Objectives: To identify synergistic combinations of clinically available agents with zoledronic acid which would enhance antitumor activity as measured by median effect isobologram analysis and apoptosis assays in vitro. Methods: The interaction of zoledronic acid as a doublet with either carboplatin, cisplatin, 5′DFUR, docetaxel, epirubicin, fluvastatin, gemcitabine, imatinib, paclitaxel, trastuzumab, or vinorelbine was studied in a 72-hour in vitro system using defined human cancer cell lines grown as a monolayer in exponential phase. Drug effect on growth was measured by a standard MTT assay. Median effect isobologram analysis was applied to the results to determine the presence of synergism, additive effects, or antagonism of drug combinations. Synergistic combinations were also assayed by a cytoplasmic histone-associated DNA fragmentation apoptosis assay to verify that the effect was not cytostatic. Results: Zoledronic acid with gemcitabine demonstrated global cytotoxic synergy across 7 of 8 cell lines. Clinically achievable concentrations of fluvastatin with zoledronic acid also demonstrated synergy in 7 of 8 cell lines. All the breast cancer cell lines were sensitive. Zoledronic acid and epirubicin were antagonistic in all 4 breast cell lines studied. Conclusions: Combinations of zoledronic acid with either gemcitabine or fluvastatin may have a therapeutic role in treatment of bone metastasis of selected malignancies.

Menschutkin N: İber die Einwirkung des Chlorazetyls auf phosphorige Säure. Ann Chem Pharm 1865;133:317–320.
Fleisch H: Development of bisphosphonates. Breast Cancer Res 2002;4:30–34.
Reszka AA, Rodan GA: Bisphosphonate mechanism of action. Curr Rheumatol Rep 2003;5:65–74.
Berenson JR: New advances in the biology and treatment of myeloma bone disease. Semin Hematol 2001;38:15–20.
Body JJ: Bisphosphonates in the treatment of metastatic breast cancer. J Mammary Gland Biol Neoplasia 2001;6:477–485.
Coleman RE: Bisphosphonates for the prevention of bone metastases. Semin Oncol 2002;29:43–49.
Corey E, Brown LG, Quinn JE, Poot M, Roudier MP, Higano CS, Vessella RL: Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer. Clin Cancer Res 2003;9:295–306.
Finley RS: Bisphosphonates in the treatment of bone metastases. Semin Oncol 2002;29:132–138.
Yoneda T, Michigami T, Yi B, Williams PJ, Niewolna M, Hiraga T: Use of bisphosphonates for the treatment of bone metastasis in experimental animal models. Cancer Treat Rev 1999;25:293–299.
Berenson JR: Treatment of hypercalcemia of malignancy with bisphosphonates. Semin Oncol 2002;29:12–18.
Neville-Webbe H, Coleman RE: The use of zoledronic acid in the management of metastatic bone disease and hypercalcaemia. Palliat Med 2003;17:539–553.
Santini D, Vespasiani Gentilucci U, Vincenzi B, Picardi A, Vasaturo F, La Cesa A, Onori N, Scarpa S, Tonini G: The antineoplastic role of bisphosphonates: from basic research to clinical evidence. Ann Oncol 2003;14:1468–1476.
Mundy GR: Bisphosphonates as anticancer drugs. Expert Opin Investig Drugs 1999;8:2009–2015.
Rogers MJ: New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 2003;9:2643–2658.
Benford HL, Frith JC, Auriola S, Monkkonen J, Rogers MJ: Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. Mol Pharmacol 1999;56:131–140.
Coxon FP, Helfrich MH, Van’t Hof R, Sebti S, Ralston SH, Hamilton A, Rogers MJ: Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 2000;15:1467–1476.
Senaratne SG, Mansi JL, Colston KW: The bisphosphonate zoledronic acid impairs Ras membrane (correction of impairs membrane) localisation and induces cytochrome c release in breast cancer cells. Br J Cancer 2002;86:1479–1486.
Russo P, Loprevite M, Cesario A, Ardizzoni A: Farnesylated proteins as anticancer drug targets: from laboratory to the clinic. Curr Med Chem Anti-Canc Agents 2004;4:123–138.
Witters LM, Crispino J, Fraterrigo T, Green J, Lipton A: Effect of the combination of docetaxel, zoledronic acid, and a COX-2 inhibitor on the growth of human breast cancer cell lines. Am J Clin Oncol 2003;26:S92–S97.
