Epothilone B is a more potent antiangiogenic than paclitaxel in a human tumor-based angiogenesis model

Abstract

Abstract Introduction: We have previously shown that Epothilone B, a microtubule stabilizer, is a potent antiangiogenic in an intact human tumor-based angiogenesis assay. Clinical studies have demonstrated Epothilone B can be effective in patients resistant to the microtubule stabilizer paclitaxel. Methods: We hypothesized that equimolar doses of Epothilone B would be more potent than paclitaxel in our in vitro human tumor angiogenesis assay. To evaluate our hypothesis discarded portions of eleven fresh human tumors were obtained. Tumor fragments were embedded in fibrin-thrombin clots in 96 well plates. Drug-treated wells contained a control nutrient media supplemented with Epothilone B or paclitaxel at equimolar (10–6 to 10–10 M) concentrations. Wells were assessed over time and evaluated for onset of neovessel invasion (%I) and the degree of subsequent angiogenic development (angiogenic index, AI). Epothilone B (10–8 M) and paclitaxel (10–8 M) were compared at a statistical significance level of 5%. Results: At doses of 10–6 M, both Epothilone B and paclitaxel completely inhibited angiogenesis. Epothilone B was statistically superior to paclitaxel in its ability to block angiogenic initiation in 4 of 11 (36%) of the cases studied, and demonstrated a numerical advantage in 9 out of the 11 (82%) cases. Epothilone B was statistically superior to paclitaxel in prohibiting subsequent angiogenic proliferation in 5/11(45%) tumors, and showed a numerical advantage in 8/11 (73%) specimens. Conclusions: At equimolar, clinically relevant (10–8M) drug doses, Epothilone B exhibits statistical and numerical advantage over paclitaxel's ability to inhibit human tumor-derived angiogenesis.