A selective cyclooxygenase-2 inhibitor, NS-398, enhances the effect of radiation in vitro and in vivo preferentially on the cells that express cyclooxygenase-2

It has been proposed that Cyclooxygenase (COX)-2 inhibitors may be able to enhance the effects of chemotherapeutic or radiation treatment; however, cu rrently few studies have been reported that define the radiation-enhancing effect of COX-2 inhibitors. We conducted in vitro radiation survival experi ments using rat intestinal epithelial cells which were stably transfected w ith COX-2 cDNA in the sense (RIE-S) and antisense (RIE-AS) orientations to investigate the potential radiosensitizing effect of the selective COX-2 in hibitor, NS-398. Apoptosis was measured using 7-aminoactinomycin-D with flo w cytometry to investigate underlying mechanisms for the effect of NS-398 o n radiosensitivity. The same experiments were repeated with NCI-H460 human lung cancer cells, which express COX-2 constitutively, and HCT-116 human co lon cancer cells, which lack COX-2 expression. In vivo tumor growth delay a ssays were also performed with tumors formed by H460 and HCT-116 cells. No difference was observed in the intrinsic radiation sensitivity of RIE-S and RIE-AS cells exposed to radiation alone. However, 150-400 muM of NS-398 en hanced radiosensitivity in a concentration-dependent manner in RIE-S cells with dose enhancement ratios of 1.2-1.9 at a surviving fraction of 0.25. Ho wever, this effect was not shown in RIE-AS cells. NS-398 enhanced radiosens itivity in H460 cells with a dose enhancement ratio of 1.8 but protected HC T-116 cells from the effects of radiation. Radiation-induced apoptosis was enhanced by NS-398 in RIE-S and H460 cells but not in RIE-AS and HCT- 116 c ells. Additionally, this radiation-enhancing effect in RIE-S cells seemed t o be attributable to some mechanisms other than the reversal of radioresist ance induced by COX-2. NS-398 (36 mg/kg) enhanced the effect of radiation o n H460 tumors in vivo by an enhancement factor of 2.5, however, it did not enhance the radiosensitivity of HCT- 116 tumors (enhancement factor = 1.04) . These in vitro and in vivo results suggest that selective COX-2 inhibitor s enhance the effect of radiation on tumors that express COX-2 but not on C OX-2-lacking tumors. This effect may be attributable to enhancement of radi ation-induced apoptosis. Thus, selective COX-2 inhibitors may have potentia l as radiosensitizers for treatment of human cancers.