Pemetrexed is a novel folate-directed antimetabolite. It is "multitargeted" in that it inhibits the activity of several enzymes, including thymidylate synthetase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, thereby affecting the synthesis of both purine and pyrimidine nucleic acid precursors. To avoid significant toxicity to the normal tissues, patients receiving pemetrexed should also receive low-dose folate and vitamin B12 supplementation. Pemetrexed has notable activity against certain lung cancers and, in combination with cisplatin, also against mesotheliomas. 5-Fluorouracil (5FU) represents an early example of "rational" drug design in that it originated from the observation that tumor cells incorporate radiolabeled uracil more efficiently. | Chapter 081. Principles of Cancer Treatment Part 15 Pemetrexed is a novel folate-directed antimetabolite. It is multitargeted in that it inhibits the activity of several enzymes including thymidylate synthetase dihydrofolate reductase and glycinamide ribonucleotide formyltransferase thereby affecting the synthesis of both purine and pyrimidine nucleic acid precursors. To avoid significant toxicity to the normal tissues patients receiving pemetrexed should also receive low-dose folate and vitamin B12 supplementation. Pemetrexed has notable activity against certain lung cancers and in combination with cisplatin also against mesotheliomas. 5-Fluorouracil 5FU represents an early example of rational drug design in that it originated from the observation that tumor cells incorporate radiolabeled uracil more efficiently into DNA than normal cells especially gut. 5FU is metabolized in cells to 5 FdUMP which inhibits thymidylate synthetase TS . In addition misincorporation can lead to single-strand breaks and RNA can aberrantly incorporate FUMP. 5FU is metabolized by dihydropyrimidine dehydrogenase and deficiency of this enzyme can lead to excessive toxicity from 5FU. Oral bioavailability varies unreliably but orally administered analogues of 5FU such as capecitabine have been developed that allow at least equivalent activity to many parenteral 5FU-based approaches to refractory cancers. Intravenous administration of 5FU leads to bone marrow suppression after short infusions but to stomatitis after prolonged infusions. Leucovorin augments the activity of 5FU by promoting formation of the ternary covalent complex of 5FU the reduced folate and TS. Less frequent toxicities include CNS dysfunction with prominent cerebellar signs and endothelial toxicity manifested by thrombosis including pulmonary embolus and myocardial infarction. Cytosine arabinoside ara-C is incorporated into DNA after formation of ara-CTP resulting in S-phase-related toxicity. Continuous infusion schedules
