Clinical activity of pemetrexed: a multitargeted antifolate anticancer agent

Pemetrexed is a new generation antifolate anticancer agent that inhibits several folate-dependent enzymes required for production of DNA and RNA intermediates. Early studies showed significant hematologic and nonhematologic toxicities with this agent. However it was found that many of these toxicities related to functional folate status and could be markedly reduced through routine supplementation with folic acid and vitamin B(12), without adversely affecting efficacy. Phase III studies with pemetrexed have established a clinical role for this drug as a single agent in the second-line treatment of non-small cell lung cancer and in combination with cisplatin for the frontline treatment of unresectable malignant pleural mesothelioma. Clinical trials of pemetrexed alone or in combination with other chemotherapeutic agents have shown considerable activity in many tumor types including colorectal, pancreatic and breast cancer, and urothelial tumors.