General Description
White to nearly white crystalline powder; practically odorless. Used as an anti neoplastic drug, chemosterilant for insects.
Reactivity Profile
FLUOROURACIL(51-21-8) may be sensitive to prolonged exposure to light. Solutions discolor on storage. This chemical can react with oxidizing agents and strong bases. Incompatible with methotrexate sodium.
Air & Water Reactions
Insoluble in water.
Hazard
Questionable carcinogen.
Health Hazard
Minimum toxic dose in humans is approximately 450 mg/kg (total dose) over 30 days for the ingested drug. Intravenous minimum toxic dose in humans is a total dose of 6 mg/kg over three days. Depression of white blood cells occurred after intravenous administrative of a total dose of 480 mg/kg over 32 days. Occasional neuropathy and cardiac toxicity have been reported. Do not use during pregnancy. Patients with impaired hepatic or renal function, with a history of high-dose pelvic irradiation or previous use of alkylating agents should be treated with extreme caution. Patients with nutritional deficiencies and protein depletion have a reduced tolerance to fluorouracil.
Potential Exposure
This material is used as an antineo plastic drug for cancer treatment and as a chemosterilant
for insects.
Fire Hazard
Emits very toxic fumes of flourides and nitrogen oxides when heated to decomposition. Avoid decomposing heat.
First aid
If this chemical gets into the eyes, remove any
contact lenses at once and irrigate immediately for at least
15 minutes, occasionally lifting upper and lower lids. Seek
medical attention immediately. If this chemical contacts the
skin, remove contaminated clothing and wash immediately
with soap and water. Seek medical attention immediately.
If this chemical has been inhaled, remove from exposure,
begin rescue breathing (using universal precautions, includ ing resuscitation mask) if breathing has stopped and CPR if
heart action has stopped. Transfer promptly to a medical
facility. When this chemical has been swallowed, get medi cal attention. Give large quantities of water and induce
vomiting. Do not make an unconscious person vomit. Keep
victim quiet and maintain normal body temperature.
Shipping
UN2811 Toxic solids, organic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name
Required.
Incompatibilities
Incompatible with oxidizers (chlorates,
nitrates, peroxides, permanganates, perchlorates, chlorine,
bromine, fluorine, etc.); contact may cause fires or explo sions. Keep away from alkaline materials, strong bases,
strong acids, oxoacids, epoxides, methotrexrate sodium,
sources of heat.
Description
5-Fluorouracil (5-FU) is a prodrug form of the thymidylate synthase inhibitor fluorodeoxyuridylate (FdUMP).
1 It is also converted to the active metabolites FUTP and FdUTP, which induce RNA and DNA damage, respectively.
In vivo, 5-FU (15 mg/kg) when administered in combination with docetaxel (Item No.
11637) reduces tumor growth in B88 and CAL 27 oral squamous cell carcinoma (OSCC) mouse xenograft models.
2 Formulations containing 5-FU have been used in the treatment of colorectal, breast, gastric, and pancreatic cancers.
Chemical Properties
Fluorouracil is a white crystalline solid.
Practically odorless.
Chemical Properties
White or almost white, crystalline powder
Originator
Efudex, Roche, US,1962
Definition
ChEBI: 5-fluorouracil is a nucleobase analogue that is uracil in which the hydrogen at position 5 is replaced by fluorine. It is an antineoplastic agent which acts as an antimetabolite - following conversion to the active deoxynucleotide, it inhibits DNA synthesis (by blocking the conversion of deoxyuridylic acid to thymidylic acid by the cellular enzyme thymidylate synthetase) and so slows tumour growth. It has a role as a xenobiotic, an environmental contaminant, a radiosensitizing agent, an antineoplastic agent, an immunosuppressive agent and an antimetabolite. It is a nucleobase analogue and an organofluorine compound. It is functionally related to a uracil.
