Elsevier

The Lancet Oncology

Volume 2, Issue 6, June 2001, Pages 366-370
The Lancet Oncology

Review
Radiotherapy and cellular signalling

https://doi.org/10.1016/S1470-2045(00)00391-0Get rights and content

Summary

Developments in cellular and molecular biology in the past decade have increased our understanding of the processes by which cells respond to ionising radiation. Cells use complex protein signalling systems that recognise radiation damage to DNA and plasma membrane lipids. When damage is found, it leads to the activation of various intracellular pathways that modulate the activity of genes controlling cellular responses such as apoptosis, cell-cycle arrest, or repair. Numerous molecular targets may be activatedor inhibited in an attempt to upregulatre or downregulate the radiation response. In this review, we discuss some of the new compounds and techniques for manipulating the cell's response to radiation.

Section snippets

Cellular signalling pathways

Ionising radiation induces an ever-expanding list of genes. Immediate-early genes encode transcription factors such as JUN and EGR1 (early growth response) that can bind to specific DNA sequences and modulate the expression of other genes. Although the reason why these early response genes are induced is unclear, they may help cells survive after radiation. Interference with normal EGR1 and JUN function in human epithelial cells using dominant negative constructs reduces survival after

Ataxia telangiectasia

The rare genetic disorder ataxia telangiectasia (AT) has interested radiation oncologists because people with this condition have hypersensitivity to ionising radiation (Figure 3). It manifests clinically with oculocutaneous telangiectasia and cerebellar ataxia, and patients show a high frequency of malignancy. At the cellular level, the AT phenotype is typified by defective G1/S and G2/M cell-cycle checkpoints. These defects allow damaged DNA, which would normally be repaired during a period

P53 tumour supressor gene

The product of the P53 tumour suppressor gene is a 53 kDa nuclear phosphoprotein capable of inducing G1 cell-cycle growth arrest or apoptosis. It is stimulated by a variety of stress signals, including radiation, and eliminates damaged cells from the host. Mutations in the P53 gene are present in many human tumours and are associated with rapid tumour progression, and resistance to radiation therapy. Thus, it provides a potential target for intervention. Restoration of wild-type P53 should

RAS oncogene

The RAS oncogene has long been implicated in cellular radioresistance. Indeed, transfection of cells with activated RAS appears to increase radiation resistance.11 RAS proteins are processed in a series of reactions that require farnesylation by the enzyme farnesyl transferase. The advent of farnesyl transferase inhibitors, such as FTI-277, has opened up this cellular pathway to manipulation. FTI-277 sensitises cells with oncogenic mutations in their RAS genes to radiation, but has no effect on

Growth factors

Another area of potential therapeutic interest is the interplay between growth factors and radiation. The MAPK cascade can be activated by irradiation via a host of growth factors. It represents an adaptive cellular response to radiation that manifests itself as the accelerated cellular repopulation as seen with typical fractionated radiotherapy schemes. The epidermal growth factor receptor (EGFR) system represents a promising target since it is commonly overexpressed in many human tumours such

Radiation-induced gene therapy

Finally, a more speculative, but nevertheless interesting, area involves the use of radiation-induced gene therapy. Briefly, the principle involves the use of a radiation-inducible promoter attached to a gene, the product of which might be able to express a protein toxic to the cell, or to activate a prodrug. This gene would have to reach a large number of target cells via a vector and remain in the cells for a sufficient period of time to be activated by radiation. Furthermore, it must by

Conclusions

Radiation oncologists often question whether molecular biology can offer any real benefit to their field. But technological advances in molecular oncology over the past decade are now poised to deliver tangible gains in the clinical setting. Compounds targeting signal transduction pathways have shown activity in clinical studies and their combination with radiotherapy holds promise. Such molecular targets might be inhibited or activated to manipulate the radiation response, for example,

Search strategy and selection criteria

Data for this review were identified by searches of PubMed and MEDLINE from 1985 onwards. Only papers published in English were included. Search terms included: ‘radiation’, ‘cellular signalling’, ‘ataxia telangiectasia’, ‘RAS’, ‘P53’, and ‘growth factors’. In addition, the proceedings of the annual meetings of the American Association of Cancer Research and the American Society for Clinical Oncology from 1995–2000, were searched.

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