The oxygen fixation hypothesis: a reevaluation

The oxygen fixation hypothesis (OFH), developed in the late 1950s, is widely regarded as the most satisfactory explanation of why oxygen is a radiation sensitizer. Central to this hypothesis is the explicit belief that DNA lesions (originally called "target lesions") that are produced by x-rays with the chemical participation of oxygen pose a special threat to cell survival because these lesions cannot be chemically restored to an undamaged state. According to this hypothesis, oxygen sensitizes because these "nonrestorable" lesions ultimately increase the amount of stable DNA damage--and thus the extent of lethality--from a give dose. Using three wild-type strains of Escherichia coli, the maximum insignificant dose (MID, the maximum dose that does not reduce the survival from 1.0) was measured. The MID values are clearly strain dependent. This result is inconsistent with the OFH since the production of "nonrestorable" DNA-O2 radicals should not be affected by the genetic identity of the irradiated cell. By focusing solely on rapid events in radiation chemistry, this hypothesis does not address any role that might be played by enzymatic DNA repair. In fact, if enzymatic repair is successful, then the issue of chemical restorability is not relevant to lethality or to radiation sensitization by oxygen. Overall, these results emphasize that the OFH does not satisfactorily explain why oxygen is a sensitizer. Although the basic chemistry proposed in the OFH is undoubtedly correct, the hypothesis does not explain why the reaction products pose a special risk to the cell. Attention must also be given to enzymatic DNA repair and to its success.