MODELING THE ENHANCEMENT OF FRACTIONATED RADIOTHERAPY BY GENE-TRANSFER TO SENSITIZE TUMOR-CELLS TO RADIATION

Background and purpose: Several strategies now exist for the use of ge ne transfer methodologies to sensitize tumour cells to radiation. Thes e include the transfection of genes synthesizing cytokines, p53 gene r eplacement and methods based on the use of HSV-tk and gangcyclovir. Ve ry recently, the sequencing of radioprotector or repair genes, such as ATM, Ku80 and XRCC2, has made it possible to consider the design of g ene transfer strategies resulting in protector gene knock-out. Selecti vity of transfected gene expression might be achieved by use of tissue -specific promoters or by the trophism of viral vectors. The purpose o f this study was to evaluate the probable efficacy of such strategies. Methods: We have modelled gene transfer-mediated radiosensitization o f tumour cells during radiotherapy, focusing on anti-protector gene st rategies, to explore the role of transfection frequency, sensitizing e fficacy, transfection stability, untransfectable subpopulations, the t iming of gene therapy and the treatment schedule structure. Results: W e predict a substantial therapeutic benefit of gene transfer treatment (with at least weekly transfection) which modifies cellular radiosens itivity by a factor of 1.5 or more, despite modest efficiency of cellu lar transfection (e.g. 50%), transient retention of the transfected ge ne (e.g. 2-day half-life) and the existence of a small minority (e.g. 1%) of untransfectable cells. Conclusions: The analysis shows repeated administration of gene transfer treatment to be obligatory and implie s that the existence of untransfectable minority subpopulations (i.e. cells inaccessible to the vector) will be the major limiting factor in therapy. Experimental work is needed to confirm these predictions bef ore clinical studies begin. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.