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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1989 Oct;80(10):1006–1013. doi: 10.1111/j.1349-7006.1989.tb01641.x

Multidrug Resistance in Cultured Human Leukemia and Lymphoma Cell Lines Detected by a Monoclonal Antibody, MRK16

Yasushi Ishida 1, Tomoko Ohtsu 1, Hirofumi Hamada 2, Yoshikazu Sugimoto 2, Kensei Tobinai 1, Keisuke Minato 1, Takashi Tsuruo 2, Masanori Shimoyama 1,✉
PMCID: PMC5917883  PMID: 2575608

Abstract

Forty cultured human leukemia and lymphoma cell lines never exposed to anticancer agents in culture, apart from doxorubicin (ADM)‐resistant K562/ADM, were examined for reactivity with a monoclonal antibody, MRK16 in F(ab′)2 form [MRK16‐F(ab′)2], which recognizes P‐glycoprotein (P‐gp). The relative resistance index to various drugs was calculated by dividing the 50% growth inhibitory concentration (IC50) of the test cell line by IC50 of K562, which was the negative control in the antibody experiment. MRK16‐F(ab′)2 reacted with four cell lines, K562/ADM, KYO‐1, HEL and CMK, which had relative resistance index values of 2 or more to vincristine (VCR), vindesine, vinblastine, ADM, daunorubicin, mitoxantrone (MIT), etoposide (VP‐16) and actinomycin‐D (ACT‐D). The level of resistance to VCR and ADM in these cell lines decreased significantly in the presence of 10 μM verapamil in vitro. Significant expression of mRNA of P‐gp gene was also detected in K562/ADM, KYO‐1 and HEL. MRK16‐F(ab′)2 did not react with 36 other cell lines. Among them, three cell lines, PL‐21, P31/FUJ and KOPM‐28, had relative resistance index values of 2 or more to anthracyclines, MIT and VP‐16, but not to vinca alkaloids or ACT‐D. The level of ADM‐resistance in these cell lines did not decrease significantly in the presence of 10 μM verapamil. Five cell lines, ATL‐1K, HL‐60, KMOE‐2, ML‐1 and U266, had relative resistance index values of 2 or more to some of the drugs, but not to the others, and 19 other cell lines did not. These results indicate that the reactivity of MRK16‐F(ab′)2 correlates with a relative resistance index of 2 or more to all these drugs in cultured human leukemia and lymphoma cell lines.

Keywords: Multidrug resistance, Monoclonal antibody, Leukemia, Lymphoma, Culture cell

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REFERENCES

  • 1. ) Pastan , I. and Gottesman , M.Multiple‐drug resistance in human cancer . N. Engl. J. Med. , 316 , 1388 – 1393 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Fine , R. L. and Chabner , B. A.Multidrug resistance . In “ Cancer Chemotherapy,” Vol. 8 , ed. Pinedo H. M. and Chabner B. A. , pp. 117 – 128 ( 1986. ). Elsevier Science Publishers; , New York ). [Google Scholar]
  • 3. ) Tsuruo , T. , Lida‐Saito , H. , Kawabata , H. , Oh‐hara , T. , Hamada , H. and Utakoji , T.Characteristics of resistance to adriamycin in human myelogenous leukemia K562 resistant to adriamycin and isolated clones . Jpn. J, Cancer Res. , 77 , 682 – 692 ( 1986. ). [PubMed] [Google Scholar]
  • 4. ) Danø , K.Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells . Biochim. Biophys. Acta , 323 , 466 – 483 ( 1973. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Inaba , M. , Kobayashi , H. , Sakurai , Y. and Johnson , R. K.Active efflux of daunorubicin and adriamycin in sensitive and resistant sublines of P388 leukemia . Cancer Res. , 39 , 2200 – 2203 ( 1979. ). [PubMed] [Google Scholar]
  • 6. ) Karter , N. , Riordan , J. R. and Ling , V.Cell surface P‐glycoprotein associated with multidrug resistance in mammalian cell lines . Science , 221 , 1285 – 1288 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Tsuruo , T. , Iida , H. , Tsukagoshi , S. and Sakurai , Y.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 ( 1981. ). [PubMed] [Google Scholar]
  • 8. ) Tsuruo , T. , Iida , H. , Tsukagoshi , S. and Sakurai , Y.Potentiation of vincristine and adriamycin effects in human hemopoietic tumor cell lines by calcium antagonists and calmodulin inhibitors . Cancer Res. , 43 , 2267 – 2272 ( 1983. ). [PubMed] [Google Scholar]
  • 9. ) Riordan , J. R. , Deuchars , K. , Kartner , N. , Alon , N. , Trent , J. and Ling , V.Amplification of P‐glycoprotein genes in multidrug‐resistant mammalian cell lines . Nature , 316 , 817 – 819 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Scotto , K. W. , Biedler , J. L. and Melera , P. W.Amplification and expression of genes associated with multidrug resistance in mammalian cells . Science , 232 , 751 – 755 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Roninson , I. B. , Chin , J. E. , Choi , K. , Gros , P. , Housman , D. E. , Fojo , A. , Shen , D. w. , Gottesman , M. M. and Pastan , I.Isolation of human mdr DNA sequences amplified in multidrug‐resistant KB carcinoma cells . Proc. Natl Acad. Sci. USA , 83 , 4538 – 4542 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. ) Sugimoto , Y. and Tsuruo , T.DNA‐mediated transfer and cloning of a human multidrug‐resistant gene of adria‐mycin‐resistant myelogenous leukemia K562 . Cancer Res. , 47 , 2620 – 2625 ( 1987. ). [PubMed] [Google Scholar]
  • 13. ) Fojo , A. T. , Ueda , K. , Slamon , D. J. , Poplack , D. G. , Gottesman , M. M. and Pastan , I.Expression of a multi‐drug resistance gene in human tumors and tissues . Proc. Natl. Acad. Sci. USA , 84 , 265 – 269 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. ) Fojo , A. T. , Shen , D‐w. , Mickley , L. A. , Pastan , I , and Gottesman , M. M.Intrinsic drug resistance in human kidney cancer is associated with expression of a human multidrug‐resistance gene . J. Clin. Oncol , 5 , 1922 – 1927 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Hamada , H. and Tsuruo , T.Functional role for the 170‐to 180‐kDa glycoprotein specific to drug‐resistant tumor cells as revealed by monoclonal antibodies . Proc. Natl. Acad. Sci. USA , 83 , 7785 – 7789 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. ) Lamoyi , E. and Nisonoff , A.Preparation of F(ab′)2 fragments from mouse IgG of various subclasses . J. lmmunol. Methods , 56 , 235 – 243 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Yamada , H. and Shimoyama , M.Growth inhibitory activity of human lymphoblastoid and fibroblast interferons in vitro . Gann , 74 , 299 – 307 ( 1983. ). [PubMed] [Google Scholar]
  • 18. ) Shibata , T. , Shimada , Y. and Shimoyama , M.Time‐dependent cytotoxic action of human recombinant α interferon (Ro22‐8181) in vitro and the sensitivity of various cultured leukemia and lymphoma cell lines to it . Jpn. J. Clin. OncoL , 15 , 67 – 75 ( 1985. ). [PubMed] [Google Scholar]
  • 19. ) Hanada , M. and Shimoyama , M.Influence of fetal calf serum on growth‐inhibitory activity of human recombinant γ‐interferon (GI‐3) in vitro . Jpn. J. Cancer Res. , 77 , 1153 – 1160 ( 1986. ). [PubMed] [Google Scholar]
