Alan Hilary Calvert, MD

The articles in this supplement to ONCOLOGY, “Clinical Update onPemetrexed,” are presented by leading international clinical andpreclinical investigators in the arenas of thoracic, gastrointestinal, breast, andgynecologic cancers. They cover a wide range of topics that focus on the promisingagent pemetrexed (Alimta).

Pemetrexed (Alimta) is a novel antimetabolite that inhibits the folatedependentenzymes thymidylate synthase, dihydrofolate reductase, andglycinamide ribonucleotide formyltransferase. Pemetrexed has demonstratedactivity in clinical trials in a variety of tumor types, includinglung, breast, colon, mesothelioma, pancreatic, gastric, bladder, headand neck, and cervix. Pemetrexed is rapidly metabolized into activepolyglutamate forms that are potent inhibitors of several tetrahydrofolatecofactor-requiring enzymes critical to the synthesis of purines and thymidine.Functionally, pemetrexed acts as a prodrug for its polyglutamateforms. Two different transporters are known to take extracellular folates,and some antifolates, into the cell. These are the reduced folate carrierand the folate receptor. One of the many attributes that make pemetrexedunique is that methodology has been developed to eliminate and controlmany of its associated clinical toxicities. Multivariate analyses demonstratedthat pretreatment total plasma homocysteine levels significantlypredicted severe thrombocytopenia and neutropenia, with orwithout associated grade 3/4 diarrhea, mucositis, or infection. Routinevitamin B12 and folic acid supplementation have resulted in decreasedfrequency/severity of toxicities associated with pemetrexed without affectingefficacy, making this novel antifolate a safe and efficaciousanticancer agent.