Thymidylate synthase inhibitors for non-small cell lung cancer

Expert Opin Investig Drugs. 2011 Oct;20(10):1343-56. doi: 10.1517/13543784.2011.617742. Epub 2011 Sep 9.


Introduction: The folate-dependent enzyme thymidylate synthase (TS) plays a pivotal role in DNA replication/repair and cancer cell proliferation, and represents a valid target for the treatment of several tumor types, including NSCLC. NSCLC is the leading cause of cancer-related mortality, and several TS inhibitors have gone into preclinical and clinical testing, with pemetrexed emerging for its approval and widespread use as first-/second-line and maintenance therapy for this disease.

Areas covered: This review summarizes the therapeutic options in NSCLC, as well as the background and rationale for targeting TS. The authors also review recent pharmacogenetic studies and data from clinical trials evaluating novel TS inhibitors, hoping that the reader will gain a comprehensive overview of the field of TS inhibition, specifically relating to drugs used or being developed for lung cancer patients.

Expert opinion: TS is a validated target in NSCLC. However, benefits from conventional chemotherapy in NSCLC have plateaued, and more cost-effective results should be obtained with individualized treatment. Accordingly, the clinical success for TS inhibitors may depend on our ability to correctly administer these agents following biomarker-driven patient selection, including TS genotype and expression, and using the right combination therapy.

Publication types

  • Review

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Glutamates / adverse effects
  • Glutamates / pharmacology*
  • Glutamates / therapeutic use
  • Guanine / adverse effects
  • Guanine / analogs & derivatives*
  • Guanine / pharmacology
  • Guanine / therapeutic use
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Molecular Targeted Therapy
  • Pemetrexed
  • Thymidylate Synthase / antagonists & inhibitors*


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Glutamates
  • Pemetrexed
  • Guanine
  • Thymidylate Synthase