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²¹¹At Radioimmunotherapy of Subcutaneous Human Ovarian Cancer Xenografts: Evaluation of Relative Biologic Effectiveness of an -Emitter In Vivo

¹ Department of Radiation Physics, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden
² Department of Oncology, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden
³ Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York
⁴ Positron Emission Tomography and Cyclotron Unit, Copenhagen, Denmark

The use of -particle emitters in radioimmunotherapy (RIT) appears to be promising. We previously obtained convincing results in the treatment of microscopic intraperitoneal ovarian cancer in nude mice by using the -emitter ²¹¹At. This study was performed to evaluate the relative biological effectiveness (RBE) of ²¹¹At compared with that of ⁶⁰Co -irradiation in an RIT model. Our endpoint was growth inhibition (GI) of subcutaneous xenografts. Methods: GI after irradiation was studied with subcutaneous xenografts of the human ovarian cancer cell line NIH:OVCAR-3 implanted in nude mice. The animals received an intravenous injection of ²¹¹At-labeled monoclonal antibody MX35 F(ab')₂ at different levels of radioactivity (0.33, 0.65, and 0.90 MBq). Control mice received unlabeled MX35 F(ab')₂ only. To calculate the mean absorbed dose to tumor, a separate biodistribution study established the uptake of ²¹¹At in tumors and organs at different times after injection. External irradiation of the tumors was performed with ⁶⁰Co. Tumor growth was monitored, and the normalized tumor volume (NTV) was calculated for each tumor. GI was defined by dividing the NTV values by the fitted NTV curve obtained from the corresponding control mice. To compare the biologic effects of the 2 radiation qualities, the mean value for GI (from day 8 to day 23) was plotted for each tumor as a function of its corresponding absorbed dose. From exponential fits of these curves, the doses required for a GI of 0.37 (D₃₇) were derived, and the RBE of ²¹¹At was calculated. Results: The biodistribution study showed the uptake of the immunoconjugate by the tumor (amount of injected radioactivity per gram) to be 14% after 7 h. At 40 h, the ratio of uptake in tumors to uptake in blood reached a maximum value of 6.2. The administered activities of ²¹¹At corresponded to doses absorbed by tumors of 1.35, 2.65, and 3.70 Gy. The value (mean ± SEM) for D₃₇ was 1.59 ± 0.08 Gy. Tumor growth after ⁶⁰Co external irradiation showed a value for D₃₇ of 7.65 ± 1.0 Gy. The corresponding RBE of ²¹¹At irradiation was 4.8 ± 0.7. Conclusion: Using a tumor GI model in nude mice, we were able to derive an RBE of -particle RIT with ²¹¹At. The RBE was found to be 4.8 ± 0.7.

Key Words: astatine • radioimmunotherapy • relative biological effectiveness • xenografts

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