Enhanced expression of thymidylate synthase mediates resistance of uterine cervical cancer cells to radiation.

It has been shown that there is an inverse relationship between the level of thymidylate synthase (TS) and therapeutic outcomes in patients with malignancies including cervical cancer. To clarify the mechanism of the poor prognosis of cervical cancer with high TS expression, we introduced TS cDNA to the human uterine cervical cancer cell line SKG-II and evaluated the effect of TS expression on its radiosensitivity. After selection, stable transformants of SKG-II cells expressing high level of TS (SKG-II/TS) and control cells (SKG-II/luciferase) were obtained. The level of TS measured by the FdUMP-TS binding assay was significantly higher (p < 0.05) in SKG-II/TS than in control (2.0 +/- 0.1 and 1.3 +/- 0.1 pmol/mg, respectively). No difference was observed in in vitro cell growth or in vivo tumor growth. On evaluation of in vitro radiosensitivity, the 50% growth inhibitory dose (ID(50)) was 3.1 +/- 0.1 Gy in SKG-II/TS and was significantly higher (p < 0.01) than that in control (2.2 +/- 0.1 Gy). From these results, it is suggested that one of the reasons of poor outcome of cervical cancer to radiation is high TS expression.