Theoretical basis for low-dose CDDP/5-FU therapy]

The theoretical basis for low-dose cisplatin (CDDP)/5-fluorouracil (5-FU) therapy is rather clear. CDDP can inhibit methionine-uptake into tumor cells and cause depletion of folate cofactors including 5-CH3FH4 and FH4, which are essential for the formation of a ternary complex with thymidylate synthetase and 5-fluorodeoxyuridine, an active metabolite of 5-FU. The literature on this mechanism are reviewed herein, and the methionine-dependency of human cancer xenografts and the modulation of 5-FU-cytotoxicity through methionine-depletion are reported.