oncol Res 4:281–290Google Scholar
  4. 4.
    Chaudhary PM, Roninson IB (1993) Induction of multidrug resistance in human cells by transient exposure to different chemotherapeutic drugs. J Natl Cancer Inst 85:632–639Google Scholar
  5. 5.
    Chin K-V, Tanaka S, Darlington G, Pastan I, Gottesman MM (1990) Heat shock and aresenite increase expression of the multidrug resistance (MDR1) gene in human renal carcinoma cells. J Biol Chem 265:221–226Google Scholar
  6. 6.
    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 1:361–365Google Scholar
  7. 7.
    Chung TD, Drake FH, Tan KB, Per SR, Crooke ST, Mirabelli CK (1989) Characterization and immunological identification of cDNA clones encoding two human DNA topoisomerase II isozymes. Proc Natl Acad Sci USA 86:9431–9435Google Scholar
  8. 8.
    Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM, Deeley RG (1992) Overexpression of a transporter gene in a multi-drug-resistant human lung cancer cell line. Science 258:1650–1654Google Scholar
  9. 9.
    Cornwell MM, Smith DE (1993) A signal transduction path-way for activation of the mdr1 promoter involves the protooncogene c-raf kinase. J Biol Chem 268:15347–15350Google Scholar
  10. 10.
    Cornwell MM, Smith DE (1993) SP1 activates the mdr1 promoter through one of two distinct G-rich regions that modulate promoter activity. J Biol Chem 268:19505–19511Google Scholar
  11. 11.
    Davies SM, Robson CN, Davies SL, Hickson ID (1988) Nuclear topoisomerase II levels correlate with the sensitivity of mammalian cells to intercalating agents and epipodophyllotoxins. J Biol Chem 263:17724–17729Google Scholar
  12. 12.
    Diaz-Meco MT, Berra E, Municio MM, Sanz L, Lozano J, Dominguez I, Diaz-Golpe V, Lain De Lera MT, Alcami J, Paya CV, Arenzana-Scisdedos F, Virelizier J-L, Moscat J (1993) A dominant negative protein Cζ subspecies blocks NF-κB activation. Mol Cell Biol 13:4770–4775Google Scholar
  13. 13.
    Fairchild CR, Ivy SP, Rushmore T, Lee G, Koo P, Goldsmith ME, Myers CE, Farber E, Cowan KH (1987) Carcinogen-induced mdr overexpression is associated with xenobiotic resistance in rat preneoplastic liver nodules and hepatocellular carcinomas. Proc Natl Acad Sci USA 84:7701–7705Google Scholar
  14. 14.
    Fernandes DJ, Danks MK, Beck WT (1990) Decreased nuclear matrix DNA topoisomerase II in human leukemia cells resistant to VM-26 and m-AMSA. Biochemistry 29:4235–4241Google Scholar
  15. 15.
    Fine RL, Patel J, Chabner BA (1988) Phorbol esters induce multidrug resistance in human breast cancer cells. Proc Natl Acad Sci USA 85:582–586Google Scholar
  16. 16.
    Gekeler V, Frese G, Diddens H, Probst H (1988) Expression of a P-glycoprotein gene is inducible in a multidrug-resistant human leukemia cell line. Biochem Biophys Res Commun 155:754–760Google Scholar
  17. 17.
    Gekeler V, Frese G, Noller A, Handgretinger R, Wilisch A, Schmidt H, Muller CP, Dopfer R, Klingebiel T, Probst H, Niethammer D (1992). MDR1/P-glycoprotein, topoisomerase, and glutathione-S-transferaseπ gene expression in primary and relapsed-state adult and childhood leukemias. Br J Cancer 66:507–517Google Scholar
  18. 18.
    Goldstein LJ, Galski H, Fojo A, Willingham M, Lai S-L, Gazdar A, Pirker 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 29:116–124Google Scholar
  19. 19.
    Gottesman MM, Pastan I (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 62:385–427Google Scholar
  20. 20.
