CYTOTOXIC MECHANISMS OF ANTITUMOR QUINONES IN PARENTAL AND RESISTANT LYMPHOBLASTS

The group I aziridinylquinone anti-cancer agents mitomycin C, diaziquo ne or trenimon were much more cytotoxic to DT-diaphorase-enriched L517 8Y/HBM10 lymphoblasts than parental L5178Y cells and caused little oxy gen activation. Furthermore, inactivation of cellular DT-diaphorase pr evented cytotoxicity whereas catalase did not affect cytotoxicity. Thi s suggests that DT-diaphorase activated these agents and the hydroquin one formed mediated DNA alkylation, crosslinking and cytotoxicity. The group LI quinone agents phenanthrenequinone, 2-amino-1,4-naphthoquino neimine or naphthazarin were also more cytotoxic to L5178Y/HBM10 cells than parental cells and caused considerable oxygen activation. Inacti vation of DT-diaphorase, however, prevented both oxygen activation and cytotoxicity. Furthermore added catalase decreased cytotoxicity, wher eas catalase inactivation enhanced cytotoxicity. This suggests that DT -diaphorase activated these agents and the hydroquinone formed caused extensive oxygen activation sufficient to cause DNA oxidative damage a nd cytotoxicity. The group III quinone agents menadione, 2,3-dimethoxy -1,4-naphthoquinone and 2,6-dimethoxy-benzoquinone, on the other hand, were more cytotoxic to the parental cells than L5178Y/HBM10 cells and caused less oxygen activation than group II agents. Furthermore, inac tivation of DT-diaphorase enhanced cytotoxicity and prevented oxygen a ctivation than group II agents. Oxygen activation was therefore also a ttributed to hydroquinone autoxidation. However catalase did not affec t cytotoxicity towards parental cells. This suggests that DT-diaphoras e detoxified group III quinones and that cytotoxicity may involve DNA oxidative damage by the semiquinone radicals.