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Evaluation of the therapeutic efficacy of a MEK inhibitor (TAK-733) using ¹⁸F-fluorodeoxyglucose-positron emission tomography in the human lung xenograft model A549.

Ishino S, Miyake H, Vincent P, Mori I - Ann Nucl Med (2015)

Bottom Line: At a dosage of 10 mg/kg, TAK-733 treatment produced a statistically significant reduction in tumor weight from day 11 compared with the vehicle group (P < 0.05).Furthermore, this reduction in SUVmean at 10 mg/kg was maintained over time.In the two lower dosage groups (1 and 3 mg/kg), SUVmean gradually increased over time. (18)F-FDG-PET enabled early determination of late anti-tumor activity in response to TAK-733 treatment.

View Article: PubMed Central - PubMed

Affiliation: Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2 chome, Fujisawa, Kanagawa, 251-8555, Japan.

ABSTRACT

Objective: The aim of this study was to evaluate the potential of (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) for monitoring the therapeutic efficacy of TAK-733, an inhibitor of mitogen-activated protein kinase kinase, in nude rats bearing A549 (human lung carcinoma) xenografts.

Methods: TAK-733 was administered orally by gavage to nude xenograft rats for 2 weeks, at dosage levels of 0 (0.5% w/v methylcellulose solution), 1, 3, and 10 mg/kg/day (n = 8/dose). Tumor size was measured before treatment (day 0), and on days 1, 3, 7, 9, 11, and 14. PET scans were performed pretreatment (day 0), and on days 2, 4, 7, 10, and 14. Tracer accumulations in tumor tissue were quantified as the mean standard uptake value (SUVmean).

Results: No deaths or treatment-related body weight losses occurred during the study period. TAK-733 showed dose-dependent inhibition of tumor growth and (18)F-FDG uptake in tumor tissue. At a dosage of 10 mg/kg, TAK-733 treatment produced a statistically significant reduction in tumor weight from day 11 compared with the vehicle group (P < 0.05). Tumor growth was inhibited in the 10 mg/kg group with a treated/control value of 31% on day 14. The SUVmean on day 2 in this dosage group was statistically lower than that observed on day 0, and that seen in the vehicle group on day 2 (P < 0.05 for both comparisons). Furthermore, this reduction in SUVmean at 10 mg/kg was maintained over time. In the two lower dosage groups (1 and 3 mg/kg), SUVmean gradually increased over time.

Conclusions: (18)F-FDG-PET enabled early determination of late anti-tumor activity in response to TAK-733 treatment.

No MeSH data available.


Related in: MedlinePlus

SUVmean values following TAK-733 (1, 3, 10 mg/kg) or vehicle treatment in human lung carcinoma A549 tumors in a xenograft rat model. 18F-FDG-PET scans were performed on days 0, 2, 4, 7, 10, and 14. Data are expressed as mean + standard deviation (SD) (n = 8/group). Black, blue, green and redlines and markers indicate vehicle, 1, 3, and 10 mg/kg group, respectively. 18F-FDG-PET18F-Fluorodeoxyglucose-positron emission tomography, SUVmean mean standard uptake. Left absolute SUVmean, right percentage change in SUVmean from day 0. *1: P < 0.05 vs. vehicle (Wilcoxon rank-sum test), *2: P < 0.05 vs. TAK-733 1 mg/kg (Wilcoxon rank-sum test), *a: P < 0.05 vs. pretreatment (Wilcoxon rank-sum test)
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Fig6: SUVmean values following TAK-733 (1, 3, 10 mg/kg) or vehicle treatment in human lung carcinoma A549 tumors in a xenograft rat model. 18F-FDG-PET scans were performed on days 0, 2, 4, 7, 10, and 14. Data are expressed as mean + standard deviation (SD) (n = 8/group). Black, blue, green and redlines and markers indicate vehicle, 1, 3, and 10 mg/kg group, respectively. 18F-FDG-PET18F-Fluorodeoxyglucose-positron emission tomography, SUVmean mean standard uptake. Left absolute SUVmean, right percentage change in SUVmean from day 0. *1: P < 0.05 vs. vehicle (Wilcoxon rank-sum test), *2: P < 0.05 vs. TAK-733 1 mg/kg (Wilcoxon rank-sum test), *a: P < 0.05 vs. pretreatment (Wilcoxon rank-sum test)

Mentions: 18F-FDG SUVmean gradually increased over time, and to a similar extent, in the vehicle and TAK-733 1 mg/kg groups (Fig. 6). A slight reduction in SUVmean was observed in the 3 mg/kg dosage group on day 2, but this change was not statistically significant (not significant change between: vehicle and 3 mg/kg dosage group and between pretreatment and mg/kg dosage group) and values increased gradually over time thereafter. In contrast, a 13.2 % reduction in SUVmean compared with pretreatment was observed in the 10 mg/kg group on day 2 (P < 0.05), which persisted throughout the study. The percentage reduction in SUVmean from day 0 at 10 mg/kg on day 2 was significantly different to that seen in the vehicle and 1 mg/kg groups (mean + standard deviation, 87 + 8 vs. 101 + 2 % and 105 + 8 %, respectively; P < 0.05 for both comparisons). On day 14, the absolute SUVmean at 10 mg/kg was significantly lower than that reported for the vehicle group (1.5 + 0.3 vs. 2.2 + 0.3, respectively; P < 0.05). Further, the percentage change in SUVmean at 10 mg/kg on day 14 was significantly different to that observed at 1 mg/kg (91 + 14 vs. 136 + 7 %, respectively; P < 0.05) (Fig. 6).Fig. 6


Evaluation of the therapeutic efficacy of a MEK inhibitor (TAK-733) using ¹⁸F-fluorodeoxyglucose-positron emission tomography in the human lung xenograft model A549.

