Inhibition of human gastric carcinoma cell growth by atofluding derivative N3-o-toluyl-fluorouracil

Abstract

Aim: To evaluate the growth inhibition efficacy of atofluding derivative N3-o-toluyl-fluorouracil (TFU) on human gastric carcinoma cell lines SGC-7901 and MKN-45.

Methods: Cell growth inhibition by TFU was measured by MTT and clonogenic assays without or with liver microsomal enzymes. Xenografts of cancer cells in nude mice were employed to study the anti-proliferative effects of TFU in vivo.

Results: TFU inhibited the growth of SGC-7901 and MKN-45 cells. However, the inhibitory effects of TFU on cell growth were not significant. The inhibition rates were enhanced in the presence of liver microsomal enzymes, ranging 4.73%-48.57% in SGC-7901 cells and 9.0%-62.02% in MKN-45 cells. In vivo, TFU delayed the growth of SGC-7901 and MKN-45 cells in nude mice. The inhibition rates were 40.49%, 63.24%, and 75.98% in SGC-7901 cells and 40.76%, 61.41%, and 82.07% in MKN-45 cells when the oral doses were 25, 50, and 100 mg/kg, respectively. TFU treatment was generally well tolerated by mice with less than 20% reduction in body weight.

Conclusion: TFU inhibits the growth of human gastric carcinoma cells. The inhibition rates are increased in the presence of liver microsomal enzymes. The efficacy of TFU may be associated with the sustaining release of 5-fluorouracil (5-FU) mediated by the enzymes.

Figure 1

Metabolism of atofluding to into TFU and 5-FU. The acetyl group on the N1 position of atofluding was hydrolyzed in the presence of H₂O into TFU rapidly due to the influence of fluorine on the C5 position. 5-FU was transformed from TFU slowly and continually by the liver microsomal enzymes.

Figure 2

TFU inhibits MKN-45 (A) and SGC-7901 (B) cell growth in vitro. Cells were treated with TFU (0.1, 1, 10, 100, 1000 μg/mL) for up to 120 h. Viable cell numbers were evaluated by the MTT assay and expressed as percentage of untreated controls at the concurrent time point. The bars indicate means ± SD (n = 3).