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The biology of radioresistance: similarities, differences and interactions with drug resistance

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Abstract

Cells and tissues have developed a variety of ways of responding to a hostile environment, be it from drugs (toxins) or radiation (summarized in Fig. 1). Three categories of radiation damage limitation are: (i) DNA repair (ii) changes in cellular metabolism (iii) changes in cell interaction (cell contact or tissue-based resistance; whole organism based resistance).

DNA repair has been evaluated predominantly by the study of repair-deficient mutants. The function of the repair genes they lack is not fully understood, but some of their important interactions are now characterized. For example, the interaction of transcription factors with nucleotide excision repair is made clear by the genetic syndromes of xeroderma-pigmentosum groups B, D and G. These diseases demonstrate ultraviolet light sensitivity and general impairment of transcription: they are linked by impaired unwinding of the DNA required for both transcription and repair. The transfer of DNA into cells is sometimes accompanied by a change in sensitivity to radiation, and this is of special interest when this is the same genetic change seen in tumors. DNA repair has a close relationship with the cell cycle and cell cycle arrest in response to damage may determine sensitivity to that damage. DNA repair mechanisms in response to a variety of drugs and types of radiation can be difficult to study because of the inability to target the damage to defined sequencesin vivo and the lack of a statisfactory substrate forin vitro studies.

Changes in cellular metabolism as a result of ionizing radiation can impart radiation resistance, which is usually transientin vitro, but may be more significantin vivo for tissues or tumors. The mechanisms by which damage is sensed by cells is unknown. The detection of free radicals is thought likely, but distortion to DNA structure or strand breakage and a direct effect on membranes are other possibilities for which there is evidence. Changes in extracellular ATP occur in response to damage, and this could be a direct membrane effect. External purinergic receptors can then be involved in signal transduction pathways resulting in altered levels of thiol protection or triggering apoptosis. Changes in the functional level of proteins as a consequence of ionizing radiation include transcription factors, for example c-jun and c-fos; cell cycle arrest proteins such as GADD (growth arrest and DNA damage inducible proteins) and p53; growth factors such as FGF, PDGF; and other proteins leading to radioresistance. Mechanisms for intercellular resistance could be mediated by cell contact, such as gap junctions, which may help resistance to radiation in non-cycling cells. Paracrine response mechanisms, such as the release of angiogenic factors via membrane transport channels may account for tissue and tumor radiation resistance. Endocrine response mechanisms may also contribute to tissue or tumor resistance.

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    Simon N. Powell & Edward H. Abraham

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Powell, S.N., Abraham, E.H. The biology of radioresistance: similarities, differences and interactions with drug resistance. Cytotechnology 12, 325–345 (1993). https://doi.org/10.1007/BF00744671

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