open access

https://hdl.handle.net/2115/54550

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

英語

Athymic nude mice

2013-11-06

Biomed central

BMC cancer

13

525

Background: The purpose of this study was to evaluate whether early changes in 3'-deoxy-3'-H-3-fluorothymidine (H-3-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 H-3-FLT and F-18-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 H-3-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 F-18-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, H-3-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 H-3-FLT uptake may reflect the antiproliferative effect of gefitinib in a mouse model of a human epidermoid cancer.

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Creative Commons Attribution 3.0 Unported

1471-2407

AA12034763