Molecular mechanisms of SR 4233-induced hepatocyte toxicity under aerobic versus hypoxic conditions

Abstract

Summary SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide) is the lead compound of the benzotriazene-di-N oxides which are selectively toxic to tumour cells under hypoxic conditions. However much higher concentrations given to rats caused bone marrow toxicity and necrosis of the low oxygen Zone 3 part of the liver. In the following effects of SR 4233 on hepatocytes under hypoxic vs aerobic conditions have been compared.(

Zinc Finger Nuclease Knock-out of NADPH:Cytochrome P450 Oxidoreductase (POR) in Human Tumor Cell Lines Demonstrates That Hypoxia-activated Prodrugs Differ in POR Dependence

“…POR expression also strongly sensitized the cells to the N-oxides under oxic conditions (Fig. 10A), consistent with their known propensity for one-electron redox cycling (64,65), which is likely responsible for the increase in cytotoxicity. POR expression generally had less effect on sensitivity of the nitro compounds in oxic cultures, with the exception of the 5-nitroquinoline SN24349 (previously shown to undergo facile redox cycling (66)) and the structurally related 1-nitroacridine nitracrine.…”

Tirapazamine-induced DNA damage measured using the comet assay correlates with cytotoxicity towards hypoxic tumour cells in vitro

“…Consistent with this is the much lower sensitivity of the hypoxic cytotoxicity of tirapazamine to inhibition by oxygen than that reported for many other bioreductive drugs (Marshall and Rauth, 1988; (Marshall and Rauth, 1986) and ascorbate has also been reported to reduce tirapazamine under both aerobic and hypoxic conditions (Silva and O'Brien, 1993 cell cultures (typically 105-106 cells ml-') as the rate of cellular metabolism will be greatly enhanced at the much higher cell densities in vivo (10'-109 cells ml-').…”

Does reductive metabolism predict response to tirapazamine (SR 4233) in human non-small-cell lung cancer cell lines?

“…This was unequivocally substantiated in subsequent stable expression studies with human P450R cDNA (Patterson et al, 1997). In agreement, numerous metabolism studies have implicated P450R in the reduction of TPZ to SR 4317 (Cahill and White, 1990;Walton and Workman, 1990;Riley and Workman, 1992;Walton et al, 1992;Riley et al, 1993;Silva and O'Brien, 1993). It has been suggested that fundamental differences might exist between the enzymology of human breast and lung cancer cell lines in vitro (Simm et al, 1996;Brown and Wang, 1998).…”

“…EPR spectroscopic studies utilizing rat liver microsomes identified P450R as the major hepatic microsomal enzyme responsible for the reductive activation of TPZ to the one-electron nitroxide radical intermediate (Lloyd et al, 1991), which is believed to be cytotoxic in its protonated form (Costa et al, 1989;Wang et al, 1992;Brown, 1993). While the role of cytochrome P450 in the one-electron activation of TPZ is unclear , P450R has been directly implicated in a number of studies (Silva and O'Brien, 1993;Patterson et al, 1995Patterson et al, , 1997. Further, the rate of metabolism has been linked to cytotoxicity under hypoxic conditions in some but not all studies (Biedermann et al, 1991).…”