Chemokine Blockade in Combination with Cytoreductive Conditioning in Metastatic Breast Cancer

摘要

Chemokines have been shown to provide angiogenic effects. Blocking chemokines can reduce metastatic breast cancer cell growth. We proposed that cytoreductive conditioning will force the tumor to rely on angiogenesis as a survival mechanism and thus make the tumor more susceptible to chemokine blockade. We demonstrate that tumor cells increase production of IL-8 and MCP-1 transcripts in vivo in response to IL-8 neutralization and/or gamma irradiation and cytoxan administration. We have also demonstrated that IL-8 but not MCP-1 can function as autocrine growth or survival factor for MDA-231 cells in vitro but neutralization requires high concentrations of antibody. This observation is consistent with the more significant anti-tumor effect observed with anti-IL- 8 as a single agent and suggest that IL-8 promotes tumor cell growth through multiple mechanisms. We also showed that administration of anti-IL-8 and anti- MCP-1 can inhibit the formation of human breast cancer lung metastasis in a xenograft model.