Targeted Radiotherapy: Microgray Doses and the Bystander Effectby Robert J. Mairs, Natasha E. Fullerton, Michael R. Zalutsky, Marie Boyd

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TARGETED RADIOTHERAPY: MICROGRAY DOSES AND THE BYSTANDER

EFFECT

Robert J. Mairs, Natasha E. Fullerton*  Targeted Therapy Group, Division of

Cancer Science and Molecular Pathology, Glasgow University, Cancer Research UK

Beatson Laboratories, Glasgow, UK

Michael R. Zalutsky  Department of Radiology, Duke University Medical

Centre, Durham, North Carolina, USA

Marie Boyd  Targeted Therapy Group, Division of Cancer Science and

Molecular Pathology, Glasgow University, Cancer Research UK Beatson

Laboratories, Glasgow, UK  Indirect effects may contribute to the efficacy of radiotherapy by sterilizing malignant cells that are not directly irradiated. However, little is known of the influence of indirect effects in targeted radionuclide treatment. We compared γ-radiation-induced bystander effects with those resulting from exposure to three radiohaloanalogues of meta-iodobenzylguanidine (MIBG): [131I]MIBG (low linear energy transfer (LET) β-emitter), [123I]MIBG (high LET Auger electron emitter), and meta-[211At]astatobenzylguanidine ([211At]MABG) (high LET α-emitter). Cells exposed to media from γ-irradiated cells exhibited a dose-dependent reduction in survival fraction at low dosage and a plateau in cell kill at > 2 Gy. Cells treated with media from [131I]MIBG demonstrated a dose-response relationship with respect to clonogenic cell death and no annihilation of this effect at high radiopharmaceutical dosage. In contrast, cells receiving media from cultures treated with [211At]MABG or [123I]MIBG 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 neighboring untargeted cells at low and high dose respectively. We conclude that radiopharmaceutical-induced bystander effects may depend on LET and be distinct from those elicited by conventional radiotherapy.

Keywords: Radiopharmaceutical-induced bystander effect

I. INTRODUCTION

When cells are exposed to ionizing radiation, they release poisons which result in death, mutation, chromosomal aberrations or long term genomic instability in neighboring, unirradiated cells (Mothersill and

Dose-Response, 5:204–213, 2007

Formerly Nonlinearity in Biology, Toxicology, and Medicine

Copyright © 2007 University of Massachusetts

ISSN: 1559-3258

DOI: 10.2203/dose-response.07-002.Mairs

Address correspondence to Robert J. Mairs, Targeted Therapy Group, Division of Cancer

Science and Molecular Pathology, Glasgow University, Cancer Research UK Beatson

Laboratories, Glasgow, G61 1BD UK; tel: +44 (0)141 330 4126; FAX: +44 (0)141 330 4127; e-mail: r.mairs@beatson.gla.ac.uk *Current address: Clinical Trials Department, Crusade Laboratories Ltd, Department of

Neurology, Southern General Hospital, Glasgow G51 4TF; tel: +44 (0)141 4451716; FAX: +44 (0)141 -4451715; e-mail: nfullerton@crusadelabs.co.uk

Radiopharmaceutical-induced bystander effect 205

Seymour 2001; Mothersill and Seymour 2004; Lyng et al 2002; Lorimore and Wright 2003; Morgan 2003; Little 2003). These consequences, known as radiation induced biological bystander effects (RIBBE), may contribute significantly to the effectiveness of radiotherapy by sterilising malignant cells which have not been directly irradiated.

In recent years, targeted radionuclide treatment of cancer has developed as a novel and advantageous approach to radiation therapy. The basic idea is to deliver higher doses of radiation to tumor than to normal cells by means of radionuclides chemically conjugated to tumor-seeking targeting agents such as meta-iodobenzylguanidine (MIBG). By virtue of its structural similarity to noradrenaline (Wieland et al 1980), MIBG is selectively accumulated via the noradrenaline transporter (NAT) (Jacques et al 1984) which is expressed on the surfaces of cells comprising tumors of neural crest origin, for example neuroblastoma and phaeochromocytoma. Radiolabelled forms of this drug are used for scintigraphic assessment and treatment of such tumors (Simpson and Gaze 1998; Klingebiel et al 1998; Hoefnagel 1999; Rose et al 2003). NAT expression is predictive for MIBG uptake capacity (Mairs et al 1994) and quantification of NAT mRNA could be used for the selection of patients for

MIBG therapy (Carlin et al 2003).

It may be possible to compensate for heterogeneity of uptake of radiopharmaceutical, resulting in underdosing of some tumor regions, by the selection of radionuclides whose decay particles have long path lengths, enabling cross-fire irradiation of surrounding untargeted cells. However, even with long range radionuclides, because their emissions are of low

LET, sub-populations of tumor cells will receive less than a sterilizing dose.

Then again, emerging evidence suggests that radioactive emission from targeted cells is not the only bystander effect operating in radionuclide treatment of cancer. It is becoming clear that radiation-induced biological bystander effects (RIBBE) deriving from the cellular processing of the physical radiation insult, which need not interact directly with DNA, may play an important part in the overall efficacy of radionuclide targeting.

RIBBE predominate at low radiation dose and low dose rate (Carlsson et al 2003) both of which are features of targeted radionuclide treatment of cancer. Therefore bystander effects induced by radiopharmaceuticals may play a disproportionate role in the efficacy, and understanding their nature should enable the refinement of radiotherapy. Most investigations of bystander effects have involved external beam γ-irradiators and microbeams. However, in recent years important studies have been conducted of RIBBE after intracellular concentration of radiolabelled drugs.

Bishayee et al (2001) prepared clusters composed of unlabelled and [3H]thymidine-labelled cells. The resulting death of unlabelled cells was considered to be a consequence of transfer of toxic factors from cells which had incorporated [3H]thymidine in their DNA rather than crossR. J. Mairs et al. 206 fire irradiation because 3H beta-decay particles have a path length which is too short to allow direct bombarment of regions adjacent to targeted cells. Survival of unlabelled cells was increased by treatment with dimethyl sulphoxide and lindane, suggesting the involvement of free radicals and gap junctional communication respectively. In a similar study,