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Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved January 20, 2011 (received for review October 30, 2010)
Abstract
Chemotherapy-induced broad toxicities are the leading cause of the drug-induced mortality in cancer patients. Antiangiogenic drugs (ADs) in combination with chemotherapy are widely used as front-line therapy for the treatment of various human cancers. However, the beneficial mechanisms underlying combination therapy are poorly understood. Here we show that, in several murine tumor models, administration of sunitinib markedly reduced chemotherapy-induced bone marrow toxicity. Intriguingly, in a sequential treatment regimen, delivery of ADs followed by chemotherapy demonstrated superior survival benefits compared with simultaneous administration of two drugs. In murine tumor models, we show that VEGF increased chemotoxicity by synergistically suppressing bone marrow hematopoiesis with cytostatic drugs. These findings shed light on molecular mechanisms by which ADs in combination with chemotherapy produce survival benefits in cancer patients and provide conceptual information guiding future designs of clinical trials, current practice, and optimization of ADs for the treatment of cancer.
Footnotes
- 1To whom correspondence should be addressed. E-mail: Yihai.Cao{at}ki.se.
Author contributions: Y.C. designed research; D.Z., E.-M.E.H., S.L., F.C., and Y.Z. performed research; B.S. and Y.C. contributed new reagents/analytic tools; D.Z., E.-M.E.H., S.L., F.C., Y.Z., and Y.C. analyzed data; and D.Z. and Y.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1016220108/-/DCSupplemental.
Antiangiogenic agents significantly improve survival in tumor-bearing mice by increasing tolerance to chemotherapy-induced toxicity
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