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British Journal of Cancer logoLink to British Journal of Cancer
. 1994 Dec;70(6):1144–1149. doi: 10.1038/bjc.1994.462

P-glycoprotein and glutathione S-transferase pi in childhood acute lymphoblastic leukaemia.

A Sauerbrey 1, F Zintl 1, M Volm 1
PMCID: PMC2033687  PMID: 7981066

Abstract

Blast cells obtained from 104 children with untreated acute lymphoblastic leukaemia were analysed for the expression of P-glycoprotein (P-170) and glutathione S-transfer pi (GST-pi) using immunohistochemistry. Expression of P-170 was detected in 36 of 104 patients (35%) and increased GST-pi was seen in 52 patients (50%). Coexpression of both resistance proteins was observed in 22 leukaemias (21%), whereas no evidence of the resistance markers was found in 38 cases (37%). In patients with P-170-positive leukaemic cells, a significantly lower probability of remaining in first continuous complete remission (CCR) was observed when compared with patients with P-170-negative tumours (P < 0.05). However, only a trend for a more frequent expression of P-170 was found in the leukaemic cells of patients who experienced relapses (P = 0.099). Overexpression of GST-pi was correlated with a higher relapse rate (P = 0.001) and a lower probability of remaining in first CCR (P = 0.01). Expression of P-170 and GST-pi was independent of sex, FAB type, immunological subtype and initial blast cell count. The multivariate analysis indicated that only the expression of P-170 is an unfavourable prognostic factor for children with acute lymphoblastic leukaemia in addition to the prognostic clinical factors.