Manufacturing Process
A mixture of 200 grams (2 mols) of dry sodium fluoroacetate and 442 grams (2.86 mols) of diethyl sulfate was refluxed for 31? hours in an oil bath. The reaction mixture was then distilled through a fractionating column, yielding 177.3 grams of crude ethyl fluoroacetate, having a boiling range of 116° to 120°C. The material was redistilled through a fractionating column, yielding purified ethyl fluoroacetate boiling at 114° to 118°C.
In a 2-liter, 3-neck, round bottom flask, provided with stirrer, dropping funnel and reflux condenser, was placed 880 ml of absolute diethyl ether, and 47.6 grams (1.22 mols) of potassium, cut into 5 mm pieces, was suspended therein. 220 ml of absolute ethanol was added dropwise, while stirring, whereby the heat of reaction produced refluxing. In order to obtain complete dissolution of the potassium, the mixture was finally refluxed on a steam bath. The reaction mixture was then cooled in an ice bath, and a mixture of 135 grams (1.22 mols) of ethyl fluoroacetate and 96.4 grams (1.3 mols) of freshly distilled ethyl formate was added dropwise, while stirring and cooling, over a period of 2? hours. Upon completion of the addition of the ethyl formate, the reaction mixture was stirred for an additional hour while cooling, and then was allowed to stand overnight at room temperature.
At the end of this time the crystalline precipitate which had formed was filtered off with suction, washed with diethyl ether, and dried in a vacuum desiccator. The product comprised essentially the potassium enolate of ethyl fluoromalonaldehydate (alternative nomenclature, the potassium salt of fluoromalonaldehydic acid ethyl ester).
A mixture of 103.6 grams (0.6 mol) of the freshly prepared potassium enolate of ethyl fluoromalonaldehydate, 83.4 grams (0.3 mol) of Smethylisothiouronium sulfate and 32.5 grams (0.6 mol) of sodium methoxide was refluxed with stirring in 1,500 ml of absolute methanol. At first the reactants dissolved to a great extent, but very shortly thereafter precipitation occurred. The reaction mixture was refluxed for 2 hours and at the end of this time was evaporated to dryness in vacuo. The residue was treated with 280 ml of water; incomplete dissolution was observed.
The mixture obtained was clarified by filtering it through charcoal. The filtrate was acidified (to a slight Congo red acid reaction) by adding concentrated aqueous hydrochloric acid, containing 37% by weight HCl (48 ml required). The material which crystallized from the acidified solution was filtered off, washed free of sulfates with water and dried at 100°C, yielding crude Smethyl ether of 2-thio-5-fluorouracil, having a melting range from 202° to 221°C. The latter material was recrystallized by dissolving it in 2,035 ml of boiling ethylacetate and cooling to -20°C, yielding S-methyl ether of 2-thio-5fluorouracil, MP 230° to 237°C, in a sufficient state of purity that it could be used directly for the next step. A sample of the material was recrystallized from water (alternatively, from ethyl acetate) thereby raising the melting point to 241° to 243°C. For analysis the material was further purified by subliming it in vacuo at 140° to 150°/0.1 mm
A solution of 10.0 grams of purified S-methyl ether of 2-thio-5-fluorouracil, MP 230° to 237°C, in 150 ml of concentrated aqueous hydrochloric acid (containing approximately 37% by weight HCl) was refluxed under nitrogen for 4 hours. The reaction mixture was then evaporated in vacuo. The crystalline brownish residue was recrystallized from water. The resulting recrystallized product was further purified by sublimation in vacuo at 190° to 200°C (bath temperature)/0.1 mm pressure. There was obtained 5fluorouracil, in the form of colorless or pinkish-tan crystals, MP 282° to 283°C (with decomposition).
Brand name
Adrucil (Pharmacia & Upjohn); Adrucil (Sicor); Carac (Sanofi Aventis); Efudex (Valeant); Fluoroplex (Allergan).
Therapeutic Function
Cancer chemotherapy
Biological Activity
Anticancer agent. Metabolized to form fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine (FUTP). FdUMP inhibits thymidylate reductase causing a reduction in dTMP synthesis. FUTP and FdUTP are misincorporated into RNA and DNA respectively.
