Combined angiostatic therapies better inhibited neovascularization vs. monotherapy in rats

A combination of angiostatic treatments completely inhibited neovascularization in a rat model of ischemic retinopathy, a study found. Combining the drugs caused a synergistic inhibitory effect that significantly outperformed monotherapy at similar concentrations, the study authors said.

Michael I. Dorrell, PhD, and colleagues at The Scripps Research Institute in La Jolla, Calif., investigated a combination of three antiangiogenic treatments for blocking the compensatory angiogenesis that often develops due to treatment with vascular endothelial growth factor (VEGF) inhibitors, according to the study.

"These compensatory mechanisms may be what ultimately limit the therapeutic potential of antiangiogenic monotherapies, because blocking a single pathway may induce compensation by other pro-angiogenic pathways," the authors said.

The combination therapy included a VEGF aptamer chemically identical to Macugen (pegaptanib, Pfizer/OSI), a small-molecule integrin antagonist that targets endothelial cell survival (EMD472523, Merck) and a proteolytic fragment of tryptophan tRNA synthetase that blocks intracellular adhesion (T2-TrpRS).

The researchers found the drug combination inhibited more than 90% of the neovascularization present in 20 of 24 treated rat retinas. Of these, 15 (63%) showed complete inhibition of deep vascular plexus formation where no neovascular sprouts were seen, the authors said.

"This result is a striking improvement over angiostatic monotherapies, which resulted in complete inhibition in only two of 118 (2%) retinas," the authors said.

The combination treatment also showed comparable efficacy to optimal doses of monotherapy treatment after being diluted 100-fold, they noted.

"At these same ... concentrations, the angiostatic activity of each monotherapy was negligible, demonstrating that combining multiple angiostatic drugs was synergistic rather than additive," the authors said. A similar synergistic effect was observed when the researchers replaced the VEGF aptamer with Macugen or Avastin (bevacizumab, Genentech).

The potential for low doses may offer advantages to the elderly or diabetic patients, in whom circulating angiostatics could precipitate a heart attack or stroke, the authors noted.

The study is published in the Jan. 16 edition of the Proceedings of the National Academy of Sciences.