  • 20. ) Hanada , M. and Shimoyama , M.Potential limitation of growth‐inhibitory action of recombinant human tumor necrosis factor (PAC‐4D) due to easy induction of resistance: evidence in vitro . Jpn. J. Cancer Res. , 78 , 1266 – 1273 ( 1987. ). [PubMed] [Google Scholar]
  • 21. ) Inaba , S. and Shimoyama , M.Antitumor activity of quinocarmycin (K.W2152) against various cultured leukemia and lymphoma cell lines in vitro . Cancer Res. , 48 , 6029 – 6032 ( 1988. ). [PubMed] [Google Scholar]
  • 22. ) Kubonishi , L , Machida , K. , Niiya , K. , Sonobe , H. , Ohtsuki , Y. , Iwata , K. and Miyoshi , I.Establishment of a new peroxidase‐positive human myeloid cell line, PL‐21 . Blood , 63 , 254 – 259 ( 1984. ). [PubMed] [Google Scholar]
  • 23. ) Saito , H. , Bourinbaiar , A. , Ginaburg , M. , Minato , K. , Ceresi , E. , Yamada , K. , Machover , D. , Breard , J. and Mathé , G.Establishment and characterization of a new human eosinophilic leukemia cell line . Blood , 66 , 1233 – 1240 ( 1985. ). [PubMed] [Google Scholar]
  • 24. ) Okano , H. , Okumura , J. , Yagawa , K. , Tasaka , H. and Motomura , S.Human erythroid cell lines derived from a patient with acute erythremia . J. Cancer Res. Clin. OncoL , 102 , 49 – 55 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Kubonishi , I. and Miyoshi , I.Establishment of a Ph1 chromosome‐positive cell line from chronic myelogenous leukemia in blast crisis . Int. J. Cell Cloning , 1 , 105 – 117 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Mori , T. , Nishino , K. , Sugita , K. , Nakazawa , S. , Takane , K. , Uda , T. , Hayashi , Y. , Kaneko , Y. , Sakurai , M. and Mori , M.Establishment of a Ph1 chromosome‐positive cell line (KOPM‐28) from chronic myelogenous leukemia in blast crisis . Jpn. J. Clin. Hematol. , 25 , 235 ( 1983. ) ( Abstr. ) ( in Japanese ). [Google Scholar]
  • 27. ) Sato , T. , Shima , Y. , Sunami , S. , Okimoto , Y. , Sugita , K. , Nakazawa , S. , Eguchi , M. and Hayashi , Y.Establishment of a megakaryocyte cell line (CMGK‐1) from a child with acute megakaryoblastic leukemia complicated ‐with Down's syndrome . Jpn. J. Clin. Hematol. , 28 , 248 ( 1986. ) ( Abstr.) (in Japanese ). [Google Scholar]
  • 28. ) Kohler , G. , Howe , S. C. and Milstein , C.Fusion between immunoglobulin‐secreting and nonsecreting myeloma cell line . Eur. J. Immunol. , 6 , 292 – 295 ( 1976. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Maniatis , T. , Fritsch , E. F. and Sambrook , J. “ Molecular Cloning — A Laboratory Manual” ( 1982. ). Cold Spring Harbor Laboratory; , Cold Spring Harbor , N.Y . [Google Scholar]
  • 30. ) Sugimoto , Y. , Roninson , I. R. and Tsuruo , T.Decreased expression of the amplified mdr1 gene in revertants of multidrug‐resistant human myelogenous leukemia K562 occurs without loss of amplified DNA . Mol. Cell. Biol. , 7 , 4549 – 4552 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. ) Feinberg , A. P. and Vogelstein , B.A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity . Anal. Biochem. , 132 , 6 – 13 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Champlin , R. E. and Golde , D. W.Chronic myelogenous leukemia: recent advances . Blood , 65 , 1039 – 1047 ( 1985. ). [PubMed] [Google Scholar]
  • 33. ) Amaki , I. , Hattori , K. , Bennett , J. M. , Yoshida , T. , Tomonaga , M. , Ogawa , T. , Catovsky , D. , Shimoyama , M. , Ohshima , T. , Fujimoto , T. and Kamada , N.Proceedings of the International Round Table Conference, FAB classification of acute leukemia correlating with response to chemotherapy . Acta HematoL. Jpn. , 47 , 206 – 238 ( 1984. ). [PubMed] [Google Scholar]
  • 34. ) Mirchandani , I. and Palutke , M.Acute megakaryoblastic leukemia . Cancer , 50 , 2866 – 2872 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 35. ) Danks , M. K. , Yalowich , J. C. and Beck , W. T.Atypical multiple drug resistance in a human leukemic cell line selected for resistance to teniposide (VM‐26) . Cancer Res. , 47 , 1297 – 1301 ( 1987. ). [PubMed] [Google Scholar]
  • 36. ) Beck , W. T. , Cirtain , M. C. , Danks , M. K. , Felsted , R. L. , Safa , A. R. , Wolverton , J. S. , Suttle , D. P. and Trent , J. M.Pharmacological, molecular, and cytogenetic analysis of “atypical” multidrug‐resistant human leukemic cells . Cancer Res. , 47 , 5455 – 5460 ( 1987. ). [PubMed] [Google Scholar]
  • 37. ) McGrath , T. and Center , M. S.Mechanism of multidrug resistance in HL60 cells: evidence that a surface membrane protein distinct from P‐glycoprotein contributes to reduced cellular accumulation of drug . Cancer Res. , 48 , 3959 – 3963 ( 1988. ). [PubMed] [Google Scholar]

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