Фторурацил: Қолданысы, әсері және қауіпсіздігі

Chemotherapy medication

Fluorouracil (5 FU, 5 fluorouracil), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. As a cream it is used for actinic keratosis, basal cell carcinoma, and skin warts. Side effects of use by injection are common. How it works is not entirely clear, but it is believed to involve blocking the action of thymidylate synthase and thus stopping the production of DNA. It is on the World Health Organization's List of Essential Medicines. In 2021, it was the 281st most commonly prescribed medication in the United States, with more than 800,000 prescriptions.

Fluorouracil has been given systemically for anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers). It has also been given topically (on the skin) for actinic keratoses, skin cancers and Bowen's disease Other uses include ocular injections into a previously created trabeculectomy bleb to inhibit healing and cause scarring of tissue, thus allowing adequate aqueous humor flow to reduce intraocular pressure.

Fluorouracil is contraindicated in patients who are severely debilitated and in patients with bone marrow suppression due to either radiotherapy or chemotherapy.

The United States package insert warns that acute cerebellar syndrome has been observed following injection of fluorouracil and may persist after cessation of treatment. Symptoms include ataxia, nystagmus, and dysmetria.

There is very little difference between the minimum effective dose and maximum tolerated dose of 5 FU, and the drug exhibits marked individual pharmacokinetic variability. Therefore, an identical dose of 5 FU may result in a therapeutic response with acceptable toxicity in some patients and unacceptable and possibly life threatening toxicity in others. The limitations of BSA based dosing prevent oncologists from being able to accurately titer the dosage of 5 FU for the majority of individual patients, which results in sub optimal treatment efficacy or excessive toxicity. Studies have also shown that dosing based on the concentration of 5 FU in plasma can greatly increase desirable outcomes while minimizing negative side effects of 5 FU therapy. One such test that has been shown to successfully monitor 5 FU plasma levels and which "may contribute to improved efficacy and safety of commonly used 5 FU based chemotherapies" is the My5 FU test.

It may increase the INR and prothrombin times in people on warfarin.

The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5 fluorouracil, capecitabine, and tegafur. Genetic variations within the DPD gene (DPYD) can lead to reduced or absent DPD activity, and individuals who are heterozygous or homozygous for these variations may have partial or complete DPD deficiency; an estimated 0.2% of individuals have complete DPD deficiency. Those with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines; examples of toxicities include myelosuppression, neurotoxicity and hand foot syndrome. Calcium folinate provides an exogenous source of reduced folinates and hence stabilises the 5 FU TS complex, hence enhancing 5 FU's cytotoxicity.

In 1954, Abraham Cantarow and Karl Paschkis found liver tumors absorbed radioactive uracil more readily than did normal liver cells. Charles Heidelberger, who had earlier found that fluorine in fluoroacetic acid inhibited a vital enzyme, asked Robert Duschinsky and Robert Schnitzer at Hoffmann La Roche to synthesize fluorouracil. Some credit Heidelberger and Duschinsky with the discovery that 5 fluorouracil markedly inhibited tumors in mice. The original 1957 report
In 1958, Anthony R. Curreri, Fred J. Ansfield, Forde A. McIver, Harry A. Waisman, and Charles Heidelberger reported the first clinical findings of 5 FU's activity in cancer in humans.

In 2003, scientists isolated 5 fluorouracil derivatives, closely related compounds, from the marine sponge, Phakellia fusca, collected around Yongxing Island of the Xisha Islands in the South China Sea. This is significant because fluorine containing organic compounds are rare in nature, and also because manmade anticancer drugs are not frequently found to have analogues in nature.

The name "fluorouracil" is the INN, USAN, USP name, and BAN. The form "5 fluorouracil" is often used; it shows that there is a fluorine atom on the 5th carbon of a uracil ring.