Graaf MR, Richel DJ, van Noorden CJ, Guchelaar HJ: Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer. Cancer Treat Rev 2004;30:609–641.
Budman DR, Calabro A: In vitro search for synergy and antagonism: evaluation of docetaxel combinations in breast cancer cell lines. Breast Cancer Res Treat 2002;74:41–46.
Budman DR, Calabro A, Kreis W: Synergistic and antagonistic combinations of drugs in human prostate cancer cell lines in vitro. Anticancer Drugs 2002;13:1011–1016.
Budman DR, Calabro A, Wang LG, Liu XM, Stiel L, Adams LM, Kreis W: Synergism of cytotoxic effects of vinorelbine and paclitaxel in vitro. Cancer Invest 2000;18:695–701.
Budman DR, Calabro A: Studies of synergistic and antagonistic combinations of conventional cytotoxic agents with the multiple eicosanoid pathway modulator LY 293111. Anticancer Drugs 2004;15:877–881.
Budman DR, Calabro A, Kreis W: In vitro effects of dexrazoxane (Zinecard) and classical acute leukemia therapy: time to consider expanded clinical trials? Leukemia 2001;15:1517–1520.
Budman DR, Calabro A, Kreis W: In vitro evaluation of synergism or antagonism with combinations of new cytotoxic agents. Anticancer Drugs 1998;9:697–702.
Mosmann T: Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55–63.
Kreis W, Budman DR, Calabro A: Unique synergism or antagonism of combinations of chemotherapeutic and hormonal agents in human prostate cancer cell lines. Br J Urol 1997;79:196–202.
Liu X, Yue P, Zhou Z, Khuri FR, Sun SY: Death receptor regulation and celecoxib-induced apoptosis in human lung cancer cells. J Natl Cancer Inst 2004;96:1769–1780.
Greco W, Bravo G, Parsons J: The search for synergy: a critical review from a response surface perspective. Pharmacol Rev 1995;47:331–385.
Chen T, Berenson J, Vescio R, Swift R, Gilchick A, Goodin S, LoRusso P, Ma P, Ravera C, Deckert F, Schran H, Seaman J, Skerjanec A: Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol 2002;42:1228–1236.
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.
Green JR: Antitumor effects of bisphosphonates. Cancer 2003;97:840–847.
Clezardin P: The antitumor potential of bisphosphonates. Semin Oncol 2002;29:33–42.
Zhang P, Lun M, Siegelmann-Danieli N, Blasick T, Brown R: Pamidronate resistance and associated low Ras levels in breast cancer cells: a role for combinatorial therapy. Ann Clin Lab Sci 2004;34:263–270.
Kato T, Hashikabe H, Iwata C, Akimoto K, Hattori Y: Statin blocks Rho/Rho-kinase signalling and disrupts the actin cytoskeleton: relationship to enhancement of LPS-mediated nitric oxide synthesis in vascular smooth muscle cells. Biochim Biophys Acta 2004;1689:267–272.
Wang HR, Li JJ, Huang CX, Jiang H: Fluvastatin inhibits the expression of tumor necrosis factor-alpha and activation of nuclear factor-kappaB in human endothelial cells stimulated by C-reactive protein. Clin Chim Acta 2005;353:53–60.
Fenton JW 2nd, Jeske WP, Catalfamo JL, Brezniak DV, Moon DG, Shen GX: Statin drugs and dietary isoprenoids downregulate protein prenylation in signal transduction and are antithrombotic and prothrombolytic agents. Biochemistry (Mosc) 2002;67:85–91.
Mantha A, Hanson J, Goss G, Lagarde A, Lorimer I, Dimitroulakos J: Targeting the mevalonate pathway inhibits the function of the epidermal growth factor receptor. Clin Cancer Res 2005;11:2398–2407.
Vogt U, Bielawski KP, Bosse U, Schlotter CM: Breast tumour growth inhibition in vitro through the combination of cyclophosphamide/metotrexate/5-fluorouracil, epirubicin/cyclophosphamide, epirubicin/paclitaxel, and epirubicin/docetaxel with the bisphosphonates ibandronate and zoledronic acid. Oncol Rep 2004;12:1109–1114.
Linn J, Duggan D, Chen I, Ellsworth R: Physiological disposition of alendronate, a potent antiosteolytic bisphosphonate in laboratory animals. Drug Metab Dispos 1991;19:926–932.
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