    Hsu SI, Cohen D, Kirschner LS, Lothstein L, Hartstein M, Horwitz SB (1990) Structural analysis of the mouse mdr1a (P-glycoprotein) promoter reveals the basis for differential transcript heterogeneity in multidrug-resistant J774.2 cells. Mol Cell Biol 10:3596–3606Google Scholar
  21. 21.
    Kato S, Nishimura J, Yufu Y, Ideguchi H, Umemura T, Nawata H (1982) Modulation of expression of multidrug resistance gene (mdr-1) by adriamycin. FEBS Lett 308:175–178Google Scholar
  22. 22.
    Kohno K, Sato S, Takano H, Matsuo K, Kuwano M (1989) The direct activation of human multidrug resistance gene (mdr1) by anticancer agents. Biochem Biophys Res Commun 165:1415–1421Google Scholar
  23. 23.
    Kohno K, Sato S-I, Uchiumi T, Takano H, Kato S, Kuwano M (1990) Tissue-specific enhancer of the human multidrug-resistance (mdr1) gene. J Biol Chem 265:19690–19696Google Scholar
  24. 24.
    Kohno K, Sato S-I, Uchiumi T, Takano H, Tanimura H, Miyazaki M, Matsuo K-I, Hidaka K, Kuwano M (1992) Activation of the human multidrug resistance 1 (mdr1) gene promoter in response to inhibitors of DNA topoisomerases. Int J Oncol 1:73–77Google Scholar
  25. 25.
    Li S, Sedivy JM (1993) Raf-1 protein kinase activates the NF-κB transcription factor by dissociating the cytoplasmic NF-κB-IκB complex. Proc Natl Acad Sci USA 90:9247–9251Google Scholar
  26. 26.
    Licht T, Fiebig H-H, Bross KJ, Herrmann F, Berger D, Shoemaker R, Mertelsmann R (1991) Induction of multiple-drug resistance during anti-neoplastic chemotherapy in vitro. Int J Cancer 49:630–637Google Scholar
  27. 27.
    Ma DDF, Davey RA, Harman DH, Isbister JP, Scurr RD, Mackertich SM, Dowden G, Bell DR (1987) Detection of a multidrug resistant phenotype in acute non-lymphoblastic leukaemia. Lancet 17:135–137Google Scholar
  28. 28.
    Madden MJ, Morrow CS, Nakagawa M, Goldsmith ME, Fairchild CR, Cowan KH (1993) Identification of 5′ and 3′ sequences involved in the regulation of transcription of the human mdr1 gene in vivo. J Biol Chem 268:8290–8297Google Scholar
  29. 29.
    Marino PA, Gottesman MM, Pastan I (1990) Regulation of the multidrug resistance gene in regenerating rat liver. Cell Growth Diff 1:57–62Google Scholar
  30. 30.
    Mattern J, Volm M (1993) Multiple pathway drug resistance (review). Int J Oncol 2:557–561Google Scholar
  31. 31.
    Mickley LA, Bates SE, Richert ND, Currier S, Tanaka S, Foss F, Rosen N, Fojo AT (1989) Modulation of the expression of a multidrug resistance gene mdr-1/P-glycoprotein) by differentiating agents. J Biol Chem 264:18031–18040Google Scholar
  32. 32.
    Mirski SE, Evans CD, Almquist KC, Slovak ML, Cole SPC (1993) Altered topoisomerase IIα in a drug-resistant small cell lung cancer cell line selected in VP-16. Cancer Res 53:4866–4873Google Scholar
  33. 33.
    Miyazaki M, Kohno K, Uchiumi T, Tanimura H, Matsuo, K-I, Nasu M, Kuwano M (1992) Activation of human multidrug resistance-1 gene promoter in response to heat shock stress. Biochem Biophys Res Commun 187:677–684Google Scholar
  34. 34.
