[Conceptual changes in cancer chemotherapy--biochemical modulation of 5-FU]

Recently, the demand for more useful therapies for cancer patients has increased. We describe in this paper a therapeutic modality based on a self-rescuing concept (SRC), and which features dual activity, i.e., an effect-enhancing activity and an adverse reaction-reducing activity. We present the theory and practice of S-1, a novel oral fluoropyrimidine anticancer agent designed to enhance anticancer activity and reduce gastrointestinal toxicity through the deliberate combination of the following components: the oral fluoropyrimidine agent tegafur; a DPD inhibitor (CDHP) which is more potent than uracil, which is used in UFT; and an ORTC inhibitor (Oxo) which localizes in the gastrointestinal tract. S-1 is a combination drug with a molar ratio of 1:0.4:1 in FT, CDHP, and Oxo, respectively. A clinical pharmacology study was conducted to examine blood concentrations of 5-FU after twice-a-day administration of S-1 at a dose of 40 mg/m2. Blood concentrations of 5-FU were found to be 60 to 200 ng/ml in all twelve patients examined. The overall response rate was 44.6% (45/101). In addition, the incidence of adverse reactions judged to be grade 3 or higher was 10% or less. We have also reported a combination therapy with 5-FU (civ) (5-FU: 250 to 350 mg/body, 24-hour cvi, consecutive days) and low-dose cisplatin (CDDP: 3 to 5 mg/body, i.v., 5 days/week), in which CDDP was used as a modulator of 5-FU. Low-dose FP therapy provided response rates as high as 40 to 60% in 163 patients with various gastrointestinal cancers other than pancreas cancer. The incidence of the adverse reactions of nausea and vomiting which were judged to be grade 3 or higher was 2.5% (4/163). The incidences of other adverse reactions were 1% or less. In line with the theory and practice of combination therapy with 5-FU (cvi) 24 hr cvi; 5-FU: 750 to 1,000 mg/body/day on Monday, Wednesday, and Friday (withdrawal on Tuesday, Thursday, Saturday and Sunday) intermittent administration and low-dose CDDP (3 to 5 mg/body/day day 1-5/w) consecutive administration was utilized in which there was a difference in cell cycle between gastrointestinal mucosal cell and tumor cell, or between bone marrow cell and tumor cell. Few adverse reactions, e.g., diarrhea and stomatitis, were observed despite the overall response rate being as high as 52.4% (22/42). The incidence of adverse reaction judged to be grade 3 or higher was as low as 9.3% (5/54), with an incidence of 9.3% (5/54) in Grade 3 or higher myelotoxicity. We intend in the future to combine the abovementioned therapeutic modalities, which provoke fewer adverse reactions and are easy on patients with cancer in an effort to further increase their life expectancy.