A possible combination of hypoxic cell sensitizer with an oxic protector: implications for radiotherapy

This paper discusses the results of experiments using γ-rays and a hypoxic sensitizer metronidazole (MET) and also a well-known protector, mercaptoethylamine (MEA), individually and in combination, on the survival of the yeast S. cerevisiae BZ 34. MET (5mM) gave a hypoxic enhancement ratio (ER) of 1·3. MEA (5mM, 10mM) gave a dose-modifying factor (DMF) of 1·9 and 2·3 respectively for euoxic cells. However, the DMFs for hypoxic cells were 1·0 and 1·1 for 5 and 10mM concentrations of MEA. A combination of 5mM MEA and 5mM MET gave a DMF of 2·0 for euoxic cells and the ER remained at 1·3 for hypoxic cells. The "effective" oxygen enhancement ratios were 2·3 and 1·7 for the control and the sensitizer respectively. In the combination this value was equal to or even slightly less than 1. All DMF, ER and OER values were derived from D(0) values of the survival curves. The values based on 10% survival are almost equal to those derived from D(0) values. All the survival curves gave the same extrapolation number, showing that the chemicals individually or in combination were truly dose-modifying.These results indicate that protectors such as MEA could be preferentially protecting euoxic cells, and that combining such "oxic protectors" with a hypoxic sensitizer could result in protecting euoxic cells while the sensitization of hypoxic cells was not much reduced. The implications of our results for radiotherapy are discussed. It appears that the use of nontoxic oxic protectors may be a useful adjuvant in overcoming the hypoxic-cell problem in radiotherapy.