Abstract
BackgroundTechnetium-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 99mTc MIBI in vitro and doxorubicin in vivo.MethodsIn 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 (99mTc MIBI) was administered to cell suspensions at 48 h after irradiation. Cell radioactivity was measured, and Cin/Cout 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). Cin/Cout ratios were calculated and compared among the groups.ResultsCin/Cout 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 Cin/Cout 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 Cin/Cout in the N-L group and that of the N-0 group. However, the Cin/Cout ratio in the 3-L and 6-L groups was significantly higher than that in the 3-0 and 6-0 groups.ConclusionsIrradiation decreased MDR in NSCLC cells. In combination with a low-dose MDR modulator, GG918, MDR transport function was synergistically reduced 48 h post-irradiation.
Highlights
Technetium-99m methoxyisobutylisonitrile (Tc technetium-99 metastable methoxyisobutylisonitrile (MIBI)) is a substrate with the same uptake kinetics as doxorubicin
There was no change after 9-Gy irradiation, followed by 48 h of culturing, as shown for the cells in Figure 3, with both Pgp and breast cancer-resistant protein (BCRP) being proportion score (PS) 5 + intensity score (IS) 3 = 8
This study revealed enhanced uptake of 99mTc MIBI in non-small cell lung cancer (NSCLC) cells in vitro after 6- and 9-Gy irradiation, and an extended intracellular doxorubicin residence time in in vivo xenografted NSCLC tumours at 48 h after 9-Gy irradiation, there was no difference in the expression of Pgp and BCRP between cells before and after 9-Gy irradiation immunocytochemically
Summary
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). Lung cancer that is detected in the advanced stage may be treated with molecular-targeted drugs; it is commonly treated. Combination therapies are often discontinued because of the side effects of both irradiation and anticancer drugs. The overexpression of P-glycoprotein (Pgp) and breast cancer-resistant protein (BCRP) in the membranes of tumour cells plays a major role in the development of MDR [3,4]. Cancer cells bearing the MDR phenotype are capable of eliminating anticancer drugs, such as cisplatin or doxorubicin, by using Pgp and BCRP as an efflux channel protein, thereby diminishing their chemotherapeutic actions [4]
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