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Detection of tumor apoptotic response in vivo after a single dose of chemotherapy with ~(99)Tc~m-rh-Annexin Ⅴ

ZHANG Xin1, LI Ya-ming2, ZHANG Yan-jun1, JI Xiao-peng3, TAO Li1, ZHANG Jian-ying4, ZHAO Zhen-zhen4, TIAN Ai-juan3, ZHU Yi1, YANG Chun1, ZHAO Ming3 (1. Department of Nuclear Medicine, the First Hospital Affiliated to Dalian Medical University, Dalian Liaoning 116011, China; 2. Department of Nuclear Medicine, the First Hospital Affiliated to China Medical University, Shenyang 110001, China; 3. Department of Nuclear Medicine, the Second Hospital Affiliated to Dalian Medical University, Dalian Liaoning 116023, China; 4. Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China)  
Objective: To analyse the biodistribution of 99Tcm directly labelled recombinant human Annexin Ⅴ(99Tcm-rh-Annexin Ⅴ) in mice and to determine the effectiveness of imaging with this agent as a reflection of the degree of apoptosis after the first dose of chemotherapy. Methods: The biodistribution of 99Tcm-rh-Annexin Ⅴ was studied using purebred 615 mice(group A). After SPECT imaging, the animals were sacrified. The tissue samples were weighed and radioactivity was determined with a well-type scintillation counter. The accumulation of 99Tcm-rh-Annexin Ⅴ in the tissues was expressed as %ID/g(percentage activity of injection dose per gram of tissue). Eight days after being inoculated with allogenic hepatoma cells(Hca-F25) into the subcutaneos tissue of the right axillary fossa, the mice(group B)were randomly divided into four groups(B1, n=6; B2, n=5; B3, n=3; B4, n=3). Group B1 and group B3 received a single dose of cyclophosphamide(150mg/kg, intraperitoneally). Group B1 and group B2 were injected 99Tcm-rh-Annexin Ⅴ(5.55MBq/0.5μg/0.1ml/per mouse) intravenously 20hrs later, at the same time group B3 and group B4 received the same doses of 99Tcm without being labelled with Annexin Ⅴ. Radioactivity in tissues(tumor, blood, muscle) was determined 6hrs later. Apoptotic cells were detected with Annexin Ⅴ/PI flow cytometry. The morphological changes of the apoptotic hepatoma cells were observed by light and transmission electron microscopies. Results: The kidney had the highest concentration of radioactivity at all time points. On the other hand the liver uptake was lower and other organs showed the least concentration of 99Tcm-rh-Annexin Ⅴ. Cyclophosphamide treatment significantly increased the tumor uptake of 99Tcm-rh-Annexin Ⅴ[(0.48±0.16)%ID/g for group B1 and 0.30±0.06 for group B2, P0.05]. Tumor uptake of 99Tcm-rh-Annexin Ⅴ of group B1 correlated well with the number of Annexin Ⅴ/PI-positive cells in the tumor(r=0.813, P=0.04), on the other hand, group B2, group B3 and group B4 had no correlation(r=0.386, P=0.241). Conclusion: Tumor uptake of 99Tcm-rh-Annexin Ⅴ was significantly increased by a single dose of cyclophosphamide treatment, and the increase was concordant with the number of Annexin Ⅴ/PI-positive cells in tumor. The current results are suggestive of the utility of 99Tcm-rh-Annexin Ⅴ as a noninvasive means to assess tumor response, although further testing is required.
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