GLUTATHIONE DEPLETION SELECTIVELY IMPOSED ON MU-GLUTATHIONE S-TRANSFERASE OVERPRODUCING CELLS INCREASES NITROGEN-MUSTARD TOXICITY

Glutathione (GSH) contributes to the detoxification of anticancer drug s through the operation of specific glutathione S-transferases (GST) a nd innate, or acquired, overexpression of this enzyme family has been frequently observed in tumor cell lines. In the GMA32 line of Chinese hamster fibroblasts, we showed that GSH starvation produced by exposin g cells to buthionine sulfoximine (BSO) increased the toxicity of chlo rambucil and melphalan, but not that of N,N'-bis (2-chloroethyl)-N-nit rosourea (BCNU), cisplatine and doxorubicin. This indicates that effic ient mechanisms of detoxification using GSH operate for chlorambucil a nd melphalan, but not for the other drugs in these cells. We then show ed that GSH depletion could be selectively and transiently induced in the mu GST overexpressing cen line derived from GMA32, HC474, by expos ing cells to substrates specific to the overexpressed isozyme. Exposin g cells to such a substrate, trans-stilbene oxide, does not alter the sensibility of GMA32 cells to melphalan and chlorambucil, but increase s that of HC474 cells to these drugs, to an extent comparable to that obtained with BSO. This observation highlights the possibility of expl oiting GST overexpression, a frequent feature of tumor cells, to selec tively sensitize these undesirable cells to anticancer drugs.