Mice constitutively lacking alleles of the p53 tumour suppressor gene spontaneously develop lymphomas and sarcomas. We report here that a single dose of 4 Gy radiation dramatically decreases the latency for tumour development in p53 heterozygous mice. The pattern of genetic alterations at the remaining wild type allele in these tumours differs substantially from spontaneous tumours from similar mice indicating that p53 itself may have been a target for radiation-induced alterations. Lower dose irradiation (1 Gy) of preweanling p53 null mice also significantly decreases tumour latency, suggesting that there are additional genetic targets involved in radiation-induced malignancy. Thus p53-deficient mice provide a sensitive model system for studies of the consequences of radiation exposure.

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Meta-iodobenzylguanidine conjugated to 131 I-iodine is an methods: (1) survival of clonogens derived from monolayer effective agent for the targeted radiotherapy of tumors of culture; (2) survival of clonogens derived from disaggreneural crest origin which express the noradrenaline transgated multicellular spheroids; and (3) spheroid growth porter (NAT). The therapeutic application of 131 I MIBG is delay. 131 I MIBG was twice as toxic to cells in spheroids presently limited to the treatment of phaeochromocytoma, compared with those in monolayers, consistent with a neuroblastoma, carcinoid and medullary thyroid carcigreater effect of radiation cross-fire (radiological bystander noma. To determine the feasibility of MIBG targeting for a effect) from 131 I ␤-radiation in the three-dimensional tumor wider range of tumor types, we employed plasmidspheroids. The highest concentration of 131 I MIBG tested mediated transfer of the NAT gene into a human glioblas-(1 MBq/ml) was nontoxic to UVW control cells or spheroids toma cell line (UVW) which does not express the NAT transfected with the NAT gene in reverse orientation. gene. This resulted in a 15-fold increase in uptake of MIBG These findings are encouraging for the development of by the host cells. A dose-dependent toxicity of 131 I MIBG NAT gene transfer-mediated 131 I MIBG therapy. to the transfectants was demonstrated using three

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Auger-emitting radionuclides have potential for the therapy of cancer due to their high level of cytotoxicity and short-range biological effectiveness. Biological effects are critically dependent on the sub-cellular (and sub-nuclear) localization of Auger emitters. Mathematical modelling studies suggest that there are theoretical advantages in the use of radionuclides with short half-lives (such as 123I) in preference to those (such as 125I) with long half-lives. In addition, heterogeneity of radionuclide uptake is predicted to be a serious limitation on the ultimate therapeutic effect of targeted Auger therapy. Possible methods of targeting include the use of analogues of DNA precursors such as iodo-deoxyuridine and molecules which bind DNA such as steroid hormones or growth factors. A longer term possibility may be the use of molecules such as oligonucleotides which can discriminate at the level of DNA sequence. It seems likely that the optimal clinical role of targeted Auger therapy will be as one component of a multi-modality therapeutic strategy for the treatment of selected malignant diseases.

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Radiobiological modelling of the risk of radiation-induced tumours following high dose radiation implies a general form for the dose-response relationship. Generally, risk will rise with radiation dose at low doses, reach a maximum value and then decline with further increase in dose. The magnitude of risk and the dose at which this risk is maximum are strongly dependent on the kinetics of repopulation by surviving normal and mutant cells and on genetic factors likely to differ between tissues and between individuals. The most reliable way to reduce the risk of second tumours is to reduce radiation dose further at sites where the dose is already low. These sites are usually distant from the primary treatment volume. For illustrative purposes, we have compared the predicted relative risks of second tumours at "distant sites" for treatment plans giving similar dose distributions (dose volume histograms) at the primary site. We suggest that dose reduction to distant sites could be of significant benefit in reducing the risk of second tumours. Further improvement will require more detailed knowledge of the radiation sensitivities and mutagenicities, together with the repopulation kinetics of the various cell lineages within the treatment volume.

Summary Radiolabelled meta-iodobenzylguanidine (MIBG) is selectively taken up by tumours of neuroendocrine origin, where its cellular localization is believed to be cytoplasmic. The radiopharmaceutical [1311]MIBG is now widely used in the treatment of neuroblastoma, but other radioconjugates of benzylguanidine have been little studied. We have investigated the cytotoxic efficacy of beta, alpha and Auger electronemitting radioconjugates in treating neuroblastoma cells grown in monolayer or spheroid culture. Using a no-carrier-added synthesis route, we produced 1231-, 1251-, 1311-and 211At-labelled benzylguanidines and compared their in vitro toxicity to the neuroblastoma cell line SK-N-BE(2c) grown in monolayer and spheroid culture. The Auger electron-emitting conjugates ([1231]MIBG and [1251]MIBG) and the alpha-emitting conjugate ([211At]MABG) were highly toxic to monolayers and small spheroids, whereas the beta-emitting conjugate [1311]MIBG was relatively ineffective. The Auger emitters were more effective than expected if the cellular localization of MIBG is cytoplasmic. As dosimetrically predicted however, [211At]MABG was found to be extremely potent in terms of both concentration of radioactivity and number of atoms ml-' administered. In contrast, the Auger electron emitters were ineffective in the treatment of larger spheroids, while the beta emitter showed greater efficacy. These findings suggest that short-range emitters would be well suited to the treatment of circulating tumour cells or small clumps, whereas beta emitters would be superior in the treatment of subclinical metastases or macroscopic tumours. These experimental results provide support for a clinical strategy of combinations ('cocktails') of radioconjugates in targeted radiotherapy.Keywords: meta-iodobenzylguanidine; neuroblastoma; tageted radiotherapy; astatine Meta-iodobenzylguanidine (MIBG) is a structural analogue of the neuroadrenergic blocking drugs bretylium and guanethidine. It is selectively accumulated by an active mechanism in cells of neural crest origin. Radiolabelled MIBG allows the scintigraphic imaging of neural crest tumours (Weiland et al, 1980) and ['311]MIBG is used in the treatment of neuroblastoma and phaeochromocytoma (Hartmann et al, 1987;Mastrangelo, 1987;Schwabe et al, 1987;Voute et al, 1988). Clinical experience since 1984 has demonstrated its potential, with an objective response rate of 35% in patients with progressive heavily pretreated disease (Hoefnagel, 1994). Clinical studies are now evaluating the role of ['311]MIBG at an earlier stage in therapy, either as a first line treatment or in combination with other treatment modalities (DeKraker et al, 1995;Gaze et al, 1995;Mastrangelo et al, 1995).Although many patients show beneficial responses to ['311]MIBG treatment, a significant number subsequently relapse from previously undetected tumour sites (Sisson et al, 1989). This suggests that microtumours below the limit of clinical detectability have survived ['311]MIBG therapy. A possible explanation for the rela...