Antitumour agent potentiator— eniluracil
5-Fluorouracil (5-FU) is an important drug for the treatment of a variety of tumours, including colorectal, breast, gastric and pancreatic cancers. It has poor oral availability, however, and must be administered intravenously. Over 80% of the drug is broken down rapidly by the enzyme dihydropyrimidine dehydrogenase (DPD), so it has a plasma half life of just 6–20min.
GlaxoSmithKline is investigating the related compound eniluracil as an inactivator of DPD, a process that would prevent 5-FU being broken down and hence potentiating its cytotoxic effects and enabling successful oral administration. Trials have shown that co-administration of eniluracil increased 5-FU's bioavailability by 100%, decreased clearance by a factor of more than 20, and increased its half life by four to six hours.
Thirty-three patients with advanced or metastatic breast cancer were treated with the combination in an open label Phase II study. The disease stabilised and improvement of symptoms was seen in seven patients, and there were 16 partial responses. Reported side effects included diarrhoea, various forms of cytopenia, nausea and mucositis1.
In another trial, patients with primary colorectal tumours were evaluated in a placebo-controlled study to see if eniluracil had any effect on DPD activity within the tumour, which is believed to be a mechanism of 5-FU resistance. Patients were given the drug for three days prior to surgery. The 10 patients who received eniluracil appeared to have undetectable intratumour DPD levels, and the enzyme also seemed to be suppressed in the white blood cells and gut mucosal cells2.
Further trials are required to establish the efficacy and safety of the drug in the potentiation of 5-FU in cancer therapy, but results thus far are promising, and it may ultimately mean that oral dosing of this important cancer drug could replace its intravenous administration in many cases.