Synergistic Effect of Methionine‐depleting Total Parenteral Nutrition with 5‐Fluorouracil on Human Gastric Cancer: A Randomized, Prospective Clinical Trial

Methionine‐depleting total parenteral nutrition (Met‐depleting TPN), infusing AO‐90 amino acid solution (lacking both L‐methionine and L‐cysteine) as a sole nitrogen source, showed synergistic effects with 5‐fluorouracil (5‐FU) in tumor‐bearing rats and in clinical trials with gastrointestinal tract cancers. In this study, the effect of Met‐depleting TPN with 5‐FU upon thymidylate synthase (TS) activity was examined, and the histological effect of this treatment on human gastric cancer was evaluated. Fourteen preoperative advanced gastric cancer patients were divided randomly into two groups. Seven cases were given Met‐depleting TPN for 7 days before surgery with continuous intravenous administration of 5‐FU (500 mg/body per day; total 4.0 g/body) (AO‐90 group). The other 7 received conventional L‐methionine‐containing TPN with 5‐FU (control group). All patients underwent gastrectomy without complications due to these treatments. Resected materials were examined for TS kinetics, and the anti‐cancer effect was also assessed histopathologically. The specimens in the AO‐90 group showed marked degeneration of cancer, while almost no effect was seen in the control group. The free TS activity of carcinoma tissue in the AO‐90 group was decreased and the TS inhibition rate was increased in comparison with the control group (P= 0.0165 and P= 0.0243, respectively). Met‐depleting TPN appears to play a role as a biomodulator of 5‐FU in human gastric cancer.