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Basic Science Investigations |
1 Division of Nuclear Medicine, Toronto General Hospital, Toronto, Ontario, Canada
2 Department of Pathology, Toronto General Hospital, Toronto, Ontario, Canada
3 Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada
4 Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
5 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
6 Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada
7 Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada
The epidermal growth factor receptor (EGFR) is an attractive target for the design of radiotherapeutic agents for breast cancer because it is present on almost all estrogen receptor-negative, hormone-resistant tumors with a poor prognosis. In this study, we describe the antitumor effects and normal tissue toxicity of the novel Auger electron-emitting radiopharmaceutical 111In-labeled diethylenetriaminepentaacetic acid-human epidermal growth factor (111In-DTPA-hEGF) administered to athymic mice bearing EGFR-positive human breast cancer xenografts. Methods: Mice bearing subcutaneous MDA-MB-468 or MCF-7 human breast cancer xenografts were treated with 5 weekly doses of 111In-DTPA-hEGF (total, 27.7–92.5 MBq or 5–17 µg). Treatment was commenced 6 wk after tumor cell implantation (established tumors) or 1 wk after implantation (nonestablished tumors). Antitumor effects were assessed by use of the slope of the tumor growth curve. Normal tissue toxicity was assessed by use of plasma alanine transaminase and creatinine levels, hematologic indices (leukocytes, platelets, erythrocytes, and hemoglobin), histopathologic examination of the liver and kidneys, and changes in body weight. The uptake of 111In-DTPA-hEGF in tumors of different sizes (<5–200 mm3) was investigated, and microdosimetry estimates were calculated. Results: 111In-DTPA-hEGF exhibited strong antitumor effects against established MDA-MB-468 xenografts, decreasing their growth rate 3-fold compared with that in normal saline-treated mice (slopes, 0.0225 and 0.0737 d-1, respectively; P = 0.002). The antitumor effects of 111In-DTPA-hEGF were much more profound in mice with small, nonestablished MDA-MB-468 tumors, which regressed, than in saline-treated mice (slopes, -0.009 and 0.0297 d-1, respectively; P < 0.001). The growth of MCF-7 xenografts, with a 100-fold-lower level of EGFR expression, was modestly inhibited by 111In-DTPA-hEGF compared with that in saline-treated mice (slopes, 0.0250 and 0.0488 d-1, respectively; P = 0.051). There was a 1.4- to 2-fold decrease in leukocyte and platelet counts with 111In-DTPA-hEGF treatment, but these counts remained in the normal ranges. There was no change in other biochemical or hematologic parameters or body weight. There was no evidence of morphologic damage to the liver or kidneys. A strong inverse relationship was observed between radiopharmaceutical uptake and tumor size, with small tumors (<5 mm3) accumulating >30% of the injected dose (%ID) per gram, compared with 5 %ID/g for tumors measuring 6–30 mm3. Exceptionally high uptake (>80 %ID/g) was achieved in tumors measuring 1–2 mm3. Microdosimetry estimates indicated that the nucleus of an MDA-MB-468 cell would receive 90–1,400 cGy, depending on the level of radiopharmaceutical uptake. Conclusion: 111In-DTPA-hEGF exhibited strong antitumor effects against MDA-MB-468 breast cancer xenografts overexpressing EGFR. The highest tumor localization, radiation-absorbed doses, and growth inhibition were achieved for small, nonestablished tumors, suggesting that the radiopharmaceutical may be most valuable for the treatment of small-volume metastatic breast cancer or occult micrometastases in an adjuvant setting.
Key Words: 111In • epidermal growth factor • epidermal growth factor receptor • Auger electrons • breast cancer
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