THE BIOLOGY OF RADIORESISTANCE - SIMILARITIES, DIFFERENCES AND INTERACTIONS WITH DRUG-RESISTANCE

Cells and tissues have developed a variety of ways of responding to a hostile environment, be it from drugs (toxins) or radiation (summarize d 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 b ased resistance). DNA repair has been evaluated predominantly by the s tudy of repair-deficient mutants. The function of the repair genes the y lack is not fully understood, but some of their important interactio ns are now characterized. For example, the interaction of transcriptio n 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 tr anscription: 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 thi s 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 ce ll cycle arrest in response to damage may determine sensitivity to tha t 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 sequences in vivo and the lack of a sa tisfactory substrate for in vitro studies. Changes in cellular metabol ism as a result of ionizing radiation can impart radiation resistance, which is usually transient in vitro, but may be more significant in v ivo for tissues or tumors. The mechanisms by which damage is sensed by cells is unknown. The detection of free radicals is thought likely, b ut distortion to DNA structure or strand breakage and a direct effect on membranes are other possibilities for which there is evidence. Chan ges in extracellular ATP occur in response to damage, and this could b e a direct membrane effect. External purinergic receptors can then be involved in signal transduction pathways resulting in altered levels o f thiol protection or triggering apoptosis. Changes in the functional level of proteins as a consequence of ionizing radiation include trans cription factors, for example c-jun and c-fos; cell cycle arrest prote ins 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 medi ated by cell contact, such as gap junctions, which may help resistance to radiation in non-cycling cells. Paracrine response mechanisms, suc h as the release of angiogenic factors via membrane transport channels may account for tissue and tumor radiation resistance. Endocrine resp onse mechanisms may also contribute to tissue or tumor resistance.