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Antiproliferative Efficacy of the Third-Generation Bisphosphonate, Zoledronic Acid, Combined with Other Anticancer Drugs in Leukemic Cell Lines

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Abstract

Bisphosphonates are widely used to treat bone diseases and appear to possess antitumor activity. Moreover, we recently found that a third-generation bisphosphonate, zoledronic acid (ZOL), synergistically interacts with imatinib in vitro and in vivo to induce antileukemic activity, and others have reported that ZOL interacts synergistically with paclitaxel. Thus, the efficacy of other antileukemic agents combined with ZOL should be evaluated experimentally. In this study, we investigated the effects of concurrent and sequential combinations of ZOL with several commonly used antileukemic agents, including imatinib, on the in vitro growth of leukemia cell lines. As a complement to our previous finding that ZOL synergistically augments the effects of imatinib, we report here that ZOL acts additively when administered concurrently with hydroxyurea (HU), cytarabine (Ara-C), or daunorubicin (DNR) in some leukemic cell lines. Furthermore, one day of ZOL pretreatment augmented the sensitivity of imatinib and Ara-C. Therefore, concurrent or sequential administration of ZOL with imatinib, HU, Ara-C, or DNR may increase the efficacy of leukemia treatment.

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References

  1. Rogers MJ, Watts DJ, Russel RG. Overview of bisphosphonates.Cancer. 1997;80:1652–1660.

    Article  PubMed  CAS  Google Scholar 

  2. Green JR. Chemical and biological prerequisites for novel bisphosphonate molecules: results of comparative preclinical studies.Semin Oncol. 2001;28:4–10.

    Article  PubMed  CAS  Google Scholar 

  3. Senaratne SG, Pirianov G, Mansi JL, Arnett TR, Colston KW. Bisphosphonates induce apoptosis in human breast cancer cell lines.Br J Cancer. 2000;82:1459–1468.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Jagdev SP, Coleman RE, Shipman CM, Rostami HA, Croucher PI. The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel.Br J Cancer. 2001;84:1126–1134.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Lee MV, Fong EM, Singer FR, Guenette RS. Bisphosphonate treatment inhibits the growth of prostate cancer cells.Cancer Res. 2001;61:2602–2608.

    PubMed  CAS  Google Scholar 

  6. Tassone P, Forciniti S, Galea E, et al. Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines.Leukemia. 2000;14:841–844.

    Article  PubMed  CAS  Google Scholar 

  7. Derenne S, Amiot M, Barille S, et al. Zoledronate is a potent inhibitor of myeloma cell growth and secretion of IL-6 and MMP-1 by the tumoral environment.J Bone Miner Res. 1999;14:2048–2056.

    Article  PubMed  CAS  Google Scholar 

  8. Kuroda J, Kimura S, Segawa H, et al. The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate.Blood. 2003;102:2229–2235.

    Article  PubMed  CAS  Google Scholar 

  9. Chou TC. The median effect principal and the combination index for quantitation of synergism and antagonism. In: Chou TC, Rideout DC, eds.Synergism and Antagonism in Chemotherapy. San Diego, Calif: Academic Press; 1991:61–102.

    Google Scholar 

  10. Chow KU, Ries J, Weidmann E, et al. Induction of apoptosis using 2’,2’ difluorodeoxycytidine (gemcitabine) in combination with antimetabolites or anthracyclines on malignant lymphatic and myeloid cells: antagonism or synergism depends on incubation schedule and origin of neoplastic cells.Ann Hematol. 2000;79:485–492.

    Article  PubMed  CAS  Google Scholar 

  11. Berenson J, Ravera C, Ma P, et al. Population pharmacokinetics (PK) of zometa [abstract].Proc Am Soc Clin Oncol. 2000:209a. Abstract 814.

  12. Sato M, Grasser W, Endo N, et al. Bisphosphonate action: alendronate localization in rat bone and effects on osteoclast ultrastructure.J Clin Invest. 1991;88:2095–2105.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Center for Drug Evaluation and Research. Approval page. Zometa (zoledronic acid) injection. Pharmacology review(s). Part 2:84. Available at: http://www.fda.gov/cder/foi/nda/2001/21-223***Zometa. htm. Accessed October 9, 2003.

  14. Hiraga T, Williams PJ, Mundy GR, Yoneda T. The bisphosphonate ibandronate promotes apoptosis in MDA-MB-231 human breast cancer cells in bone metastases.Cancer Res. 2001;61:4418–4424.

    PubMed  CAS  Google Scholar 

  15. Canellos GP, DeVita VT, Gold GL, Chabner BA, Schein PS, Young RC. Combination chemotherapy for advanced breast cancer: response and effect on survival.Ann Intern Med. 1976;84:389–392.

    Article  PubMed  CAS  Google Scholar 

  16. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.N Engl J Med. 2001;344:1031–1037.

    Article  PubMed  CAS  Google Scholar 

  17. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.N Engl J Med. 2001;344:1038–1042.

