Dihydropyrimidine dehydrogenase inhibitory fluoropyrimidines: a novel class of oral antineoplastic agents

Protracted intravenous regimens of 5-fluorouracil (5-FU) produce fewer toxic effects and greater response rates than do bolus infusion regimens. An effective oral regimen would allow a protracted course of 5-FU without the need for central venous lines and the associated increase in complications, such as venous thrombosis, infection, and line slippage. Dihydropyrimidine dehydrogenase (DPD) is the primary catabolic enzyme of 5-FU. The varying levels of DPD located in the gastrointestinal tract make the absorption of oral 5-FU and resultant plasma levels erratic. The use of 5-FU pro-drugs and/or DPD inhibitors can overcome this absorption problem and allow for oral dosing of fluoropyrimidines. In Japan, oral fluoropyrimidines have been used for decades and have gained widespread acceptance in the treatment of cancer. More recently, encouraging clinical results have led to the development of a new generation of oral fluoropyrimidines, commonly referred to as DPD inhibitory fluoropyrimidines, that specifically target DPD. Several DPD inhibitory fluoropyrimidines are in advanced stages of clinical development in the United States. As studies have shown so far, DPD inhibitory fluoropyrimidine can prolong exposure to 5-FU, while causing fewer toxic effects, and may have therapeutic advantage over intravenous 5-FU.