Fluorouracil or 5-Fluorouracil

5-fluorouracil - also known as 5-FU - is an anticancer drug belonging to the family of antimetabolites .

5-fluorouracil - Chemical Structure

It is considered a drug of considerable importance, which is why it was included in the list of essential drugs prepared by the World Health Organization. This list contains all those drugs that must be present in a basic health system.

Indications

For what it uses

5-fluorouracil can be used - alone or in combination with other anticancer drugs - to treat various types of cancer, including:

Breast cancer;
Colorectal cancer;
Stomach cancer;
Pancreatic cancer;
Ovarian cancer;
Uterine cancer;
Bladder cancer.

Usually, 5-fluorouracil is used to treat patients in whom surgery or other means is not possible.

Furthermore, 5-FU can be formulated in the form of topical creams or ointments in the treatment of:

warts;
cysts;
Actinic keratosis;
Bowen's disease (also known as squamous cell carcinoma in situ; it can be considered as an initial phase of an intraepidermal form of squamous cell carcinoma);
Other types of skin cancer, both benign and malignant.

Warnings

5-fluorouracil must be administered under the strict supervision of a doctor who specializes in the administration of anticancer drugs, particularly in the use of powerful antimetabolites.

Since fluorouracil has a high toxicity and a low safety margin, patients must be carefully and constantly monitored during treatment and hospitalization is recommended at least during the initial chemotherapy cycle.

Intake of 5-fluorouracil can cause elevated toxicity in blood cells and severe gastrointestinal bleeding; for these reasons the treatment should be stopped if the following signs of toxicity occur:

Leukopenia (lowering of the number of white blood cells in the bloodstream);
Diarrhea, watery stools and frequent bowel movements;
Vomit is not treatable;
Stomatitis and esophagopharyngitis (at the first visible sign).

Interactions

Administration of immunosuppressive drugs and radiotherapy carried out in conjunction with 5-fluorouracil treatment increase their toxicity at the level of the immune system; in these cases it may be necessary to reduce the amount of drug administered.

Fluorouracil and Vaccines

Since 5-fluorouracil has immunosuppressive activity, treated patients should be careful if they are to be vaccinated .

If patients are given a killed virus vaccine a reduced antibody response could occur. The time between the end of 5-fluorouracil therapy and the recovery of the patient's ability to respond to the vaccine depends on the type of pathology, the drug doses used, the intensity and the type of immunosuppression that the drug has generated. Generally, this period varies from three months to one year.

If, on the other hand, patients are given a live attenuated virus vaccine, the reduced antibody response results in an increase in the replication of the virus with a consequent increase in the side effects of the vaccine itself. In this case, therefore, the vaccination must be carried out with caution and only with prior authorization from the doctor who administers the anticancer chemotherapy.

Other interactions

Administration of calcium folinate concomitantly with 5-fluorouracil therapy may increase its toxicity. Calcium folinate is usually used as an antidote in the case of super-dosing with methotrexate (another antitumor drug belonging to the antimetabolite family) in order to reduce the side effects on the hematopoietic system (the system responsible for the production of blood cells) and mucous membranes of the digestive system.

Calcium folinate is also used in the treatment of anemia caused by a lack of folate.

In addition, 5-fluorouracil intake may interfere with some laboratory tests resulting in an increase in transaminases, alkaline phosphatase, bilirubin and lactic dehydrogenase in the blood.

Plasma albumin, on the other hand, may decrease due to malabsorption caused by the drug itself.

An increase in 5-hydroxyindolacetic acid in the urine may also occur.

Side effects

5-fluorouracil therapy can induce multiple side effects, including:

Gastrointestinal tract disorders

Treatment with 5-FU can cause stomatitis, esophagopharyngitis (resulting in flaking and ulceration), diarrhea and watery stools, enteritis, cramps, nausea and vomiting.

Skin disorders

Therapy can lead to dry skin, cracking and photosensitivity; the latter can manifest itself with the appearance of erythema or with an increased pigmentation of the skin.

Hand-Foot Syndrome

5-fluorouracil can cause this syndrome which is characterized by a tingling sensation that occurs in the hands and feet, followed by pain, redness, swelling and erythema.

Myelosuppression

5-FU induces myelosuppression, ie it promotes bone marrow suppression . Consequently, there is a reduced haematopoiesis (reduced synthesis of blood cells). The decrease in blood cell production can lead to:

anemia (reduced amount of hemoglobin in the blood);
leukopenia (reduced number of white blood cells) with consequent increased susceptibility to infection contraction ;
thrombocytopenia (reduced number of platelets) with increased risk of bleeding .

Cardiovascular disorders

Treatment with 5-fluorouracil may lead to angina pectoris and myocardial ischemia .

Pathologies affecting the eye

5-FU can induce visual changes, reduce visual acuity (ie the ability to perceive fine details in objects), increase tearing and induce photophobia . It can also induce diplopia (double vision) and cause total or partial obstruction of the tear duct ( stenosis ).

Pathology affecting the central nervous system

5-fluorouracil therapy may induce lethargy, headache, weakness, malaise . It can also lead to the appearance of acute cerebellar syndrome accompanied by disorientation and confusion .

Pathologies affecting the vascular system

Following administration of 5-FU arterial aneurysm, arterial ischemia, arterial thrombosis and embolism may occur.

Since fluorouracil is administered by infusion, thrombophlebitis, abscesses and infections at the site where the cannula is inserted, extraction of the cannula from the venous vessel and / or on-site leakage of infusion fluid may also occur.

Other side effects

Treatment with 5-fluorouracil can lead to epistaxis (blood to the nose) and to nail alterations, including loss.

Action mechanism

5-fluorouracil belongs to the family of antimetabolites . It appears to perform its cytotoxic action in three different ways:

Inhibits thymidylate synthase, a fundamental enzyme in DNA synthesis;
It binds to RNA, thus giving rise to an abnormal RNA;
It inhibits the synthesis of new RNA by blocking one of the enzymes involved in this operation: uracil phosphatase .

DNA and RNA are fundamental for cell division and replication, therefore 5-fluorouracil - inhibiting its synthesis - induces an unbalanced cell growth that leads to the death of the cell itself.

Mode of Use - Posology

5-fluorouracil - either by injection into a vein or by intravenous infusion - appears as a clear liquid.

For vein injection, the drug is administered through a cannula introduced into a vein in an arm or hand.

For intravenous infusion (drip infusion), the liquid can be administered through a cannula or through a central venous catheter that is placed under the skin in a vein near the clavicle.

In general, the initial dose of drug that is administered is 12 mg / kg of body weight; the daily dose should not exceed 800 mg. In any case, the dosage is established by the doctor specialized in the administration of anticancer drugs based on the type of tumor to be treated and the patient's condition.

5-fluorouracil ointment for topical use, on the other hand, is applied directly to the skin in the area to be treated.

Pregnancy and breastfeeding

Women of childbearing potential should not start 5-fluorouracil therapy until a possible pregnancy has been excluded.

The drug should only be used in the case of serious illnesses for which safer drugs do not exist or are not effective; in any case, this decision must be taken exclusively by the oncologist.

Women being treated with the drug should not breast-feed.

Since the drug induces genetic mutations, a pregnancy is not advisable before five years from the end of chemotherapy.

In young male patients, sterility may arise which, in some cases, can become permanent.