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Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells

Leukemia volume 19, pages 1306–1311 (2005)Cite this article

Abstract

Acute promyelocytic leukemia (APL) cells express a considerable level of CD33, which is a target of gemtuzumab ozogamicin (GO), and a significantly lower level of P-glycoprotein (P-gp). In this study, we examined whether GO was effective on all-trans retinoic acid (ATRA)- or arsenic trioxide (ATO)-resistant APL cells. Cells used were an APL cell line in which P-gp was undetectable (NB4), ATRA-resistant NB4 (NB4/RA), NB4 and NB4/RA that had been transfected with MDR-1 cDNA (NB4/MDR and NB4/RA/MDR, respectively), ATO-resistant NB4 (NB4/As) and blast cells from eight patients with clinically ATRA-resistant APL including two patients with ATRA- and ATO-resistant APL. The efficacy of GO was analyzed by 3H-thymidine incorporation, the dye exclusion test and cell cycle distribution. GO suppressed the growth of NB4, NB4/RA and NB4/As cells in a dose-dependent manner. GO increased the percentage of hypodiploid cells significantly in NB4, NB4/RA and NB4/As cells, and by a limited degree in NB4/MDR and NB4/RA/MDR cells. Similar results were obtained using blast cells from the patients with APL. GO is effective against ATRA- or ATO-resistant APL cells that do not express P-gp, and the mechanism of resistance to GO is not related to the mechanism of resistance to ATRA or ATO in APL cells.

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References

  1. Sievers EL, Larson RA, Stadtmauer EA, Estey E, Lowenberg B, Dombret H, et al., Mylotarg Study Group. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 2001; 19: 3244–3254.

    Article  CAS  Google Scholar 

  2. Linenberger ML, Hong T, Flowers D, Sievers EL, Gooley TA, Bennett JM et al. Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin. Blood 2001; 98: 988–994.

    Article  CAS  Google Scholar 

  3. Naito K, Takeshita A, Shigeno K, Nakamura S, Fujisawa S, Shinjo K et al. Calicheamicin-conjugated humanized anti-CD33 monoclonal antibody (gemtuzumab zogamicin, CMA-676) shows cytocidal effect on CD33-positive leukemia cell lines, but is inactive on P-glycoprotein-expressing sublines. Leukemia 2000; 14: 1436–1443.

    Article  CAS  Google Scholar 

  4. Matsui H, Takeshita A, Naito K, Shinjo K, Shigeno K, Maekawa M et al. Reduced effect of gemtuzumab ozogamicin (CMA-676) on P-glycoprotein and/or CD34-positive leukemia cells and its restoration by multidrug resistance modifiers. Leukemia 2002; 16: 813–819.

    Article  CAS  Google Scholar 

  5. Paietta E, Andersen J, Racevskis J, Gallagher R, Bennett J, Yunis J et al. Significantly lower P-glycoprotein expression in acute promyelocytic leukemia than in other types of acute myeloid leukemia: immunological, molecular and functional analyses. Leukemia 1994; 8: 968–973.

    CAS  PubMed  Google Scholar 

  6. Estey EH, Giles FJ, Beran M, O'Brien S, Pierce SA, Faderl SH et al. Experience with gemtuzumab ozogamycin (‘mylotarg’) and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood 2002; 99: 4222–4224.

    Article  CAS  Google Scholar 

  7. Lo-Coco F, Cimino G, Breccia M, Noguera NI, Diverio D, Finolezzi E et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 2004; 104: 1995–1999.

    Article  CAS  Google Scholar 

  8. Gallaher RE . Retinoic acid resistance in acute promyelocytic leukemia. Leukemia 2002; 16: 1940–1958.

    Article  Google Scholar 

  9. Rybner C, Hillion J, Sahraoui T, Lanotte M, Botti J . All-trans retinoic acid down-regulates prion protein expression independently of granulocyte maturation. Leukemia 2002; 16: 940–948.

    Article  CAS  Google Scholar 

  10. Kitamura K, Minami Y, Yamamoto K, Akao Y, Kiyoi H, Saito H et al. Involvement of CD95-independent caspase 8 activation in arsenic trioxide-induced apoptosis. Leukemia 2000; 14: 1743–1750.

    Article  CAS  Google Scholar 

  11. Takeshita A, Shinjo K, Naito K, Ohnishi K, Sugimoto Y, Yamakawa Y et al. Role of P-glycoprotein in all-trans retinoic acid (ATRA) resistance in acute promyelocytic leukaemia cells: analysis of intracellular concentration of ATRA. Br J Haematol 2000; 108: 90–92.

    Article  CAS  Google Scholar 

  12. Takeshita A, Shinjo K, Naito K, Matsui H, Shigeno K, Nakamura S et al. P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) are induced by arsenic trioxide (As(2)O(3)), but are not the main mechanism of As(2)O(3)-resistance in acute promyelocytic leukemia cells. Leukemia 2003; 17: 648–650.

    Article  CAS  Google Scholar 

  13. Ohno R, Asou N, Ohnishi K . Treatment of acute promyelocytic leukemia: strategy toward further increase of cure rate. Leukemia 2003; 17: 1454–1463.

    Article  CAS  Google Scholar 

  14. Yang C-H, Kuo M-L, Chen J-C, Chen Y-C . Arsenic trioxide sensitivity is associated with low level of glutathione in cancer cells. Br J Cancer 1999; 81: 796–799.

    Article  CAS  Google Scholar 

  15. Walter RB, Raden BW, Hong TC, Flowers DA, Bernstein ID, Linenberger ML . Multidrug resistance protein attenuates gemtuzumab ozogamicin-induced cytotoxicity in acute myeloid leukemia cells. Blood 2003; 102: 1466–1473.

    Article  CAS  Google Scholar 

  16. Naito K, Takeshita A, Matsui H, Horii T, Maekawa M, Kitamura K et al. Multidrug resistance (MDR)-related protein 1 (MRP1) and lung resistance protein (LRP) are not the main drug resistance mechanisms of gemtuzumab ozogamicin (CMA-676) in AML. Hematol J 2002; 3: 1048a.

    Google Scholar 

Download references

Acknowledgements

We express our sincere gratitude to Ms Satoko Kanomi (Wyeth Pharmaceuticals Inc.) for continuous support, and to Ms Yoshimi Suzuki, Ms Noriko Anma and Dr Kiyoshi Shibata (Equipment Centre at Hamamatsu University School of Medicine) for technical assistance. This study was supported by Japanese grants-in-aid from the Ministry of Health and Welfare (No. 9-2) and the Ministry of Education and Science (No. 14570972).

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Authors and Affiliations

  1. Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

    A Takeshita, K Shinjo, K Naito, H Matsui, N Sahara, K Shigeno & K Ohnishi

  2. Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

    A Takeshita, T Horii, N Shirai & M Maekawa

  3. Department of Hematology, Nagoya University, Nagoya, Japan

    T Naoe

  4. Aichi Cancer Center, Nagoya, Japan

    R Ohno

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  1. A Takeshita
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Correspondence to A Takeshita.

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Takeshita, A., Shinjo, K., Naito, K. et al. Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells. Leukemia 19, 1306–1311 (2005). https://doi.org/10.1038/sj.leu.2403807

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