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  1. Angel P., Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129–157. doi: 10.1016/0304-419x(91)90011-9. [DOI] [PubMed] [Google Scholar]
  2. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A., Gralnick H. R., Sultan C. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976 Aug;33(4):451–458. doi: 10.1111/j.1365-2141.1976.tb03563.x. [DOI] [PubMed] [Google Scholar]
  3. Black S. M., Wolf C. R. The role of glutathione-dependent enzymes in drug resistance. Pharmacol Ther. 1991;51(1):139–154. doi: 10.1016/0163-7258(91)90044-m. [DOI] [PubMed] [Google Scholar]
  4. Campos L., Guyotat D., Archimbaud E., Calmard-Oriol P., Tsuruo T., Troncy J., Treille D., Fiere D. Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood. 1992 Jan 15;79(2):473–476. [PubMed] [Google Scholar]
  5. Chan H. S., Thorner P. S., Haddad G., Ling V. Immunohistochemical detection of P-glycoprotein: prognostic correlation in soft tissue sarcoma of childhood. J Clin Oncol. 1990 Apr;8(4):689–704. doi: 10.1200/JCO.1990.8.4.689. [DOI] [PubMed] [Google Scholar]
  6. Cheng A. L., Su I. J., Chen Y. C., Lee T. C., Wang C. H. Expression of P-glycoprotein and glutathione-S-transferase in recurrent lymphomas: the possible role of Epstein-Barr virus, immunophenotypes, and other predisposing factors. J Clin Oncol. 1993 Jan;11(1):109–115. doi: 10.1200/JCO.1993.11.1.109. [DOI] [PubMed] [Google Scholar]
  7. Efferth T., Mattern J., Volm M. Immunohistochemical detection of P glycoprotein, glutathione S transferase and DNA topoisomerase II in human tumors. Oncology. 1992;49(5):368–375. doi: 10.1159/000227075. [DOI] [PubMed] [Google Scholar]
  8. Endicott J. A., Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem. 1989;58:137–171. doi: 10.1146/annurev.bi.58.070189.001033. [DOI] [PubMed] [Google Scholar]
  9. Gekeler V., Frese G., Noller A., Handgretinger R., Wilisch A., Schmidt H., Muller C. P., Dopfer R., Klingebiel T., Diddens H. Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase pi gene expression in primary and relapsed state adult and childhood leukaemias. Br J Cancer. 1992 Sep;66(3):507–517. doi: 10.1038/bjc.1992.304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Goasguen J. E., Dossot J. M., Fardel O., Le Mee F., Le Gall E., Leblay R., LePrise P. Y., Chaperon J., Fauchet R. Expression of the multidrug resistance-associated P-glycoprotein (P-170) in 59 cases of de novo acute lymphoblastic leukemia: prognostic implications. Blood. 1993 May 1;81(9):2394–2398. [PubMed] [Google Scholar]
  11. Gruber A., Vitols S., Norgren S., Areström I., Peterson C., Björkholm M., Reizenstein P., Luthman H. Quantitative determination of mdr1 gene expression in leukaemic cells from patients with acute leukaemia. Br J Cancer. 1992 Aug;66(2):266–272. doi: 10.1038/bjc.1992.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Holmes J., Jacobs A., Carter G., Janowska-Wieczorek A., Padua R. A. Multidrug resistance in haemopoietic cell lines, myelodysplastic syndromes and acute myeloblastic leukaemia. Br J Haematol. 1989 May;72(1):40–44. doi: 10.1111/j.1365-2141.1989.tb07649.x. [DOI] [PubMed] [Google Scholar]
  13. Holmes J., Wareing C., Jacobs A., Hayes J. D., Padua R. A., Wolf C. R. Glutathione-s-transferase pi expression in leukaemia: a comparative analysis with mdr-1 data. Br J Cancer. 1990 Aug;62(2):209–212. doi: 10.1038/bjc.1990.262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ito Y., Tanimoto M., Kumazawa T., Okumura M., Morishima Y., Ohno R., Saito H. Increased P-glycoprotein expression and multidrug-resistant gene (mdr1) amplification are infrequently found in fresh acute leukemia cells. Sequential analysis of 15 cases at initial presentation and relapsed stage. Cancer. 1989 Apr 15;63(8):1534–1538. doi: 10.1002/1097-0142(19890415)63:8<1534::aid-cncr2820630813>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  15. Kuwazuru Y., Yoshimura A., Hanada S., Utsunomiya A., Makino T., Ishibashi K., Kodama M., Iwahashi M., Arima T., Akiyama S. Expression of the multidrug transporter, P-glycoprotein, in acute leukemia cells and correlation to clinical drug resistance. Cancer. 1990 Sep 1;66(5):868–873. doi: 10.1002/1097-0142(19900901)66:5<868::aid-cncr2820660510>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  16. Marie J. P., Zittoun R., Sikic B. I. Multidrug resistance (mdr1) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity. Blood. 1991 Aug 1;78(3):586–592. [PubMed] [Google Scholar]
  17. McQuaid S., McCann S., Daly P., Lawlor E., Humphries P. Observations on the transcriptional activity of the glutathione S-transferase pi gene in human haematological malignancies and in the peripheral leucocytes of cancer patients under chemotherapy. Br J Cancer. 1989 Apr;59(4):540–543. doi: 10.1038/bjc.1989.110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Moscow J. A., Fairchild C. R., Madden M. J., Ransom D. T., Wieand H. S., O'Brien E. E., Poplack D. G., Cossman J., Myers C. E., Cowan K. H. Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors. Cancer Res. 1989 Mar 15;49(6):1422–1428. [PubMed] [Google Scholar]
