title: Toward a Better Understanding of the Complexity of Cancer Drug Resistance.
abstract: Resistance to anticancer drugs is a complex process that results from alterations in drug targets; development of alternative pathways for growth activation; changes in cellular pharmacology, including increased drug efflux; regulatory changes that alter differentiation pathways or pathways for response to environmental adversity; and/or changes in the local physiology of the cancer, such as blood supply, tissue hydrodynamics, behavior of neighboring cells, and immune system response. All of these specific mechanisms are facilitated by the intrinsic hallmarks of cancer, such as tumor cell heterogeneity, redundancy of growth-promoting pathways, increased mutation rate and/or epigenetic alterations, and the dynamic variation of tumor behavior in time and space. Understanding the relative contribution of each of these factors is further complicated by the lack of adequate in vitro models that mimic clinical cancers. Several strategies to use current knowledge of drug resistance to improve treatment of cancer are suggested.
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; email: mgottesman@nih.gov , lavio@mail.nih.gov , hallma@mail.nih.gov.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; email: mgottesman@nih.gov , lavio@mail.nih.gov , hallma@mail.nih.gov.
authors.forename: Orit
authors.initials: O
authors.lastname: Lavi
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; email: mgottesman@nih.gov , lavio@mail.nih.gov , hallma@mail.nih.gov.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
authors.affiliation: Laboratory of Molecular Cancer Biology, Molecular Physiology Research Unit-URPhyM, Namur Research Institute for Life Sciences (NARILIS), Faculty of Medicine, University of Namur, B-5000 Namur, Belgium; email: jean-pierre.gillet@unamur.be.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gillet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents
keywords: ABCB1; P-glycoprotein; chemotherapy; multidrug resistance; platinum compounds