Factors affecting sensitivity to EO9 in rodent and human tumour cells in vitro: DT-diaphorase activity and hypoxia

Eur J Cancer. 1994;30A(7):1013-9. doi: 10.1016/0959-8049(94)90134-1.

Abstract

Twenty-three human tumour cell lines (lung, breast, and colon) and eight rodent cell lines were evaluated for their sensitivity to the quinone-based anticancer drug EO9 [3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H indole-4,7-dione)prop-beta-en-alpha-o1]. Sensitivity was compared with the intracellular levels of DT-diaphorase, and cell lines showing highest enzyme activity tended to be the most sensitive to EO9. The role of DT-diaphorase in determining drug sensitivity was confirmed by using the enzyme inhibitor dicoumarol, which protects cells containing high levels of DT-diaphorase from the cytotoxic action of EO9. Hypoxia increased the cytotoxicity of cells containing low but not high levels of DT-diaphorase, implying that both 1- and 2-electron reductive activation processes can be important for expression of EO9 toxicity. It is concluded that EO9 is a potentially useful agent in the enzyme directed approach to the use of bioreductive drugs in cancer therapy.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Aziridines / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / enzymology
  • Cricetinae
  • Humans
  • Hypoxia
  • Indolequinones*
  • Indoles / therapeutic use*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Mammary Neoplasms, Animal / drug therapy
  • Mammary Neoplasms, Animal / enzymology
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • Oxygen / metabolism
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Aziridines
  • Indolequinones
  • Indoles
  • NAD(P)H Dehydrogenase (Quinone)
  • apaziquone
  • Oxygen