Tyrosinase-induced free radical formation from VP-16,213: relationship to cytotoxicity.
Tyrosinase-dependent activation of hydroxybenzenes forms reactive compounds, including catechols and o-quinones, and some of which show antitumor activity against pigmented melanomas. Since VP-16 is a phenoxy-containing antitumor drug, forms free radicals and reactive o-quinones during peroxidative activation, we evaluated the cytotoxicity of VP-16 to both tyrosinase-containing and non-tyrosinase-containing tumor cells. Our results show that VP-16 is significantly more cytotoxic to B-16/F-10 melanoma cells than human MCF-7 breast tumor cells. Phenylthiocarbamide, an inhibitor of tyrosinase activity, selectively decreased VP-16 toxicity only in melanoma cells. Furthermore, VP-16 was readily activated to its phenoxy free radical intermediate by purified tyrosinase, indicating tyrosinase may play a role in VP-16 toxicity in pigmented melanomas.
Usui
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Biochemical Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Sinha
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BK
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D004578:Electron Spin Resonance Spectroscopy; D005047:Etoposide / Q000378:metabolism / Q000627:therapeutic use*; D005609:Free Radicals; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000201:enzymology*; D051379:Mice; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010670:Phenylthiourea / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D005609:Free Radicals; D010670:Phenylthiourea; D005047:Etoposide; D014442:Monophenol Monooxygenase