INTRODUCTION: 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.
AREAS COVERED: Here, we discuss the current understanding of DNA synthesis 
inhibitors and their mechanisms of action for the treatment of gastrointestinal 
malignancies.
EXPERT OPINION: 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.