The role of DT-diaphorase in determining the sensitivity of human tumor cells to tirapazamine (SR 4233).
OBJECTIVE
To determine the dependency of the aerobic and hypoxic toxicity of tirapazamine on the intracellular activity of DT-diaphorase.


METHODS
A panel of 18 human cell lines comprising predominantly small cell and nonsmall cell lung cancer and breast cancer lines were used. The activity of DT-diaphorase was determined in cytosolic preparations from cell lysates. The toxicity of tirapazamine was determined using the MTT assay after either 96 or 3 h aerobic exposure or 3 h treatment in hypoxia.


RESULTS
The cell lines exhibited a 5000-fold range in DT-diaphorase activity. In toxicity experiments, values of IC50 range from 10.2-120 microM and from 155-1230 for 96 and 3 h aerobic exposures, respectively. In N2, IC50s ranged from 8-55 microM. None of the toxicity values correlate with activity of DT-diaphorase, neither did the ratio of aerobic:hypoxic toxicity (differential toxicity).


CONCLUSIONS
The expression of DT-diaphorase in human tumor cells does not affect the toxicity of tirapazamine.
Patterson
A V
AV
MRC Radiobiology Unit, Chilton, Didcot, Oxon, UK.
Robertson
N
N
Houlbrook
S
S
Stephens
M A
MA
Adams
G E
GE
Harris
A L
AL
Stratford
I J
IJ
Carmichael
J
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000502:physiology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D014227:Triazines; D000077704:Tirapazamine; D016660:NAD(P)H Dehydrogenase (Quinone); C022616:thiazolyl blue