Vascular disrupting agents are an emerging class of therapeutics targeting the vascular network of solid tumors. However, their clinical progression has been hampered, primarily because of the persistence of surviving cells at the well perfused “viable rim” of tumors. In vitro, the active metabolite of (S)-2-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-3-phenylpropanamide hydrochloride (STA-9584) displayed increased potency compared with combretastatins. STA-9584 increased significant tumor regression in prostate and breast xenograft models in vivo and in an aggressive syngeneic model, demonstrating superior tumor growth inhibition compared with the combretastatin A-4 phosphate. The increased efficacy seemed to be related to effects on microvasculature in highly perfused tumor areas. Results from cardiovascular safety studies also suggest minimal risk for cardiovascular toxicity. This bioactivity profile distinguishes STA-9584 from the combretastatin class and identifies the compound as a promising new therapeutic candidate.
See article at J Pharmacol Exp Ther 2012, 343:529–538.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics