Future directions in the development of pemetrexed.
Pemetrexed is a novel antifolate that inhibits several folate-dependent enzymes in addition to thymidylate synthase. Such a drug may have theoretical advantages over fluoropyrimidines and specifically acting antifolates. Phase I studies identified a preferred schedule of an intravenous dose once every 3 weeks. Phase II studies showed a broad spectrum of activity in solid tumors (ie, non-small cell lung, colorectal, and pancreatic cancers) usually considered refractory to most antimetabolites. Binary combinations with cisplatin, carboplatin, and gemcitabine have proven feasible and show encouraging activity in lung cancer and mesothelioma. Problems of sporadic life-threatening toxicity identified in early studies of this and other antifolates have been resolved by the discovery that they were caused by functional folate deficiency and may be avoided by a low-dose nutritional supplement of folic acid and vitamin B(12). Pemetrexed is a promising new drug that should make a contribution to solid tumor oncology.
Calvert
Hilary
H
Department of Oncology, University of Newcastle Upon Tyne, Newcastle Upon Tyne, UK.
Bunn
Paul A
PA
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D019587:Dietary Supplements; D004354:Drug Screening Assays, Antitumor; D005492:Folic Acid / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000627:therapeutic use*; D005544:Forecasting; D005971:Glutamates / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D000068437:Pemetrexed; D014805:Vitamin B 12 / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D005492:Folic Acid; D014805:Vitamin B 12