    Noller A, Frese G, Neumann M, Wilisch A, Probst H, Gekeler V (1991) Drug-mediated increases of resistance and mdr1/ P-glycoprotein gene expression in human multidrug-resistant T-lymphoblastoid cell lines. J Cancer Res Clin Oncol 117:S95Google Scholar
  35. 35.
    Ogura M, Takatori T, Tsururo T (1992) Purification and characterization of NF-R1 that regulates the expression of the human multidrug resistance (MDR1) gene. Nucleic Acids Res 20:5811–5817Google Scholar
  36. 36.
    Richert ND, Aldwin L, Nitecki D, Gottesman MM, Pastan I (1988) Stability and covalent modification of P-glycoprotein in multidrug-resistant KB cells. Biochemistry 27:7607–7613Google Scholar
  37. 37.
    Sampson KE, Wolf CL, Abraham I (1993) Staurosporine reduces P-glycoprotein expression and modulates multidrug resistance. Cancer Lett 68:7–14Google Scholar
  38. 38.
    Shaw G, Kamen R (1986) A concerved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46:659–667Google Scholar
  39. 39.
    Shen D-W, Fojo A, Chin JE, Roninson IB, Richert N, Pastan I, Gottesman MM (1986) Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification. Science 232:643–645Google Scholar
  40. 40.
    Tsai-Pflugfelder M, Liu LF, Liu AA. Tewey KM, Whang-Peng J, Knutsen T, Huebner K, Croce CM, Wang JC (1988) Cloning and sequencing of cDNA encoding human DNA topoisomerase II and localization of the gene to chromosome region 17q21-22. Proc Natl Acad Sci USA 85:7177–7181Google Scholar
  41. 41.
    Tso JY, Sun XH, Kao T, Reece KS, Wu R (1985) Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene. Nucleic Acids Res 13:2485–2503Google Scholar
  42. 42.
    Uchiumi T, Kohno K, Tanimura H, Hidaka K, Asakuno K, Abe H, Uchida Y, Kuwano M (1993) Involvement of protein kinase in environmental stress-induced activation of human multidrug resistance 1 (MDR1) gene promoter. FEBS Lett 326:11–16Google Scholar
  43. 43.
    Ueda K, Pastan I, Gottesman MM (1987) Isolation and sequence of the promoter region of the human multidrug-resistance (P-glycoprotein) gene. J Biol Chem 262:17432–17436Google Scholar
  44. 44.
    Wilisch A, Noller A, Handgretinger R, Weger S, Nüssler V, Niethammer D, Probst H, Gekeler V (1993) mdr1/P-glycoprotein expression in natural killer (NK) cells enriched from peripheral or umbilical cord blood. Cancer Lett 69:139–148Google Scholar
  45. 45.
    Woessner RD, Mattern MR, Mirabelli CK, Johnson RK, Drake FH (1991) Proliferation- and cell cycle-dependent differences in expression of the 170-kilodalton and 180-kilodalton forms of topoisomerase II in NIH-3T3 cells. Cell Growth Diff 2:209–214Google Scholar
  46. 46.
    Beck J, Gekeler V, Handgretinger R, Dopfer R, Klingebiel T, Niethammer D (1994) Multifactorial MDR (mdr1, mrp and topoisomerase IIα) is induced preferentially in second and later relapses of acute lymphatic leukaemia. Br J Haematol (submitted for publication)Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • V. Gekeler
    • 1
  • J. Beck
    • 2
  • A. Noller
    • 3
  • A. Wilisch
    • 3
  • G. Frese
  • M. Neumann
    • 3
  • R. Handgretinger
    • 2
  • G. Ehninger
    • 4
  • H. Probst
    • 3
  • D. Niethammer
    • 2
  1. 1.Abteilung FP3Byk Gulden GmbHKonstanzGermany
  2. 2.KinderklinikUniversität TübingenTübingenGermany
  3. 3.Physiologisch-Chemisches InstitutUniversität TübingenTübingenGermany
  4. 4.Medizinische KlinikTübingenGermany

Personalised recommendations