Intratumoral uptake and metabolism of 5fluorouracil in implanted tumors of mice monitored by in viv

The intratumoral uptake and metabolic kinetics of 5fluorouracil (5FU) were investigated and measured in S180 tumorbearing Kunming mice and B16 tumorbearing C57 mice by in vivo 19F nuclear magnetic resonance spectroscopy (19F NMR). The cytotoxic anabolites fluorinated nucleosides/tides (FNUC) were detected as the major metabolite both in S180 tumor and B16 tumor after iv 5FU 200 mg·kg-1. The degradation products, αfluoroβureidopropionic acid (FUPA) and αfluoroβalanine (FBAL) were minor metabolites, which appeared in 19F NMR spectra obtained from the tumors. The marked individual variation was shown in the uptake and clearance of 5FU, as well as the formation of FNUC in the S180 tumors. The range of elimination t1/2ke of 5FU was 41.5 to 84.8 min, and the formation t1/2r of FNUC was changed from 26.0 to 91.9 min in the S180 carcinosarcoma. Pretreatment with methotrexate (MTX) in S180　 tumorbearing mice appeared to result in a significant enhancement of intratumoral anabolism of 5FU, and the elimination t1/2ke of 5FU was decreased to 29.9-43.4 min. Moreover, the production and formation rate of FNUC were increased significantly. In B16 tumors, the intratumoral uptake and elimination of 5FU (200 mg·kg-1, iv) were rapid. The t1/2ke of 5FU was 39±5 min, and the formation t1/2r of FNUC was 60±7 min. Pretreatment of MTX could not activated the intratumoral anabolic metabolism of 5FU, and not change the clearance profile of the drug in B16 tumors. These results demonstrate that the tumor toxicity of 5FU depends on tumor perfusion, uptake and anabolism of 5FU in the tumor tissue, and it can also be modulated by other drugs used concurrently.