Factors affecting sensitivity to EO9 in rodent and human tumour cells in vitro: DT-diaphorase activity and hypoxia.
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.
Robertson
N
N
MRC Radiobiology Unit, Chilton, Didcot, U.K.
Haigh
A
A
Adams
G E
GE
Stratford
I J
IJ
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001388:Aziridines / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D006224:Cricetinae; D006801:Humans; D000860:Hypoxia; D045563:Indolequinones; D007211:Indoles / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D007211:Indoles; D016660:NAD(P)H Dehydrogenase (Quinone); C060817:apaziquone; D010100:Oxygen