Inducible repair and the two forms of tumour hypoxia - Time for a paradigmshift

Clinical experience shows that there is a therapeutic window between 60 and 70 Gy where many tumours are eradicated, but the function of the adjacent normal tissues is preserved. This implies much more cell kill in the: tumou r than is acceptable in the normal tissue. An SF2 of 0.5 or lower is needed to account for the eradication of all tumour cells. while an SF2 of 0.8 or higher is needed to explain why these doses are tolerated by normal tissue s. No such systematic difference is known between the intrinsic sensitivity of well-oxygenated normal and tumour cells. The presence of radioresistant hypoxic cells in rumours makes it even more difficult ro understand the cl inical success. However, there is experimental evidence that starved cells lose their repair competence as a result of the depletion of cellular energ y char gr. MRS studies have shown that low ATP levels are a characteristic feature of solid tumours in rodents and man. In this paper we incorporate t he concept of repair incompetence in starving, chronically hypoxic cells. T he increased sensitivity of such cells has been derived From an analysis of mammalian cell lines showing inducible repair. It is proportional to the S F2 and highest in resistant cells. Thr distinction between acutely hypoxic radioresistant cells and chronically hypoxic radiosensitive cells provides the key to the realistic modelling of successful radiotherapy. It also open s new conceptual approaches to radiotherapy. We conclude that it is essenti al to distinguish between these two kinds of hypoxic cells in predictive as says and models.