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Basic Science Investigations |
1 Department of Radiology, Nikko Memorial Hospital, Muroran, Japan
2 Department of Tracer Kinetics, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
3 Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
4 Department of Pathological Oncology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
5 Department of Nuclear Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York
6 Division of Nuclear Medicine, Department of Radiology, Stanford University School of Medicine, Stanford, California
7 Department of Laboratory Medicine, University of Washington, Seattle, Washington
Annexin V, a human protein with a high affinity for phosphatidylserine, has been labeled with 99mTc to detect apoptosis in vivo. To determine the effectiveness of imaging with this agent as a reflection of the degree of apoptosis after the first dose of chemotherapy, we studied rats with an engrafted hepatoma. Methods: Annexin V was labeled with 99mTc (specific activity, 3.0 MBq/µg protein). Eleven days after being inoculated with allogenic hepatoma cells (KDH-8) in the left calf muscle, the rats were randomized to receive a single dose of cyclophosphamide (150 mg/kg intraperitoneally) or to serve as controls. 99mTc-annexin V was injected 20 h later. Radioactivity in tissues was determined 6 h after injection of 99mTc-annexin V. Tumor uptake of 14C-iodoanitpyrine was determined as a marker of tumor blood flow. Terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling (TUNEL) of tissue harvested at necropsy was performed to detect apoptosis in the tumor. Results: Cyclophosphamide treatment significantly increased the tumor uptake (percentage activity of injected dose per gram of tissue after normalization to the animal’s weight [%ID/g/kg]) of 99mTc-annexin V (0.070 ± 0.007 %ID/g/kg for treated rats and 0.046 ± 0.009 %ID/g/kg for controls, P < 0.001). 14C-iodoantipyrine uptake was similar in the treated and untreated groups. The number of TUNEL-positive cells in the tumor was significantly larger in the treated rats (297.70 ± 50.34 cells/mm2) than in the control rats (168.45 ± 23.60 cells/mm2, P < 0.001). Tumor uptake of 99mTc-annexin V correlated with the number of TUNEL-positive cells in the tumor (r = 0.712; P < 0.001). Conclusion: Tumor uptake of 99mTc-annexin V was significantly increased by a single dose of cyclophosphamide treatment, and the increase was concordant with the number of TUNEL-positive cells in the tumor. The current results are suggestive of the utility of 99mTc-annexin V as a noninvasive means to assess tumor response, although further testing, including clinical evaluation, is required.
Key Words: 99mTc-annexin V • apoptosis • tumor • chemotherapy
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