Ishino S, Miyake H, Vincent P, Mori I - Ann Nucl Med (2015)

SUVmean values following TAK-733 (1, 3, 10 mg/kg) or vehicle treatment in human lung carcinoma A549 tumors in a xenograft rat model. 18F-FDG-PET scans were performed on days 0, 2, 4, 7, 10, and 14. Data are expressed as mean + standard deviation (SD) (n = 8/group). Black, blue, green and redlines and markers indicate vehicle, 1, 3, and 10 mg/kg group, respectively. 18F-FDG-PET18F-Fluorodeoxyglucose-positron emission tomography, SUVmean mean standard uptake. Left absolute SUVmean, right percentage change in SUVmean from day 0. *1: P < 0.05 vs. vehicle (Wilcoxon rank-sum test), *2: P < 0.05 vs. TAK-733 1 mg/kg (Wilcoxon rank-sum test), *a: P < 0.05 vs. pretreatment (Wilcoxon rank-sum test)
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Related In: Results  -  Collection

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Fig6: SUVmean values following TAK-733 (1, 3, 10 mg/kg) or vehicle treatment in human lung carcinoma A549 tumors in a xenograft rat model. 18F-FDG-PET scans were performed on days 0, 2, 4, 7, 10, and 14. Data are expressed as mean + standard deviation (SD) (n = 8/group). Black, blue, green and redlines and markers indicate vehicle, 1, 3, and 10 mg/kg group, respectively. 18F-FDG-PET18F-Fluorodeoxyglucose-positron emission tomography, SUVmean mean standard uptake. Left absolute SUVmean, right percentage change in SUVmean from day 0. *1: P < 0.05 vs. vehicle (Wilcoxon rank-sum test), *2: P < 0.05 vs. TAK-733 1 mg/kg (Wilcoxon rank-sum test), *a: P < 0.05 vs. pretreatment (Wilcoxon rank-sum test)
Mentions: 18F-FDG SUVmean gradually increased over time, and to a similar extent, in the vehicle and TAK-733 1 mg/kg groups (Fig. 6). A slight reduction in SUVmean was observed in the 3 mg/kg dosage group on day 2, but this change was not statistically significant (not significant change between: vehicle and 3 mg/kg dosage group and between pretreatment and mg/kg dosage group) and values increased gradually over time thereafter. In contrast, a 13.2 % reduction in SUVmean compared with pretreatment was observed in the 10 mg/kg group on day 2 (P < 0.05), which persisted throughout the study. The percentage reduction in SUVmean from day 0 at 10 mg/kg on day 2 was significantly different to that seen in the vehicle and 1 mg/kg groups (mean + standard deviation, 87 + 8 vs. 101 + 2 % and 105 + 8 %, respectively; P < 0.05 for both comparisons). On day 14, the absolute SUVmean at 10 mg/kg was significantly lower than that reported for the vehicle group (1.5 + 0.3 vs. 2.2 + 0.3, respectively; P < 0.05). Further, the percentage change in SUVmean at 10 mg/kg on day 14 was significantly different to that observed at 1 mg/kg (91 + 14 vs. 136 + 7 %, respectively; P < 0.05) (Fig. 6).Fig. 6

Bottom Line: At a dosage of 10 mg/kg, TAK-733 treatment produced a statistically significant reduction in tumor weight from day 11 compared with the vehicle group (P < 0.05).Furthermore, this reduction in SUVmean at 10 mg/kg was maintained over time.In the two lower dosage groups (1 and 3 mg/kg), SUVmean gradually increased over time. (18)F-FDG-PET enabled early determination of late anti-tumor activity in response to TAK-733 treatment.

View Article: PubMed Central - PubMed

Affiliation: Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2 chome, Fujisawa, Kanagawa, 251-8555, Japan.

ABSTRACT

Objective: The aim of this study was to evaluate the potential of (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) for monitoring the therapeutic efficacy of TAK-733, an inhibitor of mitogen-activated protein kinase kinase, in nude rats bearing A549 (human lung carcinoma) xenografts.

Methods: TAK-733 was administered orally by gavage to nude xenograft rats for 2 weeks, at dosage levels of 0 (0.5% w/v methylcellulose solution), 1, 3, and 10 mg/kg/day (n = 8/dose). Tumor size was measured before treatment (day 0), and on days 1, 3, 7, 9, 11, and 14. PET scans were performed pretreatment (day 0), and on days 2, 4, 7, 10, and 14. Tracer accumulations in tumor tissue were quantified as the mean standard uptake value (SUVmean).

Results: No deaths or treatment-related body weight losses occurred during the study period. TAK-733 showed dose-dependent inhibition of tumor growth and (18)F-FDG uptake in tumor tissue. At a dosage of 10 mg/kg, TAK-733 treatment produced a statistically significant reduction in tumor weight from day 11 compared with the vehicle group (P < 0.05). Tumor growth was inhibited in the 10 mg/kg group with a treated/control value of 31% on day 14. The SUVmean on day 2 in this dosage group was statistically lower than that observed on day 0, and that seen in the vehicle group on day 2 (P < 0.05 for both comparisons). Furthermore, this reduction in SUVmean at 10 mg/kg was maintained over time. In the two lower dosage groups (1 and 3 mg/kg), SUVmean gradually increased over time.

Conclusions: (18)F-FDG-PET enabled early determination of late anti-tumor activity in response to TAK-733 treatment.

No MeSH data available.


Related in: MedlinePlus