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. 1992 May;65(5):691–697. doi: 10.1038/bjc.1992.146

Different types of non-P-glycoprotein mediated multiple drug resistance in children with relapsed acute lymphoblastic leukaemia.

R Pieters 1, T Hongo 1, A H Loonen 1, D R Huismans 1, H J Broxterman 1, K Hählen 1, A J Veerman 1
PMCID: PMC1977370  PMID: 1350207

Abstract

Although cellular drug resistance is considered to be an important cause of the poor prognosis of children with relapsed acute lymphoblastic leukaemia (ALL), the knowledge of drug resistance in these patients is very limited. Different aspects of drug resistance were studied in 17 children with relapsed ALL. The in vitro sensitivity profile was determined using the MTT assay. Cells from relapsed children were significantly more resistant to 6-thioguanine, prednisolone, cytosine arabinoside, daunorubicin (DNR), mustine-HCl and mafosfamide but not to L-asparaginase and vincristine (VCR) than cells from 41 children with ALL at initial diagnosis. Some relapsed patients showed a general drug resistance while others were resistant to only 1-3 drugs. The relevance of the multidrug resistance (MDR) model was analysed: In all DNR- and VCR resistant cases a co-resistance to drugs not involved in the MDR model was found. P-glycoprotein was not detected in any of 28 untreated and 14 relapsed samples tested. VCR- and DNR accumulation in the most resistant cells were not lower than in sensitive cells. Resistance modifiers did not potentiate the cytotoxicity of VCR and DNR. We conclude that resistance to anthracyclines and vinca alkaloids in childhood relapsed ALL is not due to P-glycoprotein mediated MDR. Different types of drug resistance varying from a resistance to only one drug to a general chemoresistance, can be detected in children with relapsed ALL. VCR and L-asparaginase seemed to be only infrequently involved in drug resistance. Knowledge of drug resistance might lead to more effective and less toxic therapies for children with relapsed ALL.

