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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

Anti-proliferative effects of TAK-733 in tumor tissue. a Representative images showing H&E staining and Ki-67 immunohistochemical staining in the vehicle and TAK-733 10 mg/kg dosage groups. Magnification is ×45. b Mean Ki-67 index in each dosage group (%). Data are expressed as mean + standard deviation (SD) (n = 8/group). *P < 0.025 vs. vehicle (Shirley–Williams test)
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Fig4: Anti-proliferative effects of TAK-733 in tumor tissue. a Representative images showing H&E staining and Ki-67 immunohistochemical staining in the vehicle and TAK-733 10 mg/kg dosage groups. Magnification is ×45. b Mean Ki-67 index in each dosage group (%). Data are expressed as mean + standard deviation (SD) (n = 8/group). *P < 0.025 vs. vehicle (Shirley–Williams test)

Mentions: H&E staining images revealed tumor cell necrosis in the 10 mg/kg group (Fig. 4a). Staining showed pyknotic nuclei and eosinophilic cytoplasm in multifocal lesions. Ki-67-positive cells were frequently detected in the tumor tissue from the vehicle group; however, Ki-67 nuclear staining was barely detectable in the TAK-733 10 mg/kg dosage group (Fig. 4a). A statistically significant decrease in the Ki-67 index was observed in the 1, 3, and 10 mg/kg dosage groups (P < 0.025 vs. vehicle for all comparisons) (Fig. 4b).Fig. 4


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)

Anti-proliferative effects of TAK-733 in tumor tissue. a Representative images showing H&E staining and Ki-67 immunohistochemical staining in the vehicle and TAK-733 10 mg/kg dosage groups. Magnification is ×45. b Mean Ki-67 index in each dosage group (%). Data are expressed as mean + standard deviation (SD) (n = 8/group). *P < 0.025 vs. vehicle (Shirley–Williams test)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4526591&req=5

Fig4: Anti-proliferative effects of TAK-733 in tumor tissue. a Representative images showing H&E staining and Ki-67 immunohistochemical staining in the vehicle and TAK-733 10 mg/kg dosage groups. Magnification is ×45. b Mean Ki-67 index in each dosage group (%). Data are expressed as mean + standard deviation (SD) (n = 8/group). *P < 0.025 vs. vehicle (Shirley–Williams test)
Mentions: H&E staining images revealed tumor cell necrosis in the 10 mg/kg group (Fig. 4a). Staining showed pyknotic nuclei and eosinophilic cytoplasm in multifocal lesions. Ki-67-positive cells were frequently detected in the tumor tissue from the vehicle group; however, Ki-67 nuclear staining was barely detectable in the TAK-733 10 mg/kg dosage group (Fig. 4a). A statistically significant decrease in the Ki-67 index was observed in the 1, 3, and 10 mg/kg dosage groups (P < 0.025 vs. vehicle for all comparisons) (Fig. 4b).Fig. 4

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