Biochem/physiol Actions
A potent antitumor agent that affects pyrimidine synthesis by inhibiting thymidylate synthetase, thus depleting intracellular dTTP pools. It is metabolized to ribonucleotides and deoxyribonucleotides, which can be incorporated into RNA and DNA. Treatment of cells with 5-FU leads to an accumulation of cells in S-phase and has been shown to induce p53 dependent apoptosis.
Mechanism of action
5-Fluorouracil (FU) is converted intracellularly to several active metabolites: fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP), and fluorouridine triphosphate (FUTP). The active metabolites of 5-FU disrupt RNA synthesis (FUTP), inhibit the action of thymidylate synthase (TS)—a nucleotide synthetic enzyme (FdUMP)—and can also be directly misincorporated into DNA (FdUTP). The rate-limiting enzyme in 5-FU catabolism is dihydropyrimidine dehydrogenase (DPD), which converts 5-FU to dihydrofluorouracil (DHFU). Over 80% of administered 5-FU is normally catabolized primarily in the liver, where DPD is abundantly expressed.
5-Fluorouracil (5-FU) is converted to three major active metabolites: (1) fluorodeoxyuridine monophosphate (FdUMP), (2) fluorodeoxyuridine triphosphate (FdUTP), and (3) fluorouridine triphosphate (FUTP). The main mechanism of 5-FU activation is conversion to fluorouridine monophosphate (FUMP) either directly by orotate phosphoribosyl transferase (OPRT), or indirectly via fluorouridine (FUR) through the sequential action of uridine phosphorylase (UP) and uridine kinase (UK). FUMP is then phosporylated to fluorouridine diphosphate (FUDP), which can be either further phosphorylated to the active metabolite fluorouridine triphosphate (FUTP), or converted to fluorodeoxyuridine diphosphate (FdUDP) by ribonucleotide reductase (RR). In turn, FdUDP can either be phosphorylated or dephosphorylated to generate the active metabolites FdUTP and FdUMP respectively. An alternative activation pathway involves the thymidine phosphorylase catalyzed conversion of 5-FU to fluorodeoxyuridine (FUDR), which is then phosphorylated by thymidine kinase (TK) to the thymidylate synthase (TS) inhibitor, FdUMP. Dihydropyrimidine dehydrogenase (DPD)-mediated conversion of 5-FU to dihydrofluorouracil (DHFU) is the rate-limiting step of 5-FU catabolism in normal and tumor cells.
Mechanism of action
Another action proposed for 5-fluorouracil may involve
the incorporation of the nucleotide 5-fluorouridine
triphosphate (5-FUTP) into RNA. The cytotoxic
role of these “fraudulent” 5-fluorouracil-containing
RNAs is not well understood.
Several possible mechanisms of resistance to 5-fluorouracil
have been identified, including increased synthesis
of the target enzyme, altered affinity of thymidylate
synthetase for FdUMP, depletion of enzymes
(especially uridine kinase) that activate 5-fluorouracil
to nucleotides, an increase in the pool of the normal
metabolite deoxyuridylic acid (dUMP), and an increase
in the rate of catabolism of 5-fluorouracil.
The drug has been administered orally, but absorption
by this route is erratic. The plasma half-life of 5-
fluorouracil after intravenous injection is 10 to 20 minutes.
It readily enters CSF. Less than 20% of the parent
compound is excreted into the urine, the rest being
largely metabolized in the liver.
Pharmacology
Local inflammatory reactions characterized
by erythema, edema, crusting, burning, and pain are
common (and, some would argue, desirable) but may be
minimized by reduced frequency of application or use
in combination with a topical corticosteroid.
Clinical Use
5-Fluorouracil (Efudex, Fluoroplex) is an antimetabolite
used for the topical treatment of actinic keratoses. It
is also useful for the treatment of superficial basal cell
carcinomas when conventional surgical modalities are
impractical.