  19. Musto P., Cascavilla N., Di Renzo N., Ladogana S., La Sala A., Melillo L., Nobile M., Matera R., Lombardi G., Carotenuto M. Clinical relevance of immunocytochemical detection of multidrug-resistance-associated P-glycoprotein in hematologic malignancies. Tumori. 1990 Aug 31;76(4):353–359. doi: 10.1177/030089169007600410. [DOI] [PubMed] [Google Scholar]
  20. Musto P., Melillo L., Lombardi G., Matera R., di Giorgio G., Carotenuto M. High risk of early resistant relapse for leukaemic patients with presence of multidrug resistance associated P-glycoprotein positive cells in complete remission. Br J Haematol. 1991 Jan;77(1):50–53. doi: 10.1111/j.1365-2141.1991.tb07947.x. [DOI] [PubMed] [Google Scholar]
  21. Pieters R., Hongo T., Loonen A. H., Huismans D. R., Broxterman H. J., Hählen K., Veerman A. J. Different types of non-P-glycoprotein mediated multiple drug resistance in children with relapsed acute lymphoblastic leukaemia. Br J Cancer. 1992 May;65(5):691–697. doi: 10.1038/bjc.1992.146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pirker R., Wallner J., Geissler K., Linkesch W., Haas O. A., Bettelheim P., Hopfner M., Scherrer R., Valent P., Havelec L. MDR1 gene expression and treatment outcome in acute myeloid leukemia. J Natl Cancer Inst. 1991 May 15;83(10):708–712. doi: 10.1093/jnci/83.10.708. [DOI] [PubMed] [Google Scholar]
  23. Rodriguez C., Commes T., Robert J., Rossi J. F. Expression of P-glycoprotein and anionic glutathione S-transferase genes in non-Hodgkin's lymphoma. Leuk Res. 1993 Feb;17(2):149–156. doi: 10.1016/0145-2126(93)90060-x. [DOI] [PubMed] [Google Scholar]
  24. Rothenberg M. L., Mickley L. A., Cole D. E., Balis F. M., Tsuruo T., Poplack D. G., Fojo A. T. Expression of the mdr-1/P-170 gene in patients with acute lymphoblastic leukemia. Blood. 1989 Sep;74(4):1388–1395. [PubMed] [Google Scholar]
  25. Sato H., Preisler H., Day R., Raza A., Larson R., Browman G., Goldberg J., Vogler R., Grunwald H., Gottlieb A. MDR1 transcript levels as an indication of resistant disease in acute myelogenous leukaemia. Br J Haematol. 1990 Jul;75(3):340–345. doi: 10.1111/j.1365-2141.1990.tb04346.x. [DOI] [PubMed] [Google Scholar]
  26. Schisselbauer J. C., Silber R., Papadopoulos E., Abrams K., LaCreta F. P., Tew K. D. Characterization of glutathione S-transferase expression in lymphocytes from chronic lymphocytic leukemia patients. Cancer Res. 1990 Jun 15;50(12):3562–3568. [PubMed] [Google Scholar]
  27. Schlaifer D., Laurent G., Chittal S., Tsuruo T., Soues S., Muller C., Charcosset J. Y., Alard C., Brousset P., Mazerrolles C. Immunohistochemical detection of multidrug resistance associated P-glycoprotein in tumour and stromal cells of human cancers. Br J Cancer. 1990 Aug;62(2):177–182. doi: 10.1038/bjc.1990.256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Teeter L. D., Eckersberg T., Tsai Y., Kuo M. T. Analysis of the Chinese hamster P-glycoprotein/multidrug resistance gene pgp1 reveals that the AP-1 site is essential for full promoter activity. Cell Growth Differ. 1991 Sep;2(9):429–437. [PubMed] [Google Scholar]
  29. Tidefelt U., Elmhorn-Rosenborg A., Paul C., Hao X. Y., Mannervik B., Eriksson L. C. Expression of glutathione transferase pi as a predictor for treatment results at different stages of acute nonlymphoblastic leukemia. Cancer Res. 1992 Jun 15;52(12):3281–3285. [PubMed] [Google Scholar]
  30. Ubezio P., Limonta M., D'Incalci M., Damia G., Masera G., Giudici G., Wolverton J. S., Beck W. T. Failure to detect the P-glycoprotein multidrug resistant phenotype in cases of resistant childhood acute lymphocytic leukaemia. Eur J Cancer Clin Oncol. 1989 Dec;25(12):1895–1899. doi: 10.1016/0277-5379(89)90367-2. [DOI] [PubMed] [Google Scholar]
  31. Volm M., Bak M., Jr, Efferth T., Lathan B., Mattern J. Immunocytochemical detection of a resistance-associated glycoprotein in tissue culture cells, ascites tumors and human tumor xenografts by Mab 265/F4. Anticancer Res. 1988 Jul-Aug;8(4):531–535. [PubMed] [Google Scholar]
  32. Volm M., Mattern J., Efferth T., Pommerenke E. W. Expression of several resistance mechanisms in untreated human kidney and lung carcinomas. Anticancer Res. 1992 Jul-Aug;12(4):1063–1067. [PubMed] [Google Scholar]
  33. Volm M., Mattern J., Samsel B. Overexpression of P-glycoprotein and glutathione S-transferase-pi in resistant non-small cell lung carcinomas of smokers. Br J Cancer. 1991 Oct;64(4):700–704. doi: 10.1038/bjc.1991.384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Volm M., Mattern J., Samsel B. Relationship of inherent resistance to doxorubicin, proliferative activity and expression of P-glycoprotein 170, and glutathione S-transferase-pi in human lung tumors. Cancer. 1992 Aug 15;70(4):764–769. doi: 10.1002/1097-0142(19920815)70:4<764::aid-cncr2820700408>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  35. Volm M., Sauerbrey A., Zintl F. Dihydrofolate-reductase and thymidylate-synthase in childhood acute lymphoblastic leukemia. Anticancer Res. 1994 May-Jun;14(3B):1377–1381. [PubMed] [Google Scholar]

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