Pyrimidine Antagonists

Pyrimidine antagonists comprise nucleic acid base analogues and their prodrugs as well as nucleoside analogues that generate substrates which ultimately become incorporated into the elongating DNA and RNA strand, thus inhibiting DNA, RNA, and ultimately protein, synthesis. All require intracel-lular anabolic conversion into active nucleotide substrates.

5-Fluorouracil

5-Fluorouracil (5-FU) is the simplest and most successful uracil derivative to date in clinical use. This fluoropyrimidine undergoes anabolic activation intracellularly into fluorodi-nated nucleosides and deoxynucleotides [fluorouridine monophosphate (FUMP); fluorouridine triphosphate, FUTP; fluorodeoxyuridine monophosphate, FdUMP; fluorodeoxyuri-dine triphosphate, FdUTP)] (see Figure 2.5). FdUMP inhibits TS and prevents formation of, and consequently depletes the available pool of, thymidylate necessary for generating dTTP; as a result, FdUTP and dUTP become the "preferred" substrates of reactions catalyzed by DNA polymerase, affecting DNA stability. Moreover, incorporation of FUTP in RNA interferes with proper RNA synthesis and function. 5-Flurodeoxyuridine (5-FUDR) or floxuridine is a fluoropyrimi-dine deoxynucleoside analogue that also undergoes similar metabolic conversion intracellularly to generate FUTP, FdUTP, and TS-inhibiting FdUMP. Genetic polymorphisms in TS may also affect treatment response. In vivo and in vitro studies have shown that lower TS activity is correlated with better antitumor response.

After intravenous administration, 5-FU readily penetrates the CSF and extracellular third-space fluid collections, such as ascites or pleural effusions. It has a short half-life (10-15 minutes). Both 5-FU and 5-FUDR are extensively catabolized

(more than 85%). The initial rate-limiting step in degradation involves the enzyme dihydropyrimidine dehydrogenase (DPD), which is widely expressed in tissues including the liver, GI mucosa, leukocytes, and kidney. Thus, 5-FU is poorly absorbed orally. Because of its size, the liver has the highest total content of DPD and is a major site of 5-FU metabolism. DPD is subject to genetic polymorphisms, with 8- to 21-fold intersubject variability. Those with low DPD activity are susceptible to severe toxicity. Greater first-pass effect (more than 90%) through the liver results in lower systemic drug levels (and, consequently, fewer side effects) with FUDR, making it the preferred agent for hepatic arterial infusion (HAI). When administered with IV bolus schedules, FUDR is catabolized to the predominant 5-FU form.86 Several important interactions between 5-FU and other agents have been described. Leucovorin expands the pool of reduced folates to enhance the inhibition of TS. Methotrexate pre-treatment increases the formation of 5-FU nucleotides. 5-FU may interfere with the repair of platinum-associated DNA damage. Ionizing radiation augments DNA damage. All these agents demonstrate preclinical as well as Phase III trial evidence for improvement in clinical activity.

Meta-analysis of several randomized trials comparing various 5-FU schedules of administration has shown the superiority of continuous infusion of 5-FU over bolus administration when given as a single agent.87 Moreover, bolus drug administration cannot achieve effective radiosensitization, as this requires constant drug exposure given the short half-life of 5-FU. Clinical toxicities also have some correlation with schedule of administration. Myelosuppression, especially leukopenia, is more pronounced with IV bolus schedules than with continuous infusion. Mucositis along the GI tract can be debilitating and dose limiting, especially with continuous infusion. Other GI symptoms, such as nausea, vomiting, and anorexia, can also be more severe with continuous infusion. With HAI regimens, systemic toxicities of 5-FU are dose limiting whereas hepatitis is usually mild. On the other hand, local-regional toxicities such as gastritis, gastric ulcers, enteritis, hepatitis, cholestasis, or cholecystitis predominate with HAI using 5-FUDR. 5-FU is currently used for GI malignancies and esophageal, head and neck, and breast cancers. 5-FUDR is principally used for HAI therapy of GI adeno-carcinoma metastatic to the liver.

Capecitabine

Capecitabine is an oral fluropyrimidine carbamate precursor of 5-FU. It was developed to overcome the degradation of 5-FU in the GI tract when administered orally. With daily administration, it simulates continuous 5-FU IV infusion, without the inconvenience and morbidity associated with indwelling catheters. It is initially metabolized by hepatic carboxylesterase into 5'-deoxy-5-fluorocytidine, which in turn is converted to 5'-deoxy-5-fluorouridine (5'-dFUR) by the enzyme cytidine deaminase found in the liver as well as tumor tissues (Figure 2.6). The final step involves thymidine phosphorylase (TP), expressed at higher levels in tumor tissues than normal cells, which converts 5'-dFUR into 5'-FU. This preferential formation of 5-FU within tumor cells results in relatively low circulating plasma levels of 5-FU. Its current use is chiefly in the treatment of metastatic breast and colo-rectal cancer.

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