Fluorouracil — API

Introduction
Fluorouracil is a white to nearly white crystalline powder that is sparingly soluble in water and alcohol. The chemical name of it is 5-fluoro-2,4(1H,3H)-pyrimidinedione. Fluorouracil is a cytotoxic chemoradiotherapy medication used to treat rectal cancer, head and neck cancer, esophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer by intravenous injection. The structure is shown in fig. 1.

Fig. 1 Structure of fluorouracil

Application in the treatment of cancer
Fluorouracil can be used in the treatment of multiple cancers. Several examples are described below[1].

Rectal cancer
Fluorouracil has effectively employed in chemoradiotherapy for rectal cancer, significantly improving survival in palliative treatment. Recently, preoperative chemoradiotherapy with fluorouracil infusion has demonstrated superiority compared with surgery or external beam radiation alone in nonrandomized studies. Sixteen recent studies involving more than 1000 patients have reported fluorouracil infusion was highly effective in reducing T3 rectal cancer tumor bulk, tumor downstaging, and sphincter preservation as well as decreasing the rates of local failures and distant metastases.

Head and neck cancer
In the treatment of head and neck cancer, fluorouracil has been used alone or in combination with cisplatin. Adelstein et al have conducted a number of chemoradiotherapy studies involving more than 300 patients with head and neck cancer using continuous infusion of fluorouracil and chemoradiotherapy in combination with cisplatin compared with standard X-ray technique. The results showed that local control or complete responses to head and neck cancer were as high as 98% when use fluorouracil alone or in combination with cisplatin.

Esophageal cancer
Some of the most successful applications of fluorouracil infusion in esophageal cancer chemoradiotherapy have been observed. Historically, the median survival for inoperable esophageal cancer treated with irradiation alone was less than 10 months, with 5-year survival less than 10%. In 1980, Byfield conducted a preliminary study of 6 patients using fluorouracil infusion and radiation therapy with an efficacy rate of up to 83%. Similarly, Lokich conducted a pilot study of 13 patients using fluorouracil infusion and chemoradiotherapy. All patients experienced clinical or pathologic tumor regression with a median survival of 16 months, and a 1-year survival of 77%.

Mechanism of action
Fluorouracil acts in several ways, but principally as a thymidylate synthase (TS) inhibitor. TS methylates deoxyuridine monophosphate (dUMP) to form deoxythymidine monophosphate (dTMP), which is a nucleotide required for DNA replication. As a TS inhibitor, fluorouracil can cause dTMP deficiency, leading to the death of rapidly dividing cancer cells.

Side effects
Common side effects of fluorouracil mainly include:

Nausea

Mucositis

Myelosuppression

Hand-foot syndrome

Vomiting

Headache

Photosensitivity

Maculopapular eruption

Diarrhea

Alopecia

Persistent hiccups