Journal of the National Cancer Institute Advance Access originally published online on September 25, 2007
JNCI Journal of the National Cancer Institute 2007 99(19):1441-1454; doi:10.1093/jnci/djm135
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© The Author 2007. Published by Oxford University Press.
REVIEW |
Drug Resistance and the Solid Tumor Microenvironment
Affiliations of authors: Division of Applied Molecular Oncology and Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada (OT, KP, IFT); Université Claude Bernard Lyon 1, ENS-CNRS UMR 5239, Oullins, France (CMG)
Correspondence to: Ian F. Tannock, MD, PhD, Princess Margaret Hospital, Ste 5-208, 610 University Ave, Toronto, ON M5G 2M9, Canada (e-mail: ian.tannock{at}uhn.on.ca).
Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment.
Manuscript received February 16, 2007; revised July 12, 2007; accepted August 3, 2007.
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J Natl Cancer Inst 2007 99: 1421.
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