title: DNA synthesis inhibitors for the treatment of gastrointestinal cancer.
abstract: BACKGROUND
  Intensive laboratory, preclinical and clinical studies have identified and validated molecular targets in cancers, leading to a shift toward the development of novel, rationally designed and specific therapeutic agents. However, gastrointestinal cancers continue to have a poor prognosis, largely due to drug resistance.
  
  
  METHODS
  Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies.
  
  
  CONCLUSIONS
  Conventional agents, including DNA synthesis inhibitors such as fluoropyrimidines and platinum analogs, remain the most effective therapeutics and are the standards against which new drugs are compared. Novel DNA synthesis inhibitors for the treatment of gastrointestinal malignancies include a combination of the antimetabolite TAS-102, which consists of trifluorothymidine with a thymidine phosphorylase inhibitor, and a novel micellar formulation of cisplatin NC-6004 that uses a nanotechnology-based drug delivery system. The challenges of translational cancer research using DNA synthesis inhibitors include the identification of drugs that are specific to tumor cells to reduce toxicity and increase antitumor efficacy, biomarkers to predict pharmacological responses to chemotherapeutic drugs, identification of ways to overcome drug resistance and development of novel combination therapies with DNA synthesis inhibitors and other cancer therapies, such as targeted molecular therapeutics. Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies.
authors.affiliation: The University of Tokyo, The Institute of Medical Science, Center for Antibody and Vaccine , 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639 , Japan hiroyasu@ims.u-tokyo.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yasui
authors.forename: Giichiro
authors.initials: G
authors.lastname: Tsurita
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D056831:Coordination Complexes / Q000627:therapeutic use; D003562:Cytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D016503:Drug Delivery Systems; D005492:Folic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006801:Humans; D049329:Nanostructures; D019384:Nucleic Acid Synthesis Inhibitors / Q000627:therapeutic use*; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D017671:Platinum Compounds / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D013936:Thymidine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D056831:Coordination Complexes; D019384:Nucleic Acid Synthesis Inhibitors; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; D011743:Pyrimidines; D003562:Cytidine; D005492:Folic Acid; D013936:Thymidine
keywords: DNA synthesis inhibitor; antimetabolite; drug delivery system; drug resistance; platinum analogs; translational cancer research