Iron-dependent hydroxyl radical formation and DNA damage from a novel metabolite of the clinically active antitumor drug VP-16.
The dihydroxy derivative of VP-16 (DHVP), a novel metabolite of the clinically active antitumor drug VP-16, was cytotoxic to human breast tumor cells. It was found that DHVP chelates iron and catalyzes the formation of hydroxyl radicals from hydrogen peroxide and reduced glutathione. Ethanol, polyethylene glycol and t-butanol inhibited the formation of DMPO-OH, suggesting that perferryl iron was not involved in OH' formation. Under conditions which formed hydroxyl radicals, DHVP also induced nicking of SV40 DNA, suggesting that the mechanism of tumor cell killing by DHVP may involve iron-dependent free radical formation.
Sinha
B K
BK
Clinical Oncology Program, National Cancer Institute, Bethesda, MD 20892.
Eliot
H M
HM
Kalayanaraman
B
B
D001943:Breast Neoplasms; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D004578:Electron Spin Resonance Spectroscopy; D005047:Etoposide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D005290:Ferric Compounds / Q000494:pharmacology*; D005609:Free Radicals; D005978:Glutathione; D006801:Humans; D006861:Hydrogen Peroxide; D006878:Hydroxides; D017665:Hydroxyl Radical
D005290:Ferric Compounds; D005609:Free Radicals; D006878:Hydroxides; C051505:3',4'-dihydroxyetoposide; D017665:Hydroxyl Radical; D005047:Etoposide; D006861:Hydrogen Peroxide; D005978:Glutathione