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Article
Metronomic Dosing of BH3 Mimetic Small Molecule Yields Robust Antiangiogenic and Antitumor Effects
Cancer Research
  • Atsushi Imai, University of Michigan School of Dentistry
  • Benjamin David Zeitlin, University of the Pacific
  • Francesco Visioli, University of Padova
  • Zhihong Dong, University of Michigan School of Dentistry
  • Sudha Krishnamurthy, University of Michigan School of Dentistry
  • Marnie Emily Light, University of KwaZulu-Natal
  • Frank Worden, University of Michigan - Ann Arbor
  • Shaomeng Wang, University of Michigan - Ann Arbor
  • Jacques E. Nör, University of Michigan School of Dentistry
ORCiD
Dr. Benjamin D. Zeitlin: 0000-0003-0110-0188
Document Type
Article
DOI
10.1158/0008-5472.CAN-10-2873
Publication Date
2-1-2012
Abstract
Bcl-2 is an antiapoptotic protein that has also been found to function as a proangiogenic signaling molecule. Improvements in antiangiogenic therapy can be engendered by metronomic dosing. Thus, we hypothesized that BH3-mimetic drugs that antagonize Bcl-2 family proteins may exert a greater efficacy when dosed metronomically. To examine this hypothesis, we employed AT101, an orally available and well-tolerated BH3-mimetic drug that has been established as effective. In a mouse xenograft model of human squamous cell carcinomas (SCC) that includes a humanized vasculature, we explored the effects of docetaxel in combination with either daily (metronomic) or weekly (bolus) doses of AT101. In addition, we explored the effect of single or combination therapy on angiogenesis and survival of endothelial or SCC cells in vitro. Metronomic AT101 therapy increased mouse survival, decreased tumor mitotic index, and decreased tumor microvessel density, compared with bolus therapy. Therapeutic potentiation was achieved by similar overall drug exposure and without altering systemic toxicities. Combinations of AT101 and docetaxel produced additive toxicity in both endothelial and SCC tumor cells. Notably, subapoptotic concentrations of AT101 potently inhibited the angiogenic potential of endothelial cells. Taken together, our findings unveil the efficacious benefits that can be achieved by metronomic delivery of BH3-mimetic drugs, in particular suggesting that SCC patients with might benefit from low-dose continuous administration of these drugs.
Citation Information
Atsushi Imai, Benjamin David Zeitlin, Francesco Visioli, Zhihong Dong, et al.. "Metronomic Dosing of BH3 Mimetic Small Molecule Yields Robust Antiangiogenic and Antitumor Effects" Cancer Research Vol. 72 Iss. 3 (2012) p. 716 - 725 ISSN: 1538-7445
Available at: http://works.bepress.com/benjamin-zeitlin/25/