Effects of oxygen radical scavengers on the inactivation of SS phi X174 DNA by the semi-quinone free radical of the antitumor agent etoposide.
We have studied the effects of oxygen radical scavengers on the inactivation of ss phi X174 DNA by the semi-quinone free radical of the antitumor agent etoposide (VP 16-213), which was generated from the ortho-quinone of etoposide at pH greater than or equal to 7.4. A semi-quinone free radical of etoposide is thought to play a role in the inactivation of ss phi X174 DNA by its precursors 3',4'-ortho-quinone and 3',4'-ortho-dihydroxy-derivative. The possible role of oxygen radicals formed secondary to semi-quinone formation in the inactivation of DNA by the semi-quinone free radical was investigated using the hydroxyl radical scavengers t-butanol and DMSO, the spin trap DMPO, the enzymes catalase and superoxide dismutase, the iron chelator EDTA and potassium superoxide. Hydroxyl radicals seem not important in the process of inactivation of DNA by the semi-quinone free radical, since t-butanol, DMSO, catalase and EDTA had no inhibitory effect on DNA inactivation. The spin trapping agent DMPO strongly inhibited DNA inactivation and semi-quinone formation from the ortho-quinone of etoposide at pH greater than or equal to 7.4 with the concomitant formation of a DMPO-OH adduct. This adduct probably did not arise from OH. trapping but from trapping of O2-(.). DMSO increased both the semi-quinone formation from and the DNA inactivation by the ortho-quinone of etoposide at pH greater than or equal to 7.4. Potassium superoxide also stimulated phi X174 DNA inactivation by the ortho-quinone at pH less than or equal to 7. From the present study, it is also concluded that superoxide anion radicals probably play an important role in the formation of the semi-quinone free radical from the ortho-quinone of etoposide, thus indirectly influencing DNA inactivation.
Van Maanen
J M
JM
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Mans
D R
DR
Lafleur
M V
MV
Van Schaik
M A
MA
de Vries
J
J
Vermeulen
N P
NP
Retèl
J
J
Lankelma
J
J
D010584:Bacteriophage phi X 174 / Q000235:genetics*; D016227:Benzoquinones; D000440:Butanols / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004277:DNA, Single-Stranded / Q000187:drug effects*; D004279:DNA, Viral / Q000187:drug effects*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D005047:Etoposide / Q000494:pharmacology*; D005609:Free Radicals; D006863:Hydrogen-Ion Concentration; D011809:Quinones / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism / Q000494:pharmacology; D020002:tert-Butyl Alcohol
D016227:Benzoquinones; D000440:Butanols; D003497:Cyclic N-Oxides; D004277:DNA, Single-Stranded; D004279:DNA, Viral; D005609:Free Radicals; D011809:Quinones; D013481:Superoxides; C039316:potassium superoxide; C025232:semiquinone radicals; D005047:Etoposide; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D004492:Edetic Acid; D002374:Catalase; D013482:Superoxide Dismutase; D020002:tert-Butyl Alcohol; D004121:Dimethyl Sulfoxide