The selective targeting of established tumor vasculature represents an attractive novel anticancer drug strategy that is distinct from inhibiting angiogenesis. Subclasses of vascular targeting agents (VTAs) under evaluation in clinical trials include drugs interacting with tubulin (such as the combretastatins and ZD6126) and the distinct microtubule-independent flavonoid 5,6-dimethyl xanthenone acetic acid AS1404 (DMXAA). DMXAA induces both direct apoptosis of tumor endothelial cells and a secondary induction of vasoactive agents including serotonin and tumor necrosis factor alpha. The drug has recently completed Phase I clinical trials. It is widely proposed that VTAs might show maximum clinical benefit when used in combination with therapies (such as cytotoxics) that selectively target the well-oxygenated periphery of tumors. We, and others, have previously demonstrated that DMXAA increases the antitumor activity of paclitaxel in preclinical models including a human tumor xenograft representative of non-small cell lung cancer and, more recently, an ovarian cancer xenograft (SKOV-3). These data support ongoing (non-small cell lung cancer) and planned (ovarian) Phase II combination trials with paclitaxel (and platins). The aim of this study was to evaluate the combination of DMXAA with docetaxel in a human prostate cancer xenograft, representative of a disease for which docetaxel has recently received US and European regulatory approval. Mice bearing established subcutaneously implanted DU145 prostate cancer xenografts were treated intravenously with either docetaxel (10mg/kg day 0 or 5mg/kg days 0,4,8), DMXAA (21mg/kg days 0,4,8) or the combination (docetaxel 10mg/kg and DMXAA 21mg/kg given concomitantly on day 0; docetaxel 5mg/kg and DMXAA 21mg/kg given concomitantly on days 0,4,8). Tumor growth was compared with that of controls. Results showed a striking, statistically significant, potentiation in antitumor efficacy in the combination arms. Median tripling times in days were 12.6 for controls; 20.2 for 10mg/kg docetaxel (day 0); 24.5 for docetaxel 5mg/kg days 0,4,8; and 33.3 for DMXAA alone but 55.5 for the 10mg/kg docetaxel 21mg/kg day 0 combination arm and >54 days for the 5mg/kg:21mg/kg days 0,4,8 combination group. There were 3 cures (43%) in the group receiving docetaxel 5mg/kg and DMXAA 21mgkg on days 0,4,8. These data indicate that the VTA DMXAA potentiates the antitumor activity of docetaxel in a preclinical model of human prostate cancer and are supportive of performing clinical trials with this combination in this disease type. Such trials are scheduled to begin in 2005.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]