Metronomic Dosing Enhances the Anti-Angiogenic Effect of Epothilone B

Abstract

High doses (10 nM) of epothilone B, a microtubule stabilizer, will inhibit the development of human tumor-derived angiogenesis following short (14 d) drug exposure times. Metronomic dosing regimes use lower drug doses and prolonged drug exposure times in an attempt to decrease toxicity compared with standard dosing schedules. We hypothesized that epothilone B would be an effective anti-angiogenic agent when administered at very low doses over an extended period of time. Fragments of four fresh human tumors were cultured in a fibrin-thrombin matrix and maintained in nutrient media plus 20% fetal bovine serum (FBS) for 56 d. Tumor fragments (n=40-60 per group) were exposed to weekly doses of epothilone B at concentrations of 10, 5, 1, 0.5, or 0.1 nM. All of these concentrations are clinically achievable. Tumor angiogenesis was assessed weekly on d 14-56 using a validated visual grading system. This system rates neovessel growth, density, and length on a 0-16 scale [angiogenic index, (AI)]. The average change in AI between d 14 and 56 was calculated for all samples and used to evaluate the metronomic response. Epothilone B produced a dose-dependent anti-angiogenic response in all tumors. Two of the four tumors demonstrated a clear and significant metronomic anti-angiogenic effect over time. Epothilone B, when dosed by a metronomic schedule may have a significant anti-angiogenic effect on human solid tumors. This study provides evidence for the potential use of epothilone B on a metronomic dosing schedule.