Clinical Use
5-Fluorouracil (FU) is widely used in the treatment of a range of cancers including breast and cancers of the aerodigestive tract, but has had the greatest impact in colorectal cancer. 5-FU-based chemotherapy improves overall and disease-free survival of patients with resected stage III colorectal cancer. Nonetheless, response rates for 5-FU-based chemotherapy as a first-line treatment for advanced colorectal cancer are only between 10 and 15%. Combination of 5-FU with newer chemotherapies, such as irinotecan and oxaliplatin, has improved the response rates for advanced colorectal cancer to between 40 and 50%.
Clinical Use
5-Fluorouracil is used in several combination regimens
in the treatment of breast cancer. It also has palliative
activity in gastrointestinal adenocarcinomas, including
those originating in the stomach, pancreas, liver,
colon, and rectum. Other tumors in which some antitumor
effects have been reported include carcinomas of
the ovary, cervix, oropharynx, bladder, and prostate.
Topical 5-fluorouracil cream has been useful in the
treatment of premalignant keratoses of the skin and superficial
basal cell carcinomas, but it should not be used
in invasive skin cancer.
Side effects
Patients who are genetically deficient in this enzyme will experience a more pronounced effect from this drug and are at significant risk for use-limiting toxicity. In general, women clear fluorouracil faster than men do. Dosage adjustments usually are not required in hepatic or renal dysfunction. Major toxicities are related to bone marrow depression, stomatitis/esophagopharyngitis, and potential GI ulceration. Nausea and vomiting are common. Solutions of fluorouracil are light sensitive, but discolored products that have been properly stored and protected from light are still safe to use.
Synthesis
Fluorouracil, 4-fluorouracil (30.1.3.3), is made by condensing the ethyl ester
of fluoroacetic acid with ethylformate in the presence of potassium ethoxide, forming
hydroxy-methylenfluoroacetic ester (30.3.1), which cyclizes by reacting it with S-methylisothiourea to 2-methylthio-4-hydroxy-5-fluoropyrimidine, which is subsequently hydrolyzed
by hydrochloric acid to fluorouracil (30.1.3.3). An alternative method of synthesizing5-fluorouracid is direct fluorination of uracil with fluorine or trifluoromethylhypofluoride.
Veterinary Drugs and Treatments
5-fluorouracil is a potent cytotoxic chemotherapeutic agent used
for the topical therapy of equine limbal and eyelid squamous cell
carcinoma. It is also used as an antimetabolite to limit fibrosis over
the body of gonioimplant devices used to artificially shunt aqueous
humor out of the eye in glaucoma as well as improve long-term
filtering performance of the implant.
1% solution applied to the affected eye three times daily.
Drug interactions
Potentially hazardous interactions with other drugs
Anticoagulants: possibly enhances effect of
coumarins.
Antipsychotics: avoid concomitant use with
clozapine, increased risk of agranulocytosis.
Cytotoxics: avoid with panitumumab.
Folic acid: toxicity of fluorouracil increased - avoid.
Metronidazole and cimetidine inhibit metabolism
(increased toxicity).
Temoporfin: increased skin photosensitivity with
topical fluorouracil
Metabolism
After intravenous injection fluorouracil is cleared rapidly
from plasma. It is distributed throughout body tissues
and fluids, and disappears from the plasma within about
3 hours. Within the target cell fluorouracil is converted
to 5-fluorouridine monophosphate and floxuridine
monophosphate (5-fluorodeoxyuridine monophosphate),
the former undergoing conversion to the triphosphate
which can be incorporated into RNA while the latter
inhibits thymidylate synthetase. About 15% of an
intravenous dose is excreted unchanged in the urine
within 6 hours. Approximately 80% is inactivated mainly
in the liver and is catabolised via dihydropyrimidine
dehydrogenase (DPD) similarly to endogenous uracil,
60-80% is excreted as respiratory carbon dioxide; urea
and other metabolites are also produced, and 2-3% by the
biliary system
References
1) Schlisky (1998), Biochemical and Clinical Pharmacology of 5-Fluorouracil; Oncology, 12 13
