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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

Effects of TAK-733 on the growth of human lung carcinoma A549 tumors in a xenograft rat model. Oral once-daily administration of TAK-733 (1, 3, 10 mg/kg) or vehicle was initiated when tumors reached a weight of 224–297 mg in A549 tumor-bearing rats. Data are expressed as mean + standard deviation (SD) (n = 8/group). Black, blue, green and redlines and markers indicate the vehicle, and TAK-733 1, 3, and 10 mg/kg dosage groups, respectively. Left A549 tumor weight (mg), right percentage change in tumor weight from day 0. *1: P < 0.05 vs. vehicle (Wilcoxon rank-sum test)
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Fig3: Effects of TAK-733 on the growth of human lung carcinoma A549 tumors in a xenograft rat model. Oral once-daily administration of TAK-733 (1, 3, 10 mg/kg) or vehicle was initiated when tumors reached a weight of 224–297 mg in A549 tumor-bearing rats. Data are expressed as mean + standard deviation (SD) (n = 8/group). Black, blue, green and redlines and markers indicate the vehicle, and TAK-733 1, 3, and 10 mg/kg dosage groups, respectively. Left A549 tumor weight (mg), right percentage change in tumor weight from day 0. *1: P < 0.05 vs. vehicle (Wilcoxon rank-sum test)

Mentions: TAK-733 treatment resulted in dose-dependent tumor growth inhibition. TAK-733 at a dosage level of 10 mg/kg produced a statistically significant reduction in estimated tumor weight compared with vehicle administration on day 11 (mean + standard deviation, 314 + 161 vs. 817 + 375 mg, respectively; P < 0.05) (Fig. 3).Fig. 3


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)

Effects of TAK-733 on the growth of human lung carcinoma A549 tumors in a xenograft rat model. Oral once-daily administration of TAK-733 (1, 3, 10 mg/kg) or vehicle was initiated when tumors reached a weight of 224–297 mg in A549 tumor-bearing rats. Data are expressed as mean + standard deviation (SD) (n = 8/group). Black, blue, green and redlines and markers indicate the vehicle, and TAK-733 1, 3, and 10 mg/kg dosage groups, respectively. Left A549 tumor weight (mg), right percentage change in tumor weight from day 0. *1: P < 0.05 vs. vehicle (Wilcoxon rank-sum test)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4526591&req=5

Fig3: Effects of TAK-733 on the growth of human lung carcinoma A549 tumors in a xenograft rat model. Oral once-daily administration of TAK-733 (1, 3, 10 mg/kg) or vehicle was initiated when tumors reached a weight of 224–297 mg in A549 tumor-bearing rats. Data are expressed as mean + standard deviation (SD) (n = 8/group). Black, blue, green and redlines and markers indicate the vehicle, and TAK-733 1, 3, and 10 mg/kg dosage groups, respectively. Left A549 tumor weight (mg), right percentage change in tumor weight from day 0. *1: P < 0.05 vs. vehicle (Wilcoxon rank-sum test)
Mentions: TAK-733 treatment resulted in dose-dependent tumor growth inhibition. TAK-733 at a dosage level of 10 mg/kg produced a statistically significant reduction in estimated tumor weight compared with vehicle administration on day 11 (mean + standard deviation, 314 + 161 vs. 817 + 375 mg, respectively; P < 0.05) (Fig. 3).Fig. 3

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