The effect of radiation exposure on multidrug resistance: In vitro and in vivo studies using non-small lung cancer cells

Abstract

Background: Technetium-99m methoxyisobutylisonitrile (Tc MIBI) is a substrate with the same uptake kinetics as doxorubicin. Multidrug resistance (MDR) is a mechanism that impedes chemotherapy of non-small cell lung cancer (NSCLC). We examined the effect of radiation exposure on MDR in NSCLC and the synergy between an MDR modulator, GG918, and radiation, using 99m Tc MIBI in vitro and doxorubicin in vivo. Methods: In vitro NSCLC cells (H1299) were exposed to radiation (3-, 6-, and 9-Gy-irradiated groups) alongside a not-irradiated (0 Gy) group. Technetium-99 metastable methoxyisobutylisonitrile ( 99m Tc MIBI) was administered to cell suspensions at 48 h after irradiation. Cell radioactivity was measured, and C in /C out ratios were calculated and compared. NSCLC cells were also subcutaneously transplanted into the left thigh of nude mice, which were subsequently raised for 2 weeks. Two groups of mice were used: mice exposed to irradiation (9-Gy-irradiated) and those that were not (not-irradiated). Doxorubicin was administered through the caudal vein at 48 h after the irradiation. Using an in vivo imaging system, intratumoural photon counts were measured. To determine the synergy between the MDR modulator and 3- or 6-Gy irradiation, the final GG918 concentration was determined: 0.1 μM (N-H, 3-H, and 6-H groups), 0.001 μM (N-L, 3-L, and 6-L groups), and 0 μM (N-0, 3-0, and 6-0 groups). C in /C out ratios were calculated and compared among the groups. Results: C in /C out after 6- or 9-Gy irradiation was significantly higher than that of the not-irradiated group (0 Gy). In vivo, fluorescence photon counts were significantly higher in the tumours of 9-Gy-irradiated mice, up to 270 min after administration of doxorubicin, as compared to the not-irradiated mice. The C in /C out ratio in the N-H, 3-H, and 6-H groups was significantly higher than that in the N-0, 3-0, and 6-0 groups. There was no significant difference between C in /C out in the N-L group and that of the N-0 group. However, the C in /C out ratio in the 3-L and 6-L groups was significantly higher than that in the 3-0 and 6-0 groups. Conclusions: Irradiation decreased MDR in NSCLC cells. In combination with a low-dose MDR modulator, GG918, MDR transport function was synergistically reduced 48 h post-irradiation.