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

Kanno S, Utsunomiya K, Kono Y, Tanigawa N, Sawada S - EJNMMI Res (2015)

Bottom Line: 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.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.In combination with a low-dose MDR modulator, GG918, MDR transport function was synergistically reduced 48 h post-irradiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, 573-1010 Osaka Japan.

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.

No MeSH data available.


Related in: MedlinePlus

Various concentrations of GG918 administered and accumulation of99mTc MIBI in cells measured at 30 min after administration. The Cin/Cout at 30 min after the addition of 99mTc MIBI is shown in the graph. The Cin/Cout of the N-H, 3-H, and 6-H groups was significantly higher than that of the N-0, 3-0, and 6-0 groups. In addition, the Cin/Cout in the N-H, 3-H, and 6-H groups was significantly higher than those in the N-L, 3-L, and 6-L groups. On the other hand, although there was no significant difference in the values between the N-0 group and the N-L group, those of the 3-L and 6-L groups were significantly higher than those of the 3-0 and 6-0 groups.
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Fig7: Various concentrations of GG918 administered and accumulation of99mTc MIBI in cells measured at 30 min after administration. The Cin/Cout at 30 min after the addition of 99mTc MIBI is shown in the graph. The Cin/Cout of the N-H, 3-H, and 6-H groups was significantly higher than that of the N-0, 3-0, and 6-0 groups. In addition, the Cin/Cout in the N-H, 3-H, and 6-H groups was significantly higher than those in the N-L, 3-L, and 6-L groups. On the other hand, although there was no significant difference in the values between the N-0 group and the N-L group, those of the 3-L and 6-L groups were significantly higher than those of the 3-0 and 6-0 groups.

Mentions: Figure 7 presents the accumulation of 99mTc MIBI in cultured NSCLC cells to which the MDR modulator GG918 had been added. Although the 99mTc MIBI accumulation in the N-H group was significantly higher than that in the N-0 and N-L groups, no significant differences in the accumulation between the N-L group and N-0 group were observed. 99mTc MIBI accumulation in the 3-H group was significantly higher than that in the 3-0 and 3-L groups. 99mTc MIBI accumulation in the 3-L group was significantly higher than that in the 3-0 group. The 6-0, 6-L, and 6-H groups also showed the same significant tendency as the 3-0, 3-L, and 3-H groups. 99mTc MIBI accumulation was enhanced by irradiation, even in the presence of a low dose of GG918.Figure 7


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

Kanno S, Utsunomiya K, Kono Y, Tanigawa N, Sawada S - EJNMMI Res (2015)

Various concentrations of GG918 administered and accumulation of99mTc MIBI in cells measured at 30 min after administration. The Cin/Cout at 30 min after the addition of 99mTc MIBI is shown in the graph. The Cin/Cout of the N-H, 3-H, and 6-H groups was significantly higher than that of the N-0, 3-0, and 6-0 groups. In addition, the Cin/Cout in the N-H, 3-H, and 6-H groups was significantly higher than those in the N-L, 3-L, and 6-L groups. On the other hand, although there was no significant difference in the values between the N-0 group and the N-L group, those of the 3-L and 6-L groups were significantly higher than those of the 3-0 and 6-0 groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385263&req=5

Fig7: Various concentrations of GG918 administered and accumulation of99mTc MIBI in cells measured at 30 min after administration. The Cin/Cout at 30 min after the addition of 99mTc MIBI is shown in the graph. The Cin/Cout of the N-H, 3-H, and 6-H groups was significantly higher than that of the N-0, 3-0, and 6-0 groups. In addition, the Cin/Cout in the N-H, 3-H, and 6-H groups was significantly higher than those in the N-L, 3-L, and 6-L groups. On the other hand, although there was no significant difference in the values between the N-0 group and the N-L group, those of the 3-L and 6-L groups were significantly higher than those of the 3-0 and 6-0 groups.
Mentions: Figure 7 presents the accumulation of 99mTc MIBI in cultured NSCLC cells to which the MDR modulator GG918 had been added. Although the 99mTc MIBI accumulation in the N-H group was significantly higher than that in the N-0 and N-L groups, no significant differences in the accumulation between the N-L group and N-0 group were observed. 99mTc MIBI accumulation in the 3-H group was significantly higher than that in the 3-0 and 3-L groups. 99mTc MIBI accumulation in the 3-L group was significantly higher than that in the 3-0 group. The 6-0, 6-L, and 6-H groups also showed the same significant tendency as the 3-0, 3-L, and 3-H groups. 99mTc MIBI accumulation was enhanced by irradiation, even in the presence of a low dose of GG918.Figure 7

Bottom Line: 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.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.In combination with a low-dose MDR modulator, GG918, MDR transport function was synergistically reduced 48 h post-irradiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, 573-1010 Osaka Japan.

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.

No MeSH data available.


Related in: MedlinePlus