Modelling the enhancement of fractionated radiotherapy by gene transfer to sensitize tumour cells to radiation.
OBJECTIVE
Several strategies now exist for the use of gene transfer methodologies to sensitize tumour cells to radiation. These include the transfection of genes synthesizing cytokines, p53 gene replacement and methods based on the use of HSV-tk and gancyclovir. Very recently, the sequencing of radioprotector or repair genes, such as ATM, Ku80 and XRCC2, has made it possible to consider the design of gene transfer strategies resulting in protector gene knock-out. Selectivity of transfected gene expression might be achieved by use of tissue-specific promoters or by the trophism of viral vectors. The purpose of this study was to evaluate the probable efficacy of such strategies.


METHODS
We have modelled gene transfer-mediated radiosensitization of tumour cells during radiotherapy, focusing on anti-protector gene strategies, to explore the role of transfection frequency, sensitizing efficacy, transfection stability, untransfectable subpopulations, the timing of gene therapy and the treatment schedule structure.


RESULTS
We predict a substantial therapeutic benefit of gene transfer treatment (with at least weekly transfection) which modifies cellular radiosensitivity by a factor of 1.5 or more, despite modest efficiency of cellular transfection (e.g. 50%), transient retention of the transfected gene (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 implies 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 before clinical studies begin.
Department of Radiation Oncology, University of Glasgow, CRC Beatson Laboratories, UK.
T E
TE
Wheldon
R J
RJ
Mairs
R P
RP
Rampling
A
A
Barrett
D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D008962:Models, Theoretical; D009369:Neoplasms / Q000532:radiotherapy / Q000628:therapy*; D011838:Radiation-Sensitizing Agents; D011878:Radiotherapy / Q000379:methods*; D014162:Transfection
D011838:Radiation-Sensitizing Agents