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Selected References

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  1. Bird M. C., Bosanquet A. G., Forskitt S., Gilby E. D. Semi-micro adaptation of a 4-day differential staining cytotoxicity (DiSC) assay for determining the in-vitro chemosensitivity of haematological malignancies. Leuk Res. 1986;10(4):445–449. doi: 10.1016/0145-2126(86)90075-5. [DOI] [PubMed] [Google Scholar]
  2. Bosanquet A. G. Correlations between therapeutic response of leukaemias and in-vitro drug-sensitivity assay. Lancet. 1991 Mar 23;337(8743):711–714. doi: 10.1016/0140-6736(91)90287-y. [DOI] [PubMed] [Google Scholar]
  3. Broxterman H. J., Kuiper C. M., Schuurhuis G. J., Tsuruo T., Pinedo H. M., Lankelma J. Increase of daunorubicin and vincristine accumulation in multidrug resistant human ovarian carcinoma cells by a monoclonal antibody reacting with P-glycoprotein. Biochem Pharmacol. 1988 Jun 15;37(12):2389–2393. doi: 10.1016/0006-2952(88)90365-6. [DOI] [PubMed] [Google Scholar]
  4. Broxterman H. J., Kuiper C. M., Schuurhuis G. J., van der Hoeven J. J., Pinedo H. M., Lankelma J. Daunomycin accumulation in resistant tumor cells as a screening model for resistance modifying drugs: role of protein binding. Cancer Lett. 1987 Apr;35(1):87–95. doi: 10.1016/0304-3835(87)90060-7. [DOI] [PubMed] [Google Scholar]
  5. Broxterman H. J., Pinedo H. M., Kuiper C. M., van der Hoeven J. J., de Lange P., Quak J. J., Scheper R. J., Keizer H. G., Schuurhuis G. J., Lankelma J. Immunohistochemical detection of P-glycoprotein in human tumor cells with a low degree of drug resistance. Int J Cancer. 1989 Feb 15;43(2):340–343. doi: 10.1002/ijc.2910430229. [DOI] [PubMed] [Google Scholar]
  6. Campling B. G., Pym J., Galbraith P. R., Cole S. P. Use of the MTT assay for rapid determination of chemosensitivity of human leukemic blast cells. Leuk Res. 1988;12(10):823–831. doi: 10.1016/0145-2126(88)90036-7. [DOI] [PubMed] [Google Scholar]
  7. Carulli G., Petrini M., Marini A., Ambrogi F. P-glycoprotein in acute nonlymphoblastic leukemia and in the blastic crisis of myeloid leukemia. N Engl J Med. 1988 Sep 22;319(12):797–798. doi: 10.1056/NEJM198809223191219. [DOI] [PubMed] [Google Scholar]
  8. Dalton W. S., Grogan T. M., Rybski J. A., Scheper R. J., Richter L., Kailey J., Broxterman H. J., Pinedo H. M., Salmon S. E. Immunohistochemical detection and quantitation of P-glycoprotein in multiple drug-resistant human myeloma cells: association with level of drug resistance and drug accumulation. Blood. 1989 Feb 15;73(3):747–752. [PubMed] [Google Scholar]
  9. Evans W. E., Petros W. P., Relling M. V., Crom W. R., Madden T., Rodman J. H., Sunderland M. Clinical pharmacology of cancer chemotherapy in children. Pediatr Clin North Am. 1989 Oct;36(5):1199–1230. doi: 10.1016/s0031-3955(16)36765-7. [DOI] [PubMed] [Google Scholar]
  10. Haber M., Norris M. D., Kavallaris M., Bell D. R., Davey R. A., White L., Stewart B. W. Atypical multidrug resistance in a therapy-induced drug-resistant human leukemia cell line (LALW-2): resistance to Vinca alkaloids independent of P-glycoprotein. Cancer Res. 1989 Oct 1;49(19):5281–5287. [PubMed] [Google Scholar]
  11. Hongo T., Fujii Y., Igarashi Y. An in vitro chemosensitivity test for the screening of anti-cancer drugs in childhood leukemia. Cancer. 1990 Mar 15;65(6):1263–1272. doi: 10.1002/1097-0142(19900315)65:6<1263::aid-cncr2820650602>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  12. Hongo T., Fujii Y., Mizuno Y., Haraguchi S., Yoshida T. O. [Anticancer drug sensitivity test using the short-term microplate culture and MTT dye reduction assay]. Gan To Kagaku Ryoho. 1987 Feb;14(2):472–478. [PubMed] [Google Scholar]
  13. Kaspers G. J., Pieters R., Van Zantwijk C. H., De Laat P. A., De Waal F. C., Van Wering E. R., Veerman A. J. In vitro drug sensitivity of normal peripheral blood lymphocytes and childhood leukaemic cells from bone marrow and peripheral blood. Br J Cancer. 1991 Sep;64(3):469–474. doi: 10.1038/bjc.1991.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ma D. D., Scurr R. D., Davey R. A., Mackertich S. M., Harman D. H., Dowden G., Isbister J. P., Bell D. R. Detection of a multidrug resistant phenotype in acute non-lymphoblastic leukaemia. Lancet. 1987 Jan 17;1(8525):135–137. doi: 10.1016/s0140-6736(87)91969-6. [DOI] [PubMed] [Google Scholar]
  15. Maruyama Y., Murohashi I., Nara N., Aoki N. Effects of verapamil on the cellular accumulation of daunorubicin in blast cells and on the chemosensitivity of leukaemic blast progenitors in acute myelogenous leukaemia. Br J Haematol. 1989 Jul;72(3):357–362. doi: 10.1111/j.1365-2141.1989.tb07716.x. [DOI] [PubMed] [Google Scholar]
  16. Mattern J., Efferth T., Bak M., Ho A. D., Volm M. Detection of P-glycoprotein in human leukemias using monoclonal antibodies. Blut. 1989 Apr;58(4):215–217. doi: 10.1007/BF00320777. [DOI] [PubMed] [Google Scholar]
