L-Cycloserine Amplifies Anti-Tumor Activity of Glutamine Antagonist

抄録

We examined the effect of simultaneous treatment with 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, and L-cycloserine, a transaminase inhibitor, on Yoshida sarcoma-bearing rats, with the aim of achieving inhibition of both glutamine catabolism and glutamate synthesis. L-Cycloserine, in a dosage of 1-30mg/kg, was intraperitoneally administered to Yoshida sarcoma-bearing rats, but the administration of L-cycloserine alone did not show any significant effect on the tumor weight. However, combined treatment with DON (1mg/kg) caused a dose-dependent reduction in the tumor weight. Amino acid analysis of the tumor tissue, performed 24h after these treatments in order to confirm their influences on amino acid metabolism in the tumor, showed that the increased glutamate level seen after treatment with DON in a previous study was suppressed by simultaneous administration of DON and 10mg/kg of L-cycloserine. These results suggest that pooled glutamate in the tumor tissue plays some role in resistance to the tumor-reducing activity of this glutamine antagonist. This, in turn, suggests that concurrent inhibition of glutamate production and blockage of glutamine utilization might result in enhanced tumor reduction in a clinical study.