Increased sensitivity of quinone resistant cells to mitomycin C.
L5178Y cells resistant to the model quinone antitumor agent, hydrolyzed benzoquinone mustard, were four-fold more sensitive to mitomycin C compared to parental cells. Mitomycin C also produced increased DNA-DNA crosslinking in these cells compared to parental L5178Y cells, but did not induce DNA double strand breaks in either cell line. The resistant cells have a 24-fold increased level of DT-diaphorase activity, an enzyme that produces two electron reduction of quinone groups. Dicoumarol, an inhibitor of DT-diaphorase, significantly inhibited crosslinking and cytotoxicity by mitomycin C in the quinone resistant cells. These findings suggest that DNA-DNA cross-linking may be a major contributor to mitomycin C cytotoxic activity in L5178Y cells, and that the hydroquinone of mitomycin C may play a major role in the crosslinking activity of this agent.
Begleiter
A
A
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
Robotham
E
E
Lacey
G
G
Leith
M K
MK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016227:Benzoquinones; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D001728:Dicumarol / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D007940:Leukemia L5178 / Q000235:genetics / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism*; D051379:Mice; D016685:Mitomycin; D008937:Mitomycins / Q000494:pharmacology*; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D016227:Benzoquinones; D008937:Mitomycins; D011809:Quinones; C040043:2-(bis(2-hydroxyethyl)amino)-1,4-benzoquinone; D016685:Mitomycin; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases