Pralatrexate is a 10-deaza-aminopterin antifolate analog, and as in the case of MTX, it is transported into the cell via the reduced folate carrier (RFC) and requires activation by FPGS to yield higher polyglutamate forms. This molecule was originally designed to be a more potent substrate for the RFC-1 carrier protein and to serve as an improved substrate for FPGS. This agent inhibits DHFR, inhibits enzymes involved in de novo purine nucleotide biosynthesis, and also inhibits TS. Pralatrexate is presently approved for use in the treatment of relapsed or refractory peripheral T-cell lymphoma. Consistent with other antifolate analogs, pralatrexate is mainly excreted in the urine, and dose modification is required in renal dysfunction. The main adverse effects include myelosuppression, skin rash, mucositis, diarrhea, and fatigue. As with pemetrexed, vitamin supplementation with folic acid and vitamin B12 appears to reduce the toxicities associated with pralatrexate, without interfering with clinical efficacy.
5-Fluorouracil (5-FU) is inactive in its parent form and requires activation via a complex series of enzymatic reactions to ribosyl and deoxyribosyl nucleotide metabolites. One of these metabolites, 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP), forms a covalently bound ternary complex with the enzyme TS and the reduced folate 5,10-methylenetetrahydrofolate, a reaction critical for the de novo synthesis of thymidylate. Formation of this ternary complex results in inhibition of DNA synthesis through “thymineless death.” 5-FU is converted to 5-fluorouridine-5′triphosphate (FUTP), which is then incorporated into RNA, where it interferes with RNA processing and mRNA translation. 5-FU is also converted to 5-fluorodeoxyuridine-5′-triphosphate (FdUTP), which is subsequently incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function. Thus, the cytotoxicity of 5-FU is thought to be mediated by the combined effects of both DNAand RNA-mediated events.
5-FU is administered intravenously, and the clinical activity of this drug is highly schedule-dependent. Because of its extremely short half-life, approximately 10–15 minutes, infusion administration schedules have been generally favored over bolus schedules. Up to 80–85% of an administered dose of 5-FU is catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD). There is an autosomal recessive pharmacogenetic syndrome involving partial or complete deficiency of the DPD enzyme that is seen in up to 5% of cancer patients. In this particular setting, severe, excessive toxicity is observed with the classic triad of myelosuppression, GI toxicity in the form of diarrhea and/or mucositis, and neurotoxicity.
5-FU remains the most widely used agent in the treatment of colorectal cancer, both as adjuvant therapy and for advanced disease. It also has activity against a wide range of solid tumors, including cancers of the breast, stomach, pancreas, esophagus, liver, head and neck, and anus. Major toxicities include myelosuppression, gastrointestinal toxicity in the form of mucositis and diarrhea, skin toxicity manifested by the hand-foot syndrome, and neurotoxicity.