    Article  PubMed  CAS  Google Scholar 

  18. Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias.Blood. 2002;100:1965–1971.

    Article  PubMed  CAS  Google Scholar 

  19. Thiesing JT, Ohno-Jones S, Kolibaba KS, Druker BJ. Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl-positive cells.Blood. 2000;96:3195–3199.

    PubMed  CAS  Google Scholar 

  20. Kano Y, Akutsu M,Tsunoda S, et al. In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents.Blood. 2001;97:1999–2007.

    Article  PubMed  CAS  Google Scholar 

  21. Topaly J, Zeller WJ, Fruehauf S. Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells.Leukemia. 2001;15:342–347.

    Article  PubMed  CAS  Google Scholar 

  22. Marley SB, Davidson RJ, Goldman JM, Gordon MY. Effects of combinations of therapeutic agents on the proliferation of progenitor cells in chronic myeloid leukaemia.Br J Haematol. 2002;116:162–165.

    Article  PubMed  CAS  Google Scholar 

  23. Hoover RR, Mahon FX, Melo JV, Daley GQ. Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336.Blood. 2002;100:1068–1071.

    Article  PubMed  CAS  Google Scholar 

  24. Porosnicu M, Nimmanapalli R, Nguyen D, Worthington E, Perkins C, Bhalla KN. Co-treatment with As2O3 enhances selective cytotoxic effects of STI-571 against Bcr-Abl-positive acute leukemia cells.Leukemia. 2001;15:772–778.

    Article  PubMed  CAS  Google Scholar 

  25. Mow BM, Chandra J, Svingen PA, et al. Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro.Blood. 2002;99:664–671.

    Article  PubMed  CAS  Google Scholar 

  26. Nimmanapalli R, Porosnicu M, Nguyen D, et al. Cotreatment with STI-571 enhances tumor necrosis factor alpha-related apoptosisinducing ligand (TRAIL or apo-2L)-induced apoptosis of Bcr-Ablpositive human acute leukemia cells.Clin Cancer Res. 2001;7:350–357.

    PubMed  CAS  Google Scholar 

  27. Karp JE. Farnesyl protein transferase inhibitors as targeted therapies for hematologic malignancies.Semin Hematol. 2001;38:16–23.

    Article  PubMed  CAS  Google Scholar 

  28. Whyte DB, Kirschmeier P, Hockenberry TN, et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors.J Biol Chem. 1997;272:14459–14464.

    Article  PubMed  CAS  Google Scholar 

  29. Li X, Liu L, Tupper JC, et al. Inhibition of protein geranylgeranylation and RhoA/RhoA kinase pathway induces apoptosis in human endothelial cells.J Biol Chem. 2002;277:15309–15316.

    Article  PubMed  CAS  Google Scholar 

  30. Schaich M, Illmer T, Aulitzky W, et al. Intensified double induction therapy with high dose mitoxantrone, etoposide, m-amsacrine and high dose ara-C for patients aged 61–65 years with acute myeloid leukemia.Haematologica. 2002;87:808–815.

    PubMed  CAS  Google Scholar 

  31. Ali SM, Esteva FJ, Hortobagyi G, et al. Safety and efficacy of bisphosphonates beyond 24 months in cancer patients.J Clin Oncol. 2001;19:3434–3437.

    Article  PubMed  CAS  Google Scholar 

  32. Samuelsson MK, Pazirandeh A, Okret S. A pro-apoptotic effect of the CDK inhibitor p57Kip2 on staurosporine-induced apoptosis in HeLa cells.Biochem Biophys Res Commun. 2002;296:702–709.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho Shogoin, 606-8507, Sakyo-ku, Kyoto, Japan

    Shinya Kimura, Junya Kuroda, Hidekazu Segawa, Kiyoshi Sato, Masaki Nogawa, Takeshi Yuasa & Taira Maekawa

  2. Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kyoto

    Junya Kuroda

  3. Department of Gastroenterology and Hematology, Shiga University of Medical Science, Otsu

    Hidekazu Segawa

  4. Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan

    Kiyoshi Sato

  5. Department of Hematology, Johann Wolfgang Goethe University, Frankfurt, Germany

    Oliver G. Ottmann

Authors
  1. Shinya Kimura
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  2. Junya Kuroda
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  3. Hidekazu Segawa
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  4. Kiyoshi Sato
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  5. Masaki Nogawa
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  6. Takeshi Yuasa
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  7. Oliver G. Ottmann
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  8. Taira Maekawa
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Correspondence to Shinya Kimura.

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Kimura, S., Kuroda, J., Segawa, H. et al. Antiproliferative Efficacy of the Third-Generation Bisphosphonate, Zoledronic Acid, Combined with Other Anticancer Drugs in Leukemic Cell Lines. Int J Hematol 79, 37–43 (2004). https://doi.org/10.1007/BF02983531

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  • DOI: https://doi.org/10.1007/BF02983531

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