Tyrosinase-induced free radical formation from VP-16,213: relationship to cytotoxicity

Free Radic Res Commun. 1990;10(4-5):287-93. doi: 10.3109/10715769009149897.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology*
  • Electron Spin Resonance Spectroscopy
  • Etoposide / metabolism
  • Etoposide / therapeutic use*
  • Free Radicals
  • Humans
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / enzymology*
  • Mice
  • Monophenol Monooxygenase / antagonists & inhibitors
  • Monophenol Monooxygenase / metabolism*
  • Phenylthiourea / pharmacology
  • Tumor Cells, Cultured

Substances

  • Free Radicals
  • Phenylthiourea
  • Etoposide
  • Monophenol Monooxygenase