Pemetrexed: an active new agent for breast cancer

Pemetrexed is a novel antifolate that inhibits three enzymes in the de novo purine and pyrimidine pathways including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. It becomes highly polyglutamated once inside cancer cells, resulting in prolonged intracellular retention and 60-fold greater inhibition of thymidylate synthase than the monoglutamated form. Several phase II and III studies have shown that pemetrexed has significant antitumor activity against a variety of tumor types including mesothelioma, non-small cell lung cancer, and colon, pancreatic, and breast cancers. Pemetrexed appears to provide non-cross-resistant cytotoxic activity against breast cancers that have been treated with anthracyclines, taxanes, and capecitabine. Preclinical studies have suggested that pemetrexed enhances the cytotoxicity of several other important chemotherapeutic agents active against breast cancer including doxorubicin, paclitaxel, cisplatin, and gemcitabine. In vitro studies have shown that pemetrexed treatment synchronizes cancer cells at the G(2)/S interphase, leading to synchronous entry into S phase. Ongoing phase II studies of pemetrexed combinations in breast cancer hope to exploit the cell cycle modulatory effects of this drug as well as its excellent tolerability.