Carbamoylation, inhibition of glutathione reductase and chemopotentiation of nitrosoureas by misonidazole

Abstract

Experiments were designed to determine whether carbamoylation-related inhibition of glutathione reductase (GR) was involved in the previously reported correlation between nitrosourea carbamoylating activity (defined by the extent of binding to L-lysine) and the magnitude of Misonidazole (MISO) chemopotentiation. The extent to which 12 different nitrosoureas (NUs) inhibited GR activity in extracts of EMT-6/Ro cells was determined and compared to the magnitude of chemopotentiation realized when each was combined with MISO for the treatment of EMT6/Ro cells in vitro. No correlation was observed between glutathione reductase inhibition and the potentiation of nitrosourea cytotoxicity by MISO in vitro, suggesting that inhibition of GR was not involved in the mechanism of MISO chemopotentiation. Furthermore, when the original correlation was re-examined with the inclusion of additional chemopotentiation data for four hydroxylated analogs of CCNU, including two which possess little or no lysine-carbamoyladng activity but which were significantly enhanced by MISO, a correlation between carbamoylation and the magnitude of MISO chemopotentiation could not be established. From these studies we conclude that NU-carbamoylating activity is not the prime determinant of interaction between MISO and the NUs.