METHIONINE-DEPLETION MODULATES THE EFFICACY OF 5-FLUOROURACIL IN HUMAN GASTRIC-CANCER IN NUDE-MICE

Human tumors are generally methionine (MET)dependent in that their gro wth is inhibited by MET-depletion down to levels that will still allow normal cell growth. The differential effect of methionine depletion o n tumor and normal cells has suggested that methionine depletion may b e able to modulate many and possibly all classes of cancer drugs. In t his report, we determined if MET-depletion could modulate 5-fluorourac il (5-FU) efficacy on the human gastric cancer xenograft, SC-I-NU in n ude mice. The tumor-bearing mice were treated with a MET-free diet and intraperitoneal administration of 5-FU at a dose of 30 mg/kg given fo r four cycles. MET depletion enhanced the antitumor activity of 5-FU b y approximately two-fold with statistical significance of p<0.05. The MET-free diet increased intratumoral thymidylate synthetase inhibition early after 5-FU administration; Therefore, MET-depletion was thought to increase the 5-FU antitumor activity by modulating intratumoral fo late metabolism. The data in this report suggest the high clinical pot ential of methionine depletion, combined with 5-FU and leucovorin on r efractory tumors such as stomach cancer.