title: Mechanisms of Drug Resistance Related to the Microenvironment of Solid Tumors and Possible Strategies to Inhibit Them.
abstract: Drug resistance can occur at the individual cellular level or as a result of properties of the tumor microenvironment. The convoluted vasculature within tumors results in robustly proliferating well-nourished cells located proximal to functional blood vessels and regions of slowly proliferating (often hypoxic) cells located distal to functional blood vessels. Irregular blood flow and large distances between functional blood vessels in solid tumors lead to poor drug distribution within them such that cells distal from functional blood vessels are exposed to ineffective concentrations of drug, resulting in therapeutic resistance. Strategies to improve or complement the distribution of anticancer drugs within tumors hold promise for increasing antitumor effects without corresponding increases in normal tissue toxicity. In particular, use of hypoxia-targeted agents and modulation of autophagy have shown promising results in enhancing the distribution of drug activity within solid tumors and hence antitumor efficacy. In this review, we describe causes of resistance to chemotherapy that relate to the microenvironment of solid tumors and the potential to improve antitumor effects by countering such mechanisms of resistance.
authors.affiliation: From the *Department of Medical Biophysics, University Health Network, University of Toronto; †Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre; and ‡University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Qian
authors.initials: Q
authors.lastname: Tan
authors.forename: Jasdeep K
authors.initials: JK
authors.lastname: Saggar
authors.forename: Man
authors.initials: M
authors.lastname: Yu
authors.forename: Marina
authors.initials: M
authors.lastname: Wang
authors.forename: Ian F
authors.initials: IF
authors.lastname: Tannock
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001343:Autophagy; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000627:therapeutic use; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs