5-Fluorouracil gastrointestinal toxicity

Houghton JA, Houghton P, Wooten RS. Mechanism of induction of gastrointestinal toxicity in the mouse by 5-fluorouracil, 5-fluorourdine, and 5-fluoro-2 -deoxyuridine. Cancer Res 1979 39 2406-2413. 

Shirasaka T, Shimamoto Y, Fukushima M. Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its anti-tumor activity in rats. Cancer Res 1993 53 4004 009. 

Her diarrhoea has almost certainly been caused by her capecitabine treatment. Capecitabine is a prodrug of 5-fluorouracil and as such may cause similar side-effects to it. Cytotoxic drugs can cause gastrointestinal toxicity such as diarrhoea due to their effect on the rapidly dividing cells of the body, including the cells of the gastrointestinal mucosa. 

Antimetabolites cause gastrointestinal toxicity including stomatitis and diarrhoea as well as bone marrow depression renal impairment potentiates the toxicity of methotrexate. Active excreHon of methotrexate by the renal tubule is blocked by salicylate, which also displaces it from plasma protein, increasing the risk of toxicity. Hepatic dysfunction potentiates the toxicity of 5-fluorouracil, since it is primarily metabolised by the liver. 

The gastrointestinal toxicity of 5-fluorouracil is well documented and often dose-limiting. However, in a retrospective 10-year survey of gastrointestinal function in 19 patients who also had inflammatory bowel disease, although it did appear to increase the risk of exacerbation of diarrhea, it was not totally conclusive, as it was difficult to evaluate the contribution of other potentially causative factors, such as radiation (88). 

When combined with fluorouracil, leucovorin enhances the binding of the fluorouracil metabolite fluorouridine monophosphate to thymidylate synthetase. DNA-directed toxicity is increased, whilst RNA-directed toxicity is not affected (146). A qualitative alteration in toxicity is reported with increased gastrointestinal toxicity (2). 

Biran S, krasnokuki D, Brufman G. [Life-threatening gastrointestinal toxicity during 5-fluorouracil therapy.] Harefuah 1977 93(3-4) 77. 

Studies using another nitroimidazole, misonidazole, in patients with colorectal cancer also found an increased incidence and severity of gastrointestinal toxicity with concurrent use, a slightly increased incidence of leucopenia and a reduction in the clearance of fluorouracil. ... 

Y. Kimura, and H. Okuda, Prevention by chitosan of myelotoxicity, gastrointestinal toxicity and immunocompetent organic toxicity induced by 5-fluorouracil without loss of antitumor activity in mice, Jpn. J. Cancer Res., 90 (7), 765-774,1999. 

The answer is a. (Hardman, pp 1247-1251.) 5-Fluorouracil is a pyrimidine antagonist that has a low neurotoxicity when compared with other fluorinated derivatives however, its major toxicities are myelosup-pression and oral or gastrointestinal ulceration. Leukopenia is the most frequent clinical manifestation of the myelosuppression. 

Further studies have validated this hypothesis, in part,4 and ultimately this inventive premise was borne out in clinical practice. As a result, 5-FU (5) was eventually approved for treatment of solid tumors, such as breast, colorectal, and gastric cancers. Marketed as Adrucil when administered intravenously, 5-FU can be used either as monotherapy or combination therapy with various cytotoxic drugs and biochemical modulators, such as leucovorin and methotrexate.5 Because 5-fluorouracil is not orally bioavailable, it must be administered by continuous infusion to optimize its efficacy due to its short half-life in plasma. In addition, 5-FU has poor selectivity toward tumors in vivo, and its distribution into tissues such as bone marrow, the gastrointestinal tract, the liver and skin causes high incidences of toxicity. In addition, in spite of its limited lipid solubility, 5-fluorouracil diffuses readily across the blood-brain barrier into cerebrospinal fluid and brain tissue.1,5... 

Barrett O Jr, Bourgeois C, Plecha FR. Fluorouracil toxicity following gastrointestinal surgery. Arch Surg 1965 91(6) 1002. ... 

Reduced folates are co-factors for the 5-fluorodeoxy-uridine monophosphate-thymidilate synthetase reaction. Leucovorin (calcium fohnate) therefore potentiates the toxicity of 5-fluorouracil, and fatal adverse effects have been reported in patients over 65 years of age receiving high-dose treatment with leucovorin simultaneously with fluorouracil. This has led some groups to recommend that initial dose levels of fluorouracil should be lowered by 20% and that therapy be stopped temporarily at the first sign of distal gastrointestinal adverse effects (SEDA-15, 414). 

Sorivudine and 5-fluorouracil (5-FU) interaction, leading to severe or fatal gastrointestinal and bone marrow toxicities. Soruvidine was withdrawn from the market in 1993. Sorivudine inhibits dihydropyrimidine dehydrogenase, an enzyme pathway responsible forfluoropyrimidine metabolism. 48... 

Biotransformation, especially phase I metabolic reactions, cannot be assumed to be synonymous with detoxification because some drugs (although a minority) and xenobiotics are converted to potentially toxic metabolites (e.g. parathion, fluorine-containing volatile anaesthetics) or chemically reactive intermediates that produce toxicity (e.g. paracetamol in cats). The term lethal synthesis refers to the biochemical process whereby a non-toxic substance is metabolically converted to a toxic form. The poisonous plant Dichapetalum cymosum contains monofluoroacetate which, following gastrointestinal absorption, enters the tricarboxylic acid (Krebs) cycle in which it becomes converted to monofluorocitrate. The latter compound causes toxicity in animals due to irreversible inhibition of the enzyme aconitase. The selective toxicity of flucytosine for susceptible yeasts (Cryptococcus neoformans, Candida spp.) is attributable to its conversion (deamination) to 5-fluorouracil, which is incorporated into messenger RNA. 

A retrospective analysis of studies in a total of 250 patients given fluorouracil for the treatment of gastrointestinal cancer found that chlorprothixene, cinnarizine, prochlorperazine, sodium pentobarbital, thiethylperazine, trimethobenzamide (in antiemetic doses) did not significantly increase toxicity or decrease therapeutic effects, when compared with a placebo. ... 

The use of fluorine, a pyridine-fluorine complex, or trifluoromethyl hypofluorite for the preparation of 5-fluorouracil and related compounds has already been mentioned (see p. 262, particularly ref. 357). Electrochemical fluorination (Simons process) of uracil also gives 5-fluorouracil, > and trifluoromethyl hypofluorite has been applied to the preparation of l-(tetra-hydro-2-furanyl)-5-fluorouracil (Ftorafur) (Scheme 49), which is claimed to have a greater activity towards cancer of the breast and the gastrointestinal tract than 5-fluorouracil, while being considerably less toxic. 6-Fluoro-thyamine (245) has been prepared from 2,4,6-trifluoro-5-methylpyrimidine... 

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