Background: To evaluate the modifications of circulating angiogenic factors, metalloproteinases and acute-phase cytokines after the first single zoledronic acid (ZA) intravenous infusion. Experimental Design: Eighteen consecutive breast cancer patients with bone metastases were evaluated for circulating levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), metalloproteinase 1 (MMP-1), metalloproteinase 2 (MMP-2), interleukins 1β, 6 and 8 (IL-1β, IL-6, IL-8), interferon γ, tumor necrosis factor α (TNF-α) and transforming growth factor β1 just before and 2 and 7 days after ZA infusion. Results: The MMP-2 basal value showed a statisticallysignificant decrease 48 h after ZA (p = 0.01), being at 7 days higher than the day 2 value (p = 0.03). The VEGF basal value showed a statisticallysignificant decrease 48 h after ZA infusion (p = 0.03), increasing above the basal level at 7 days (p = 0.07). The bFGF basal level almost significantly decreased 2 days after infusion (p = 0.06), being at 7 days higher than the basal value (p = 0.09). Comparing the day 2 values with basal ones, the linear regression model showed a significantpositive correlation between IL-8 and bFGF (p = 0.02), IL-8 and TNF-α (p < 0.0001), bFGF and TNF-α (p = 0.01), MMP-1 and TNF-α (p = 0.02). Conclusions: ZA could exert an antiangiogenic activity and inhibition of tumor cell bone invasiveness by a transient reduction of VEGF, bFGF and MMP-2 circulating levels after infusion.

Keywords:
Bone metastases, Zoledronate, Vascular endothelial growth factor, Matrix metalloproteinase 2, Acute-phase cytokines
1.
Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C, Wheeler H, Simeone JF, Seaman J, Knight RD: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med 1996;335:1785–1791.
2.
Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ: Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 1998;13:581–589.
3.
Coxon FP, Benford HL, Russell RG, Rogers MJ: Protein synthesis is required for caspase activation and induction of apoptosis by bisphosphonate drugs. Mol Pharmacol 1998;54:631–638.
4.
Alakangas A, Selander K, Mulari M, Halleen J, Lehenkari P, Monkkonen J, Salo J, Vaananen, K: Alendronate disturbs vesicular trafficking in osteoclasts. Calcif Tissue Int 2002;70:40–47.
5.
Caraglia M, D’Alessandro AM, Marra M, Giuberti G, Vitale G, Viscomi C, Colao A, Prete SD, Tagliaferri P, Tassone P, Budillon A, Venuta S, Abbruzzese A: The farnesyl transferase inhibitor R115777 (Zarnestra) synergistically enhances growth inhibition and apoptosis induced on epidermoid cancer cells by zoledronic acid (Zometa) and pamidronate. Oncogene 2004;23:6900–6913.
6.
Green JR: Chemical and biological prerequisites for novel bisphosphonate molecules: Results of comparative preclinical studies. Semin Oncol 2001;28:4–10.
7.
Pietschmann P, Stohlawetz P, Brosch S, Steiner G, Smolen JS, Peterlik M: The effect of alendronate on cytokine production, adhesion molecules expression and transendothelial migration of human peripheral blood mononuclear cells. Calcif Tissue Int 1998;63:325–330.
8.
Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM, Castronovo V, Green JR: Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002;302:1055–1061.
9.
Croucher PI, De Hendrik R, Perry MJ, Hijzen A, Shipman CM, Lippitt J, Green J, Van Marck E, Van Camp B, Vanderkerken K: Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: Evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res 2003;18:482–492.
10.
Fournier P, Boissier S, Filleur S, Guglielmi J, Cabon F, Colombel M, Clezardin P: Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002;62:6538–6544.
11.
Santini D, Vincenzi B, Avvisati G, Dicuonzo G, Battistoni F, Gavasci M, Salerno A, Denaro V, Tonini G: Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 2002;8:1080–1084.
12.
Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino FH, Colombel M, Delmas P, Delaisse JM, Clezardin P: Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 2000;60:2949–2954.
13.
Teronen O, Heikkila P, Konttinen YT, Laitinen M, Salo T, Hanemaaijer R, Teronen A, Maisi P, Sorsa T: MMP inhibition and downregulation by bisphosphonates. Ann NY Acad Sci 1999;878:453–465.
14.
Teronen O, Konttinen YT, Lindqvist C, Salo T, Ingman T, Lauhio A, Ding Y, Santavirta S, Valleala H, Sorsa T: Inhibition of matrix metalloproteinase-1 by dichloromethylene bisphosphonate (clodronate). Calcif Tissue Int 1997;61:59–61.
15.
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.
16.
Thiebaud D, Sauty A, Burckhardt P, Leuenberger P, Sitzler L, Green JR, Kandra A, Zieschang J, Ibarra de Palacios P: An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates. Calcif Tissue Int 1997;61:386–392.
17.
Zhou M, Zhang Y, Ardans JA, Wahl LM: Interferon-gamma differentially regulates monocyte matrix metalloproteinase-1 and -9 through tumor necrosis factor-alpha and caspase 8. J Biol Chem 2003;278:45406–45413.
18.
