Fluorouracil (5-FU)

Inhibits DNA synthesis through inhibition of thymidylate synthesis.

Active metabolite is 5-fluorodeoxyuridylate (5-FdUMP), binds to thymidylate synthase and inhibits it by formation of a stable tertiary complex.


Fluorouracil belongs to the category of chemotherapy called antimetabolites. 


Antimetabolites are very similar to normal substances within the cell. 


Antimetabolites are cell-cycle specific, attacking  cells at very specific phases in the cycle. 


Antimetabolites are classified according to the substances with which they interfere. 


Fluorouracil is classified as a pyrimidine analog because it interferes with DNA and RNA synthesis by mimicking the building blocks necessary for synthesis.


When the cells incorporate these substances into the cellular metabolism, they are unable to divide. 


Tumor tissues use larger amounts of uracil than non malignant tissues.

Metabolized by same enzymatic pathway associated uracil.

Bolus treatment in colorectal cancer associated with approximately 12% response rate and a median survival of 11 months.

The addition of leucovorin improves the response rate and overall survival compared to fluorouracil alone in metastatic colon cancer treatment.

Bolus injection plus leucovorin in colorectal cancer results in a response rate of 23% with a median survival of 11.5 months.

By utilizing a continuous infusion occasional patients will respond after progression on bolus 5-FU therapy.

Comparison of bolus to continuous infusion 5-FU reveals improved response rates with infusion treatment in metastastic colorectal cancer of 22% vs 14%.

Concurrent bolus and continuous infusion 5-FU can further improve response rates over either treatment alone.

Infusion treatment of fluorouracil and leucovorin in colorectal cancer results in response rates of 37% and a median survival of 13.1 months.

One mechanism of resistance is acquired gene amplification.

5FU has fewer side effects with continuous infusion compared to bolus therapy.

Cryotherapy treatment before 5-FU administration can reduce the incidence of oral mucositis.

31-34% of patients treated with 5FU have related toxicities, with 61% of these cases secondary to reduced activity in dihydropyrimidine dehydrogenase enzyme.

The initial and rate limiting enzyme of the pyrimidine catabolic pathway dihydropyrimidine dehydrogenase enzyme degrades 5FU to 5-fluoro-dihydrouracil.

Decreased dihydropyrimidine dehydrogenase enzyme (DPD) activity can decrease 5FU metabolism resulting in increased half life and toxicity.

Dihydropyrimidine dehydrogenase deficiency a pharmacogenetic syndrome that can lead to life threatening toxicity following the administration of 5FU at standard doses, with severe mucositis, neuropathy, myelosuppression, and death.

DPD deficiency can result in fatal bone marrow suppression, mucositis and cerebellar toxicity.

The gene encoding DPD enzyme is located at 1p22 and consists of 23 exons (Wei X).

DPD deficiencies can result from base substitutions, splicing, deficits, and frameshift mutations, and 40 different polymorphisms have been reported (Ridge S).

5FU toxicity in has been reported associated with 17 DPD mutations.

Prevalence of dihydropyrimidine dehydrogenase deficiency is approximately 3-5% in the white population and 8% in Afro-Americans.

Homozygote and heterozygote DPD dysfunction is estimated to be present in 0.1% and 3 to 5% of the population, respectively.

DPYD2A is the most common polymorphism associated with 5FU toxicity.

DPYD2A polymorphism is associated with exon 14 being skipped with a G to A translocation at intron 14 resulting in the formation of an inactive enzyme.

DPD enzyme deficiency has been identified in 61% of patients with severe five if you toxicity and the DPYD2A polymorphism has been identified and 50% of patients with grade 4 neutropenia.

Since most patients with severe 5FU toxicity have normal DPD enzyme activity, multiple genes and other factors are thought to be involved with this drug’s toxicity.


5-FU cream, interferes with DNA and RNA synthesis, thereby creating a thymine deficiency that resulting in unbalanced cellular growth and cell death. 


Pregnancy category D 


No breast feeding while using 5-FU.


Side effects: 


Diarrhea


Nausea and possible occasional 

vomiting


Mouth sores


Poor appetite


Watery eyes


Photophobia 


Taste changes, metallic taste in mouth during infusion


Discoloration along vein


Low blood counts 


Onset: 7-10 days 

Nadir: 9-14 days 

Recovery: 21-28 days


Skin reactions: 


Dry, cracking, peeling skin. 


Hyyperpigmentation, darkening of the skin where previous radiation treatment has been given,  thinning of hair.


Nail changes – discoloration, loss of nails are rare.


Hand -foot syndrome (Palmar-plantar erythrodysesthesia or PPE) -skin rash, swelling, redness, pain and/or peeling of the skin on the palms of hands and soles of feet. 


Serious adverse reactions to Fluorouracil are; chest pain, EKG changes and increases in cardiac enzymes: These symptoms are very rare but increased for patients with a prior history of heart disease.


Use of ice chips in the mouth 10-15 minutes before and after IV injections of Fluorouracil may reduce the incidence and severity of mouth sores.


To treat/prevent mouth sores, a soft toothbrush, and rinsing  three times a day with 1/2 to 1 teaspoon of baking soda and/or 1/2 to 1 teaspoon of salt mixed with 8 ounces of water.




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