Radiation quality-dependent bystander effects elicited by targeted radionuclides

Abstract

The efficacy of radiotherapy may be partly dependent on indirect effects, which can sterilise malignant cells that are not directly irradiated. However, little is known of the influence of these effects in targeted radionuclide treatment of cancer. We determined bystander responses generated by the uptake of radioiodinated iododeoxyuridine ([*I]IUdR) and radiohaloanalogues of meta-iodobenzylguanidine ([*I]MIBG) by noradrenaline transporter (NAT) gene-transfected tumour cells. NAT specifically accumulates MIBG. Multicellular spheroids that consisted of 5% of NAT-expressing cells, capable of the active uptake of radiopharmaceutical, were sterilised by treatment with 20 kBqmL(-1) of the alpha-emitter meta-[211At]astatobenzylguanidine ([211At]MABG). Similarly, in nude mice, retardation of the growth of tumour xenografts containing 5% NAT-positivity was observed after treatment with [131I]MIBG. To determine the effect of subcellular localisation of radiolabelled drugs, we compared the bystander effects resulting from the intracellular concentration of [131I]MIBG and [131I]IUdR (low linear energy transfer (LET) beta-emitters) as well as [123I]MIBG and [123I]IUdR (high LET Auger electron emitters). [*I]IUdR is incorporated in DNA whereas [*I]MIBG accumulates in extranuclear sites. Cells exposed to media from [131I]MIBG- or [131I]IUdR-treated cells demonstrated a dose-response relationship with respect to clonogenic cell death. In contrast, cells receiving media from cultures treated with [123I]MIBG or [123I]IUdR exhibited dose-dependent toxicity at low dose but elimination of cytotoxicity with increasing radiation dose (i.e. U-shaped survival curves). Therefore radionuclides emitting high LET radiation may elicit toxic or protective effects on neighbouring untargeted cells at low and high dose respectively. It is concluded that radiopharmaceutical-induced bystander effects may depend on LET of the decay particles but are independent of site of intracellular concentration of radionuclide.