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¹¹¹In-Labeled EGF Is Selectively Radiotoxic to Human Breast Cancer Cells Overexpressing EGFR

Division of Nuclear Medicine and Department of Pathology, Toronto General Hospital, University Health Network, Toronto
Department of Radiation Oncology, Princess Margaret Hospital, University Health Network, Toronto
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto
Departments of Medical Imaging, Pharmaceutical Sciences, and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

Correspondence: For correspondence or reprints contact: Jean Gariépy, PhD, Department of Medical Biophysics, University of Toronto, 610 University Ave., Toronto, Ontario, Canada M5G 2M9.

ABSTRACT

Our objective was to determine whether the internalization and nuclear translocation of human epidermal growth factor (hEGF) after binding to its cell surface receptor (EGFR) could be exploited to deliver the Auger electron emitter ¹¹¹In into EGFR-positive breast cancer cells for targeted radiotherapy. Methods: hEGF was derivatized with diethylenetriamine pentaacetic acid (DTPA) and radiolabeled with ¹¹¹In-acetate. The internalization of ¹¹¹In-DTPA-hEGF by MDA-MB-468 breast cancer cells (1.3 x 10⁶ EGFRs/cell) was determined by displacement of surface-bound radioactivity by an acid wash. The radioactivity in the cell nucleus and chromatin, isolated by differential centrifugation, was measured. The effect on the growth rate of MDA-MB-468 or MCF-7 (1.5 x 10⁴ EGFRs/cell) cells was determined after treatment in vitro with ¹¹¹ In-DTPA-hEGF, unlabeled DTPA-hEGF, or ¹¹In-DTPA. The surviving fraction of MDA-MB-468 or MCF-7 cells treated in vitro with ¹¹¹In-DTPA-hEGF was determined in a clonogenic assay. The radiotoxicity in vivo against normal hepatocytes or renal tubular cells was evaluated by measuring alanine aminotransferase (ALT) or creatinine levels in mice administered high amounts of ¹¹¹In-DTPA-hEGF (equivalent to human doses up to 14,208 MBq) and by light and electron microscopy of the tissues. Results: Approximately 70% of ¹¹¹In-DTPA-hEGF was internalized by MDA-MB-468 cells within 15 min at 37°C and up to 15% was translocated to the nucleus within 24 h. Chromatin contained 10% of internalized radioactivity. The growth rate of MDA-MB-468 cells was decreased 3-fold by treatment with ¹¹¹In-DTPA-hEGF (45–60 mBq/cell). Treatment with unlabeled DTPA-hEGF caused a 1.5-fold decrease in growth rate, whereas treatment with ¹¹¹In-DTPA had no effect. Targeting of MDA-MB-468 cells with up to 130 mBq/cell of ¹¹¹In-DTPA-hEGF resulted in a 2-logarithm decrease in their surviving fraction. No decrease in the growth rate or surviving fraction of MCF-7 cells was evident. There was no evidence of hepatotoxicity or renal toxicity in mice administered high amounts of ¹¹¹In-DTPA-hEGF. Radiation dosimetry estimates suggest that the radiation dose to an MDA-MB-468 cell targeted with ¹¹¹In-DTPA-hEGF could be as high as 25 Gy with up to 19 Gy delivered to the cell nucleus. Conclusion: ¹¹¹In-DTPA-hEGF is a promising novel radiopharmaceutical for targeted Auger electron radiotherapy of advanced, hormone resistant breast cancer.

Key Words: breast cancer • epidermal growth factor • ¹¹¹In • Auger electrons • epidermal growth factor receptor

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