[HTML] Mechanism of 5-fluorouracil required resistance in human hepatocellular carcinoma cell line Bel7402
Fluorouracil kháng Bel-7402
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| Pronunciation | /ˌflʊroʊˈjʊrəˌsɪl/[1] |
| Trade names | Adrucil, Carac, Efudex, Efudix, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682708 |
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| Pregnancy category | |
| Routes of administration | IV (infusion or bolus) and topical |
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| Pharmacokinetic data | |
| Bioavailability | 28 to 100% |
| Protein binding | 8 to 12% |
| Metabolism | Intracellular and liver (CYP-mediated) |
| Biological half-life | 16 minutes |
| Excretion | kidney |
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| ChEMBL | |
| ECHA InfoCard | 100.000.078 |
| Chemical and physical data | |
| Formula | C4H3FN2O2 |
| Molar mass | 130.077 g/mol |
| 3D model (Jmol) | |
| Melting point | 282–283 °C (540–541 °F) |
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When used by injection most people develop side effects. Common side effects include inflammation of the mouth, loss of appetite, low blood cell counts, hair loss, and inflammation of the skin.[2] When used as a cream irritation at the site of application may occur.[3] Use of either form in pregnancy may harm the baby.[2] Fluorouracil is in the
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[hide]Medical uses[edit]
Fluorouracil has been given systemically for anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers(especially head and neck cancers).[10] It has also been given topically (on the skin) for actinic keratoses, skin cancersand Bowen's disease[10] and as eye drops for treatment of ocular surface squamous neoplasia.[11]
Contraindications[edit]
It is contraindicated in patients that are severely debilitated or in patients with bone marrow suppression due to either radiotherapy or chemotherapy.[12] It is likewise contraindicated in pregnant or breastfeeding women.[12] It should also be avoided in patients that do not have malignant illnesses.[12]
Adverse effects[edit]
During systemic use[edit]
Common (> 1% frequency):
- Nausea
- Vomiting
- Diarrhea (see below for details)
- Mucositis
- Headache
- Myelosuppression (see below for details)
- Alopecia (hair loss)
- Photosensitivity
- Hand-foot syndrome
- Maculopapular eruption
- Itch
- Cardiotoxicity (see below for details)
- Persistent hiccups
- Mood disorders (irritability, anxiety, depression)
Uncommon (0.1–1% frequency):
- Oesophagitis
- GI ulceration and bleeding
- Proctitis
- Nail disorders
- Vein pigmentation
- Confusion
- Cerebellar syndrome
- Encephalopathy
- Visual changes
- Photophobia
- Lacrimation (the expulsion of tears without any emotional or physiologic reason)
Rare (< 0.1% frequency):
- Anaphylaxis
- Allergic reactions
- Fever without signs of infection
Diarrhea is severe and may be dose-limiting and is exacerbated by co-treatment with calcium folinate.[10] Neutropenia tends to peak about 9–14 days after beginning treatment.[10] Thrombocytopenia tends to peak about 7–17 days after the beginning of treatment and tends to recover about 10 days after its peak.[10] Cardiotoxicity is a fairly common side effect, but usually this cardiotoxicity is just angina or symptoms associated with coronary artery spasm, but in about 0.55% of those receiving the drug will develop life-threatening cardiotoxicity.[medical citation needed] Life-threatening cardiotoxicity includes: arrhythmias, ventricular tachycardia and cardiac arrest, secondary to transmural ischaemia.[medical citation needed]
During topical use[edit]
Common (> 1% frequency):
- Local pain
- Itchiness
- Burning
- Stinging
- Crusting
- Weeping
- Dermatitis
- Photosensitivity
Uncommon (0.1–1% frequency):
- hyper- or hypopigmentation
- Scarring
Neurological damage[edit]
5-FU injection and topical even in small doses cause both acute central nervous system (CNS) damage and progressively worsening delayed degeneration of the CNS in mice. This latter effect is caused by 5-FU-induced damage to the oligodendrocytes that produce the insulating myelin sheaths. [20] [21]
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.[22]
Potential overdose[edit]
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.[23][24][25] 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.[23] Both overdosing and underdosing are of concern with 5-FU, although several studies have shown that the majority of colorectal cancer patients treated with 5-FU are underdosed based on today's dosing standard, body surface area (BSA).[26][27][28][29] 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.[26][27]
Numerous studies have found significant relationships between concentrations of 5-FU in blood plasma and both desirable or undesirable effects on patients.[30][31]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.[26][32] 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.[28][33][34]
Interactions[edit]
Its use should be avoided in patients receiving drugs known to modulate dihydropyrimidine dehydrogenase (such as the antiviral drug sorivudine).[12] It may also increase the INR and prothrombin times in patients on warfarin.[12] Fluoruracil's efficacy is decreased when used alongside allopurinol which can be used to decrease fluoruracil induced stomatitis through use of allopurinol mouthwash.[35]
Pharmacology[edit]
Pharmacogenetics[edit]
The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5-fluorouracil, capecitabine, and tegafur.[36] 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.[36][37] 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.[36][37]
Mechanism of action[edit]
5-FU acts in several ways, but principally as a thymidylate synthase (TS) inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine, which is a nucleoside required for DNA replication. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) to form thymidine monophosphate (dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via thymineless death.[38] Calcium folinate provides an exogenous source of reduced folinates and hence stabilises the 5-FU-TS complex, hence enhancing 5-FU's cytotoxicity.[39]
History[edit]
In 1954 Abraham Cantarow and Karl Paschkis found liver tumors absorbed radioactive uracil more readily than 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 Hoffman-La Roche to synthesize fluorouracil.[40]Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice.[41] The original 1957 report[42][43] in Nature has Heidelberger as lead author, along with N. K. Chaudhuri, Peter Danneberg, Dorothy Mooren, Louis Griesbach, Robert Duschinsky, R. J. Schnitzer, E. Pleven, and J. Scheiner.[44]
Natural analogues[edit]
In 2003 it was discovered that a closely related compound[clarification needed] is produced by a marine sponge, Phakellia fusca. This is significant because fluorine-containing organic compounds exist only rarely in nature, and also because manmade anticancer drugs are not frequently found to have analogues in nature.[45]
Interactive pathway map[edit]
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
Names[edit]
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.
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