Cytotoxic mechanisms of anti-tumour quinones in parental and resistant lymphoblasts.
The group I aziridinylquinone anti-cancer agents mitomycin C, diaziquone or trenimon were much more cytotoxic to DT-diaphorase-enriched L5178Y/HBM10 lymphoblasts than parental L5178Y cells and caused little oxygen activation. Furthermore, inactivation of cellular DT-diaphorase prevented cytotoxicity whereas catalase did not affect cytotoxicity. This suggests that DT-diaphorase activated these agents and the hydroquinone formed mediated DNA alkylation, crosslinking and cytotoxicity. The group II quinone agents phenanthrenequinone, 2-amino-1, 4-naphthoquinoneimine or naphthazarin were also more cytotoxic to L5178Y/HBM10 cells than parental cells and caused considerable oxygen activation. Inactivation of DT-diaphorase, however, prevented both oxygen activation and cytotoxicity. Furthermore added catalase decreased cytotoxicity, whereas 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 and 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, inactivation of DT-diaphorase enhanced cytotoxicity and prevented oxygen activation than group II agents. Oxygen activation was therefore also attributed to hydroquinone autoxidation. However catalase did not affect cytotoxicity towards parental cells. This suggests that DT-diaphorase detoxified group III quinones and that cytotoxicity may involve DNA oxidative damage by the semiquinone radicals.
Halinska
A
A
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Belej
T
T
O'Brien
P J
PJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002374:Catalase / Q000494:pharmacology; D004249:DNA Damage; D001728:Dicumarol / Q000494:pharmacology; D004351:Drug Resistance; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D011809:Quinones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011809:Quinones; D016685:Mitomycin; D001728:Dicumarol; D002374:Catalase; D016660:NAD(P)H Dehydrogenase (Quinone)