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

Thymidylate synthase inhibitors for non-small cell lung cancer.

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  • 1VU University Medical Center, Department of Medical Oncology, Amsterdam, The Netherlands.



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.


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.


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.

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