Assessment of early changes in 3H-fluorothymidine uptake after treatment with gefitinib in human tumor xenograft in comparison with Ki-67 and phospho-EGFR expression

BMC Cancer

Songji Zhao¹  Yuji Kuge⁴  Yan Zhao¹  Satoshi Takeuchi³  Kenji Hirata²  Toshiki Takei²  Tohru Shiga²  Hirotoshi Dosaka-Akita³  Nagara Tamaki² 

[1] Department of Tracer Kinetics & Bioanalysis, Graduate School of Medicine, Hokkaido University, Sapporo, Japan

[2] Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan

[3] Department of Medical Oncology, Hokkaido University, Sapporo, Japan

[4] Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan

关键词: Athymic nude mice;    A431;    Molecular-targeted therapy;    Gefitinib;    ³H-FLT;   

Others  :  1079468
DOI  :  10.1186/1471-2407-13-525

 received in 2013-01-12, accepted in 2013-10-30,  发布年份 2013

【 摘 要 】

Background

The purpose of this study was to evaluate whether early changes in 3′-deoxy-3′-³H-fluorothymidine (³H-FLT) uptake can reflect the antiproliferative effect of gefitinib in a human tumor xenograft, in comparison with the histopathological markers, Ki-67 and phosphorylated EGFR (phospho-EGFR).

Methods

An EGFR-dependent human tumor xenograft model (A431) was established in female BALB/c athymic mice, which were divided into three groups: one control group and two treatment groups. Mice in the treatment groups were orally administered a partial regression dose (100 mg/kg/day) or the maximum tolerated dose of gefitinib (200 mg/kg/day), once daily for 2 days. Mice in the control group were administered the vehicle (0.1% Tween 80). Tumor size was measured before and 3 days after the start of treatment. Biodistribution of ³H-FLT and ¹⁸F-FDG (%ID/g/kg) was examined 3 days after the start of the treatment. Tumor cell proliferative activity with Ki-67 was determined. Immunohistochemical staining of EGFR and measurement of phospho-EGFR were also performed.

Results

High expression levels of EGFR and Ki-67 were observed in the A431 tumor. After the treatment with 100 and 200 mg/kg gefitinib, the uptake levels of ³H-FLT in the tumor were significantly reduced to 67% and 61% of the control value, respectively (0.39 ± 0.09, 0.36 ± 0.06, 0.59 ± 0.11%ID/g/kg for 100 mg/kg, 200 mg/kg, and control groups, respectively; p < 0.01 vs. control), but those of ¹⁸F-FDG were not. After the treatment with 100 and 200 mg/kg gefitinib, the expression levels of Ki-67 in the tumor were markedly decreased (4.6 ± 2.4%, 6.2 ± 1.8%, and 10.4 ± 5.7% for 100 mg/kg, 200 mg/kg, and control groups, respectively, p < 0.01 vs. control). The expression levels of the phospho-EGFR protein also significantly decreased (29% and 21% of the control value for 100, and 200 mg/kg, respectively p < 0.01 vs. control). There was no statistically significant difference in tumor size between pre- and post-treatments in each group.

Conclusion

In our animal model, ³H-FLT uptake levels significantly decreased after the treatment with two different doses of gefitinib before a significant change in tumor size was observed. These results were confirmed by the immunohistochemical staining of Ki-67 and phospho-EGFR protein immunoassay. Thus, it was indicated that early changes in ³H-FLT uptake may reflect the antiproliferative effect of gefitinib in a mouse model of a human epidermoid cancer.

【 授权许可】

   
2013 Zhao et al.; licensee BioMed Central Ltd.

【 图 表 】

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