Fluoropyrimidines as Antifolate Drugs

Abstract

5 Fluorouracil (5FU) is a rationally designed antineoplastic agent (1,2) with distinct antifolate and antipyrimidine properties. 5FU is usually given in combination with other agents for the treatment of various types of cancer (3–11) such as cancers of the gas-trointestinal tract, breast cancer, and head and neck cancer. For combinations of leucov-orin (LV) and 5FU objective response rates between 20 and 40% have been achieved in randomized trials in patients with colorectal cancer, which means that more than 60% of the tumors are still resistant and will thereafter develop resistance. This resistance can be multifactorial (Table 1), and related to either the antipyrimidine or the antifolate prop-erties of the drug. This also implies that many patients have an intrinsic resistance to 5FU, and since almost all patients will show a relapse, this means that in the remaining tumors acquired resistance will occur. Unfortunately the mechanism of modulation-re-sistance has hardly been addressed in most of these studies.