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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

Doxorubicin fluorescence imaging. The upper section indicates an image of the 9-Gy-irradiated mouse. The lower section indicates an image of the not-irradiated mouse. The tumour site of the 9-Gy-irradiated mouse showed sufficient accumulation of doxorubicin in the upper section, whereas that of the not-irradiated mouse showed no significant accumulation of doxorubicin.
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Fig5: Doxorubicin fluorescence imaging. The upper section indicates an image of the 9-Gy-irradiated mouse. The lower section indicates an image of the not-irradiated mouse. The tumour site of the 9-Gy-irradiated mouse showed sufficient accumulation of doxorubicin in the upper section, whereas that of the not-irradiated mouse showed no significant accumulation of doxorubicin.

Mentions: Figure 5 represents a fluorescence image of a xenograft. The tumour site of the 9-Gy-irradiated mouse exhibited fluorescence, indicating an accumulation of doxorubicin, whereas the tumour site of the not-irradiated mouse did not exhibit significant fluorescence, indicating little or no doxorubicin accumulation.Figure 5


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)

Doxorubicin fluorescence imaging. The upper section indicates an image of the 9-Gy-irradiated mouse. The lower section indicates an image of the not-irradiated mouse. The tumour site of the 9-Gy-irradiated mouse showed sufficient accumulation of doxorubicin in the upper section, whereas that of the not-irradiated mouse showed no significant accumulation of doxorubicin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Doxorubicin fluorescence imaging. The upper section indicates an image of the 9-Gy-irradiated mouse. The lower section indicates an image of the not-irradiated mouse. The tumour site of the 9-Gy-irradiated mouse showed sufficient accumulation of doxorubicin in the upper section, whereas that of the not-irradiated mouse showed no significant accumulation of doxorubicin.
Mentions: Figure 5 represents a fluorescence image of a xenograft. The tumour site of the 9-Gy-irradiated mouse exhibited fluorescence, indicating an accumulation of doxorubicin, whereas the tumour site of the not-irradiated mouse did not exhibit significant fluorescence, indicating little or no doxorubicin accumulation.Figure 5

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