Methotrexate is transferred into cells via a reduced folate carrier, and it inhibits dihydrofolate reductase (DHFR) which is the enzyme that uses reduced folate as a methyl donor in the synthesis of both purines and pyrimidines. The disruption of DHFR interferes with the synthesis of tetrahydrofolate, causing an intracellular folate deficiency. The end result of this folate deficiency is that the 1-carbon transfer reactions necessary for the synthesis of DNA, RNA, and key cellular proteins cease. Methotrexate can be administered intravenously, intrathecally, and by oral route, but oral bioavailability is erratic at doses greater than 25 mg/m². It is eliminated mainly through renal excretion which is a reflection of glomerular filtration and tubular secretion. Elimination may be impaired in renal insufficiency. Around 50 % of the drug is found unchanged in the urine, suggesting that significant metabolism of methotrexate does not occur. Leucovorin (5-formyltetrahydrofolate) is used as rescue therapy for normal cells subjected to undue toxicity from methotrexate. Methotrexate is widely used in combination with other drugs in treatment of malignant disorders and also in some nonmalignant diseases. It is used in the treatment of acute lymphoblastic leukemia in children but not adults and is effective as the sole agent in choriocarcinoma [10]. Psoriasis and rheumatoid arthritis are nonmalignant disease processes that also show benefit with treatment by methotrexate.

Like methotrexate, pemetrexed works to inhibit the S-phase of the cell cycle, and it is transported into cells via a folate carrier. Its main target is to inhibit thymidylate synthase, but it also targets DHFR and other enzymes involved in de novo purine nucleotide biosynthesis [7, 10]. Supplementation with folate and vitamin B12 appears to reduce the toxicity of pemetrexed without altering its clinical efficacy. In combination with cisplatin, it is used for the treatment of non-small cell lung cancer and also mesothelioma.

5-Fluorouracil (5-FU) requires activation via several enzymatic reactions in which it ultimately prevents the de novo synthesis of thymidylate preventing DNA synthesis. It is also converted into another form which gets inserted into RNA and interferes with mRNA translation and RNA processing. Therefore, 5-FU’s cytotoxic effect works by means of both DNA and RNA inhibitory effects. 5-FU is the mainstay agent in the treatment of colorectal cancer, as both adjuvant therapy and therapy for advanced disease. It is also effective against a variety of other solid tumors. Its half-life is only 10–15 min, and therefore it is often administered as a continuous infusion over bolus dose schedules. Eighty to 85 % of the drug is metabolized by dihydropyrimidine dehydrogenase (DPD), which of note roughly 5 % of cancer patients are deficient in this enzyme [10]. DPD-deficient patients manifest severe toxic effects of myelosuppression, nausea and vomiting, diarrhea, and neurotoxicity.

This fluoropyrimidine carbamate drug has 70–80 % oral bioavailability, and it functions as a prodrug. After extensive metabolism in the liver, it is eventually hydrolyzed by thymidine phosphorylase to 5-FU directly within the tumor [10]. Thymidine phosphorylase expression is found to be significantly higher in the tissue cells of tumors when compared to normal tissue. Capecitabine is used in the treatment of metastatic breast cancer as well as metastatic colorectal cancer. In certain regimens (as illustrated by the Table 31.1 in the following section), it replaces 5-FU therapy as an oral agent.