title: Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance.
abstract: The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed 'metronomic' chemotherapy, presents an alternative to standard maximal tolerated dose (MTD) chemotherapy. The primary target of metronomic chemotherapy was originally identified as endothelial cells supporting the tumor vasculature, and not the tumor cells themselves, consistent with the emerging concept of cancer as a systemic disease involving both tumor cells and their microenvironment. While anti-angiogenesis is an important mechanism of action of metronomic chemotherapy, other mechanisms, including activation of anti-tumor immunity and a decrease in acquired therapeutic resistance, have also been identified. Here we present evidence supporting a mechanistic explanation for the improved activity of cancer chemotherapy when administered on a metronomic, rather than an MTD schedule and discuss the implications of these findings for further translation into the clinic.
authors.affiliation: Newman Lakka Institute, Floating Hospital for Children at Tufts Medical Center, Boston, MA 02111; Mathematical, Computational and Modeling Sciences Center, Arizona State University, Tempe, AZ 85287.
authors.forename: Irina
authors.initials: I
authors.lastname: Kareva
authors.affiliation: Division of Cell and Molecular Biology, Department of Biology, Boston University Boston, MA 02215.
authors.forename: David J
authors.initials: DJ
authors.lastname: Waxman
authors.affiliation: Newman Lakka Institute, Floating Hospital for Children at Tufts Medical Center, Boston, MA 02111. Electronic address: glakkaklement@tuftsmedicalcenter.org.
authors.forename: Giannoula
authors.initials: G
authors.lastname: Lakka Klement
mesh_terms: D059250:Administration, Metronomic; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D059016:Tumor Microenvironment
keywords: Angiogenesis; Anti-tumor immunity; MTDL alternative; Mechanisms of metronomic chemotherapy; Therapeutic resistance