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Radiation-Induced Biologic Bystander Effect Elicited In Vitro by Targeted Radiopharmaceuticals Labeled with -, ß-, and Auger Electron–Emitting Radionuclides

¹ Targeted Therapy Group, Division of Cancer Science and Molecular Pathology, Glasgow University, Cancer Research United Kingdom Beatson Laboratories, Glasgow, United Kingdom; ² Department of Radiology, Duke University Medical Center, Durham, North Carolina; ³ Glasgow University School for Cancer Studies, Cancer Research United Kingdom Beatson Laboratories, Glasgow, United Kingdom; and ⁴ Department of Child Health, Yorkhill Hospital, Glasgow, United Kingdom

Correspondence: For correspondence or reprints contact: Robert J. Mairs, DSc, Targeted Therapy Group, Centre for Oncology and Applied Pharmacology, Glasgow University, Cancer Research United Kingdom Beatson Laboratories, Glasgow G61 1BD, Scotland, U.K. E-mail: r.mairs{at}beatson.gla.ac.uk

Recent studies have shown that indirect effects of ionizing radiation may contribute significantly to the effectiveness of radiotherapy by sterilizing malignant cells that are not directly hit by the radiation. However, there have been few investigations of the importance of indirect effects in targeted radionuclide treatment. Our purpose was to compare the induction of bystander effects by external beam -radiation with those resultant from exposure to 3 radiohaloanalogs of metaiodobenzylguanidine (MIBG): ¹³¹I-MIBG (low-linear-energy-transfer [LET] ß-emitter), ¹²³I-MIBG (potentially high-LET Auger electron emitter), and meta-²¹¹At-astatobenzylguanidine (²¹¹At-MABG) (high-LET -emitter). Methods: Two human tumor cell lines—UVW (glioma) and EJ138 (transitional cell carcinoma of bladder)—were transfected with the noradrenaline transporter (NAT) gene to enable active uptake of MIBG. Medium from cells that accumulated the radiopharmaceuticals or were treated with external beam radiation was transferred to cells that had not been exposed to radioactivity, and clonogenic survival was determined in donor and recipient cultures. Results: Over the dose range 0–9 Gy of external beam radiation of donor cells, 2 Gy caused 30%–40% clonogenic cell kill in recipient cultures. This potency was maintained but not increased by higher dosage. In contrast, no corresponding saturation of bystander cell kill was observed after treatment with a range of activity concentrations of ¹³¹I-MIBG, which resulted in up to 97% death of donor cells. Cellular uptake of ¹²³I-MIBG and ²¹¹At-MABG induced increasing recipient cell kill up to levels that resulted in direct kill of 35%–70% of clonogens. Thereafter, the administration of higher activity concentrations of these high-LET emitters was inversely related to the kill of recipient cells. Over the range of activity concentrations examined, neither direct nor indirect kill was observed in cultures of cells not expressing the NAT and, thus, incapable of active uptake of MIBG. Conclusion: Potent toxins are generated specifically by cells that concentrate radiohalogenated MIBG. These may be LET dependent and distinct from those elicited by conventional radiotherapy.

Key Words: bystander effect • targeted radiotherapy • MIBG • radiopharmaceuticals

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