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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