title: Thymidylate synthase inhibitors for non-small cell lung cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors: VU University Medical Center, Department of Medical Oncology, Amsterdam, The Netherlands.
authors: Elena
authors: E
authors: Galvani
authors: Godefridus J
authors: GJ
authors: Peters
authors: Elisa
authors: E
authors: Giovannetti
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D005971:Glutamates / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D006147:Guanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D000068437:Pemetrexed; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase