Non-protein thiols and cellular response to drugs and radiation

Abstract

Our results have enabled us to make a number of observations concerning the reactivity of nitrocompounds and non-nitrocompounds with glutathione (GSH) and cellular nonprotein thiols (NPSH), which may be as much as 90 % GSH. We have summarized our observations as follows with respect to the different types of reactions responsible for part or all of the cellular NPSH depletion by hypoxic cell radiosensitizing drugs. (A) Some nitrocompounds, such as 4-nitroimidazoles containing a 5-sulfonamide group, react spontaneously with GSH; (B) A number of hypoxic cell radiosensitizing drugs such as chlorodinitrobenzene (CDNB), dimethylfumarate (DMF) and diethylmaleate (DEM) are substrates for the enzyme glutathione-S-transferase and form covalent bonds with GSH; (C) NPSH may be oxidized by diamide; (D) form covalent bonds with N-ethylmaleimide; (E) or be converted by thiol-reactive drug intermediates formed under anaerobic conditions. The latter reaction occurs with misonidazole, Ro-05–9963, SR 2508 and SR 255:5; its mechanism is still unknown. It is obvious from the above that there are a variety of means by which radiosensitiizing drugs can alter cellular metabolism as reflected by changes in the NPSH. It remains to be determined whether a relationship exists between altered NPSH, metabolism and the radiosensitizing capacity of nitrocompounds when used alone or in combination with other drugs. Our studies strongly suggest that potential new sensitizers be routinely examined for their capacity to react spontaneously with GSH or to remove cellular NPSH under aerobic as well as anaerobic conditions. This is especially true for radiosensitizing drugs showing anomalous behavior, i.e., better sensitization than predicted by their one-electron reduction potentials. Such screening would pay dividends insofar as drugs that are too reactive could be excluded from further in vivo study.