  17. Pieters R., Huismans D. R., Leyva A., Veerman A. J. Adaptation of the rapid automated tetrazolium dye based (MTT) assay for chemosensitivity testing in childhood leukemia. Cancer Lett. 1988 Aug 30;41(3):323–332. doi: 10.1016/0304-3835(88)90294-7. [DOI] [PubMed] [Google Scholar]
  18. Pieters R., Huismans D. R., Leyva A., Veerman A. J. Comparison of the rapid automated MTT-assay with a dye exclusion assay for chemosensitivity testing in childhood leukaemia. Br J Cancer. 1989 Feb;59(2):217–220. doi: 10.1038/bjc.1989.44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pieters R., Huismans D. R., Loonen A. H., Hählen K., van der Does-van den Berg A., van Wering E. R., Veerman A. J. Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia. Lancet. 1991 Aug 17;338(8764):399–403. doi: 10.1016/0140-6736(91)91029-t. [DOI] [PubMed] [Google Scholar]
  20. Pieters R., Loonen A. H., Huismans D. R., Broekema G. J., Dirven M. W., Heyenbrok M. W., Hählen K., Veerman A. J. In vitro drug sensitivity of cells from children with leukemia using the MTT assay with improved culture conditions. Blood. 1990 Dec 1;76(11):2327–2336. [PubMed] [Google Scholar]
  21. Rivera-Fillat M. P., Pallarés-Trujillo J., Domènech C., Grau-Oliete M. R. Comparative uptake, retention and action of vincristine, vinblastine and vindesine on murine leukaemic lymphoblasts sensitive and resistant to vincristine. Br J Pharmacol. 1988 Apr;93(4):902–908. doi: 10.1111/j.1476-5381.1988.tb11478.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Rivera G. K., Santana V., Mahmoud H., Buchanan G., Crist W. M. Acute lymphocytic leukemia of childhood: the problem of relapses. Bone Marrow Transplant. 1989 Jan;4 (Suppl 1):80–85. [PubMed] [Google Scholar]
  23. 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]
  24. Santini V., Bernabei P. A., Silvestro L., Dal Pozzo O., Bezzini R., Viano I., Gattei V., Saccardi R., Ferrini P. R. In vitro chemosensitivity testing of leukemic cells: prediction of response to chemotherapy in patients with acute non-lymphocytic leukemia. Hematol Oncol. 1989 Jul-Aug;7(4):287–293. doi: 10.1002/hon.2900070405. [DOI] [PubMed] [Google Scholar]
  25. Sargent J. M., Taylor C. G. Appraisal of the MTT assay as a rapid test of chemosensitivity in acute myeloid leukaemia. Br J Cancer. 1989 Aug;60(2):206–210. doi: 10.1038/bjc.1989.252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schuurhuis G. J., Pinedo H. M., Broxterman H. J., van Kalken C. K., Kuiper C. M., Lankelma J. Differential sensitivity of multi-drug-resistant and -sensitive cells to resistance-modifying agents and the relation with reversal of anthracycline resistance. Int J Cancer. 1990 Aug 15;46(2):330–336. doi: 10.1002/ijc.2910460232. [DOI] [PubMed] [Google Scholar]
  27. Sugawara I., Kodo H., Ohkochi E., Hamada H., Tsuruo T., Mori S. High-level expression of MRK 16 and MRK 20 murine monoclonal antibody-define proteins (170,000-180,000 P-glycoprotein and 85,000 protein) in leukaemias and malignant lymphomas. Br J Cancer. 1989 Oct;60(4):538–541. doi: 10.1038/bjc.1989.309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tidefelt U., Sundman-Engberg B., Paul C. Effects of verapamil on uptake and in vitro toxicity of anthracyclines in human leukemic blast cells. Eur J Haematol. 1988 May;40(5):385–395. doi: 10.1111/j.1600-0609.1988.tb00846.x. [DOI] [PubMed] [Google Scholar]
  29. Tidefelt U., Sundman-Engberg B., Rhedin A. S., Paul C. In vitro drug testing in patients with acute leukemia with incubations mimicking in vivo intracellular drug concentrations. Eur J Haematol. 1989 Nov;43(5):374–384. doi: 10.1111/j.1600-0609.1989.tb00323.x. [DOI] [PubMed] [Google Scholar]
  30. Twentyman P. R., Fox N. E., Rees J. K. Chemosensitivity testing of fresh leukaemia cells using the MTT colorimetric assay. Br J Haematol. 1989 Jan;71(1):19–24. doi: 10.1111/j.1365-2141.1989.tb06268.x. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Veerman A. J., Pieters R. Drug sensitivity assays in leukaemia and lymphoma. Br J Haematol. 1990 Apr;74(4):381–384. doi: 10.1111/j.1365-2141.1990.tb06323.x. [DOI] [PubMed] [Google Scholar]
  33. Weisenthal L. M., Dill P. L., Finklestein J. Z., Duarte T. E., Baker J. A., Moran E. M. Laboratory detection of primary and acquired drug resistance in human lymphatic neoplasms. Cancer Treat Rep. 1986 Nov;70(11):1283–1295. [PubMed] [Google Scholar]
  34. Weisenthal L. M., Su Y. Z., Duarte T. E., Dill P. L., Nagourney R. A. Perturbation of in vitro drug resistance in human lymphatic neoplasms by combinations of putative inhibitors of protein kinase C. Cancer Treat Rep. 1987 Dec;71(12):1239–1243. [PubMed] [Google Scholar]
  35. van Diest P. J., Smeulders A. W., Thunnissen F. B., Baak J. P. Cytomorphometry. A methodologic study of preparation techniques, selection methods and sample sizes. Anal Quant Cytol Histol. 1989 Aug;11(4):225–231. [PubMed] [Google Scholar]

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