Pemetrexed

Biochemical and cellular pharmacology, mechanisms, and clinical applications

Shrikanta Chattopadhyay, Richard G. Moran, I. David Goldman

Research output: Contribution to journalArticle

183 Citations (Scopus)

Abstract

Pemetrexed is a new-generation antifolate, approved for the treatment of mesothelioma and non-small cell lung cancer, currently being evaluated for the treatment of a variety of other solid tumors. This review traces the history of antifolates that led to the development of pemetrexed and describes the unique properties of this agent that distinguish it from other antifolates. These include (a) its very rapid conversion to active polyglutamate derivatives in cells that build to high levels and are retained for long intervals to achieve prolonged and potent inhibition of it major target enzyme thymidylate synthase, (b) its high affinity for three folate transporters, and (c) its marked sensitivity to the level of physiologic folates in cells. The latter results in the unique and paradoxical finding that when transport mediated by the major folate transporter (the reduced folate carrier) is impaired, pernetrexed activity is preserved. This is due to concurrent contraction of competing cellular physiologic folates and utilization of a novel second transport carrier for which pemetrexed has high affinity, recently identified as the proton-coupled folate transporter (PCFT). Laboratory studies are reviewed that raise the possibility of new approaches to the use of folic acid supplementation in clinical regimens with pemetrexed.

Original languageEnglish (US)
Pages (from-to)404-417
Number of pages14
JournalMolecular Cancer Therapeutics
Volume6
Issue number2
DOIs
StatePublished - Feb 2007

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Pemetrexed
Clinical Pharmacology
Folic Acid Antagonists
Folic Acid Transporters
Folic Acid
Proton-Coupled Folate Transporter
Reduced Folate Carrier Protein
Polyglutamic Acid
Thymidylate Synthase
Mesothelioma
Non-Small Cell Lung Carcinoma
History
Enzymes
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Pemetrexed : Biochemical and cellular pharmacology, mechanisms, and clinical applications. / Chattopadhyay, Shrikanta; Moran, Richard G.; Goldman, I. David.

In: Molecular Cancer Therapeutics, Vol. 6, No. 2, 02.2007, p. 404-417.

Research output: Contribution to journalArticle

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