Pantschenko AG, Pushkar I, Anderson KH, Wang Y, Miller LJ, Kurtzman SH, Barrows G, Kreutzer DL: The interleukin-1 family of cytokines and receptors in human breast cancer: Implications for tumor progression. Int J Oncol 2003;23:269–284.
19.
Sauty A, Pecherstorfer M, Zimmer-Roth I, Fioroni P, Juillerat L, Markert M, Ludwig H, Leuenberger P, Burckhard, P, Thiebaud D: Interleukin-6 and tumor necrosis factor alpha levels after bisphosphonates treatment in vitro and in patients with malignancy. Bone 1996;18:133–139.
20.
Sanders JL, Tarjan G, Foster SA, Stern PH: Alendronate/interleukin-1beta cotreatment increases interleukin-6 in bone and UMR-106 cells: Dose dependence and relationship to the antiresorptive effect of alendronate. J Bone Miner Res 1998;13:786–792.
21.
Suarez-Cuervo C, Harris KW, Kallman L, Vaananen HK, Selander KS: Tumor necrosis factor-alpha induces interleukin-6 production via extracellular-regulated kinase 1 activation in breast cancer cells. Breast Cancer Res Treat 2003;80:71–78.
22.
Ferrari L, Bajetta E, Martinetti A, Celio L, Longarini R, La Torre I, Buzzoni R, Gattinoni L, Seregni E, Bombardieri E: Could exemestane affect insulin-like growth factors, interleukin 6 and bone metabolism in postmenopausal advanced breast cancer patients after failure on aminoglutethimide, anastrozole or letrozole? Int J Oncol 2003;22:1081–1089.
23.
Dicuonzo G, Vincenzi B, Santini D, Avvisati G, Rocci L, Battistoni F, Gavasci M, Borzomati D, Coppola R, Tonini G: Fever after zoledronic acid administration is due to increase in TNF-alpha and IL-6. J Interferon Cytokine Res 2003;23:649–654.
24.
Santini D, Vincenzi B, Dicuonzo G, Avvisati, G, Massacesi C, Battistoni F, Gavasci M, Rocci L, Tirindelli MC, Altomare V, Tocchini M, Bonsignori M, Tonini G: Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 2003;9:2893–2897.
25.
Beatty G, Paterson Y: IFNγ-dependent inhibition of tumor angiogenesis by tumor-infiltrating CD4+ T cells requires tumor responsiveness to IFNγ. J Immunol 2001;166:2276–2282.
26.
Pavlakovic H, Havers W, Schweigerer L: Multiple angiogenesis stimulators in a single malignancy: Implications for anti-angiogenic tumour therapy. Angiogenesis 2001;4:259–262.
27.
Rofstad EK, Halsor EF: Vascular endothelial growth factor, interleukin 8, platelet-derived endothelial cell growth factor, and basic fibroblast growth factor promote angiogenesis and metastasis in human melanoma xenografts. Cancer Res 2000;60:4932–4938.
28.
Pakala R, Watanabe T, Benedict CR: Induction of endothelial cell proliferation by angiogenic factors released by activated monocytes. Cardiovasc Radiat Med 2002;3:95–101.
29.
Bancroft CC, Chen Z, Dong G, Sunwoo JB, Yeh N, Park C, Van Waes C: Coexpression of proangiogenic factors IL-8 and VEGF by human head and neck squamous cell carcinoma involves coactivation by MEK-MAPK and IKK-NF-B signal pathways. Clin Cancer Res 2001;7:435–442.
30.
Mundy GR, Yoneda T, Hiraga T: Preclinical studies with zoledronic acid and other bisphosphonates: Impact on the bone microenvironment. Semin Oncol 2001;28(suppl 6):35–44.
31.
Duivenvoorden WC, Hirte HW, Singh G: Transforming growth factor beta1 acts as an inducer of matrix metalloproteinase expression and activity in human bone-metastasizing cancer cells. Clin Exp Metastasis 1999;17:27–34.
32.
Stearns ME: Alendronate blocks TGF-beta1 stimulated collagen 1 degradation by human prostate PC-3 ML cells. Clin Exp Metastasis 1998;16:332–339.
33.
Hidalgo M, Eckhardt SG: Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 2001;93:178–193.
34.
Teronen O, Laitinen M, Salo T, Hanemaaijer R, Heikkila P, Konttinen YT, Sorsa T: Inhibition of matrix metalloproteinases by bisphosphonates may in part explain their effects in the treatment of multiple myeloma. Blood 2000;96:4006–4007.
35.
Giraudo E, Inoue M, Hanahan D: An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 2004;114:623–633.
36.
Coussens LM, Tinkle CL, Hanahan D, Werb Z: MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 2000;103:481–490.
37.
Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D: Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000;2:737–744.
38.
Heissig B, Hattori K, Friedrich M, Rafii S, Werb Z: Angiogenesis: Vascular remodeling of the extracellular matrix involves metalloproteinases. Curr Opin Hematol 2003;10:136–141.
39.
Pollard JW: Opinion: Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004;4:71–78.
40.
Huang S, Van Arsdall M, Tedjarati S, McCarty M, Wu W, Langley R, Fidler IJ: Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. J Natl Cancer Inst 2002;94:1134–1142.
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2005
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