Zoledronic-Acid-Induced Circulating Level Modifications of Angiogenic Factors, Metalloproteinases and Proinflammatory Cytokines in Metastatic Breast Cancer Patients

Abstract

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.

Cytokines Behavior in Multiple Myeloma Patients during Zoledronic Acid Treatment

“…About the use of zoledronic acid in solid tumor, Santini et al [4] reported that in patients with advanced solid cancer and bone metastasis, pamidronate [2] and zoledronic acid [4][5][6][7][8][9][10][11][12][13] showed antiangiogenic properties which were associated with a significant and long-lasting decrease of VEGF serum levels following bisphosphonates infusion. These observations were later confirmed by Ferretti et al [14] who observed a transient but significant reduction of VEGF and bFGF, 48 hours after the infusion of zoledronic acid in breast cancer patients with bone metastasis.…”

“…We reported different hypothetical mechanism of anti-MM activity of zoledronic acid, for which there is actually no consensus, for this reason, according with the results found in solid tumors, we explored the contribution of bisphosphonates in anti-MM activity studying its potential anti-angiogenic effect based on modification of cytokines which are pivotal in this pathogenic mechanism [11][12][13][14][15][16][17][18].…”

Sensitization of ovarian carcinoma cells with zoledronate restores the cytotoxic capacity of Vγ9Vδ2 T cells impaired by the prostaglandin E2 immunosuppressive factor: Implications for immunotherapy

“…46 Moreover, zoledronate displays antiangiogenic activity and can decrease the secretion of immunosuppressive (TGF-b, FGF-b and metalloproteinases) and proinflammatory (IL-1b, IL-6 and IL-8) factors. 42,[47][48][49][50] In a previous clinical trial designed to evaluate phosphoantigen administration in B-cell malignancies, a correlation was observed between the in vivo expansion of Vc9Vd2 T cells and the objective antitumor response. 18 An adoptive transfer immunotherapy assay has also been conducted in metastatic renal cell carcinoma by Kobayashi et al 21 and in lung carcinoma by Nakajima et al 51 These studies found that autologous Vc9Vd2 T cells are well tolerated and induce an antitumor effect.…”

The effects of zoledronic acid on neointimal hyperplasia: a rabbit carotid anastomosis model

“…(Original magnification x10, x40 and x100) expression by infiltrating macrophages and inhibited MMP-9 activity by reducing association of VEGF with its receptor on angiogenic endothelial cells in a mouse model of human cervical carcinogenesis. Additionally, ZA treatment was shown to decrease circulating levels of MMP-2, VEGF and basic fibroblast growth factor (bFGF) in metastatic breast cancer patients (38). Furthermore, alendronate which is another bisphosphonate was exerted to reduce the secretion of MMP-2 and MMP-9 by metastatic PC-3 ML cells in mice (39).…”