Effective anti-tumor immunomodulatory properties of zoledronic acid

Introduction. Zoledronic acid (Zol) is the most potent aminobisphosphonates clinically available. Preclinical in vivo data suggest that it modulates the development of bone disease, decreases tumor burden with a direct anti-cancer activity, and reduces the migration and the metastatic invasion of cancer cells. Zol efficacy in anti-cancer adjuvant therapy also rests on its anti-angiogenic properties and ability to expand gamma/delta T cells, both in vitro and in vivo. The published data thus far available concern murine models of transplanted tumors. Present work was made to assess Zol immune-mediated activity in impairing spontaneous carcinogenesis in a transgenic mouse model. Materials and Methods. To asses Zol anti-tumor and immunomodulant properties, BALBneuT mice were treated with 16 administrations of 100 μg/Kg of Zol divided into four courses of a single weekly injections for four weeks followed by a three weeks rest. Zol administration was started when mice were 7 weeks old and therefore when all the 10 mammary glands display a widespread atypical hyperplasia. Zol was administered intravenously (i.v.) or into the mammary pad (i.mam.). Mice were evaluated for: 1) tumor onset, 2) tumor multiplicity and 3) overall survival. Results. Data obtained from these first experiments have shown that a similar significant tumor growth impairment was evident in mice receiving Zol administered i.v. or i.mam. Preliminary results have demonstrated Zol capacity to induce a significant increase in the percentage of gammadelta T cells in the spleen and in the lymphonode of Zol-treated mice. Even more importantly, data obtained in IFNg knocked out -NeuT mice have shown that Zol capacity to delay tumor onset and growth and to improve NeuT-mice survival is strictly dependent on the presence of IFNgamma, which is a well known mediator of innate and adaptive immune responses. Zol immune-mediated anti-tumor properties are further and even more convincingly supported by the evidence that NeuT mice knocked-out for the gene encoding for the Fcg receptor (FcgR-KO NeuT) and NeuT mice knocked-out for the gene encoding for the perforin (PF-KO NeuT) did not benefit of Zol anti-tumor action. Conclusions. All together, these data show for the first time that Zol in vivo antitumor functions at least partially relies on broad immunomodulant properties, involving cellular and humoral immunity.