Antiproliferative Efficacy of the Third-Generation Bisphosphonate, Zoledronic Acid, Combined with Other Anticancer Drugs in Leukemic Cell Lines
Received: 18 July 2003 Revised: 27 August 2003 Accepted: 08 September 2003 DOI:
Cite this article as: Kimura, S., Kuroda, J., Segawa, H. et al. Int J Hematol (2004) 79: 37. doi:10.1007/BF02983531 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.
Key words Zoledronic acid Cytarabine Imatinib Leukemia Combination therapy References
Rogers MJ, Watts DJ, Russel RG. Overview of bisphosphonates.
Green JR. Chemical and biological prerequisites for novel bisphosphonate molecules: results of comparative preclinical studies.
Senaratne SG, Pirianov G, Mansi JL, Arnett TR, Colston KW. Bisphosphonates induce apoptosis in human breast cancer cell lines.
Br J Cancer.
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.
Lee MV, Fong EM, Singer FR, Guenette RS. Bisphosphonate treatment inhibits the growth of prostate cancer cells.
Tassone P, Forciniti S, Galea E, et al. Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines.
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.
Kuroda J, Kimura S, Segawa H, et al. The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate.
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.
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.
Berenson J, Ravera C, Ma P, et al. Population pharmacokinetics (PK) of zometa [abstract].
Proc Am Soc Clin Oncol. 2000:209a. Abstract 814.
Sato M, Grasser W, Endo N, et al. Bisphosphonate action: alendronate localization in rat bone and effects on osteoclast ultrastructure.
J Clin Invest.
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.
Hiraga T, Williams PJ, Mundy GR, Yoneda T. The bisphosphonate ibandronate promotes apoptosis in MDA-MB-231 human breast cancer cells in bone metastases.
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.
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.
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.
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.
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.
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.
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.
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.
Hoover RR, Mahon FX, Melo JV, Daley GQ. Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336.
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.
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.
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.
Karp JE. Farnesyl protein transferase inhibitors as targeted therapies for hematologic malignancies.
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.
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.
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.
Ali SM, Esteva FJ, Hortobagyi G, et al. Safety and efficacy of bisphosphonates beyond 24 months in cancer patients.
J Clin Oncol.
Samuelsson MK, Pazirandeh A, Okret S. A pro-apoptotic effect of the CDK inhibitor p57
on staurosporine-induced apoptosis in HeLa cells.
Biochem Biophys Res Commun.
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