Conceptual changes in cancer chemotherapy--biochemical modulation of 5-FU from bench to clinic

Recently, a demand for therapy of higher usefulness in cancer patients has increased. We described in this paper a therapeutic modality which is based on SRC (self-rescuing concept) featuring dual activity, i.e., effect-enhancing activity and adverse reaction-reducing activity. We presented the theory and practice of S-1, a novel oral fluoropyrimidine anti-cancer agent designed to enhance anticancer activity and reduce gastrointestinal toxicity through the deliberate combination of the following components: an oral fluoropyrimidine agent tegafur; a DPD inhibitor (CDHP) which is more potent than uracil used in UFT; and an ORTC inhibitor (Oxo) which localizes in the gastrointestinal tract. S-1, as a combination drug with a molar ratio of 1:0.4:1 in FT, CDHP, and Oxo, respectively. A clinical pharmacology study to examine blood concentrations of 5-FU after twice-a-day administration of S-1 at a dose 40 mg/m2. Consequently , blood concentrations of 5-FU were 60 to 200 ng/m/ in all twelve patients examined. The overall response rate was 44.6% (45/101). In addition, the incidence of adverse reactions judged to be G3 or higher was 10% or less. Furthermore, we referred to 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, iv, 5 days/week) in which CDDP was used as modulator of 5-FU. Low-dose FP therapy provided response rates as high as 40 to 60% in 163 patients with sorts of gastrointestinal cancers except pancreas cancer. The incidence of adverse reactions which were judged to be G3 or higher was 2.5% (4/163) in nausea and vomiting. The incidences of other adverse reactions were 1% or less. And to the theory and practice of combination therapy with 5-FU (CVI) 24-hour CVI; 5-FU: 750 to 1000 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 in which a difference in cell cycle between gastrointestinal mucosal cel l and tumor cell or between bone marrow cell and tumor cell was utilized . Little adverse reactions, e.g., diarrhea and stomatitis, were observed despite the overall response rate which was as high as 52.4% (22/42). We intend in the future to combine the above mentioned therapeutic modalities provoking less adverse reactions and being gentle to patients with cancer in an effort to further increase their life expectancy.