Enzymology of XXXX metabolic activation in @entity5 tissue: implications for enzyme-directed bioreductive drug development.

@entity1 @entity137 @entity5 @entity1138 @entity5878 @entity1139
@entity1138 ( @entity1139 ) is the prototype bioreductive DNA alkylating agent. To exploit its unique properties and maximize @entity1 responses, different therapeutic approaches have been investigated. Recently, the focus has concentrated on monitoring the levels of the proteins metabolizing the drug and relating these to activity in a regimen referred to as enzyme-directed bioreductive drug development. To be successful, it is important to understand the enzymology of metabolic activation not only in cell lines but also in @entity5 models. A general mechanism of action for @entity1139 has now emerged that is activated regardless of the source of reducing equivalents, comprising three competing pathways that give rise to unique reactive intermediates and different DNA adducts. Partitioning into the pathways is dictated by chemical considerations such as pH and drug concentration. @entity5878 stands out in this mechanism, since it is much less effective at metabolizing @entity1139 at neutral pH. At least five different enzymes can catalyse @entity1139 bioreduction in vitro, and as many activities may be present in solid @entity5 , including a series of novel mitochondrial reductases such as a cytochrome P450 reductase. Competition between reductases for @entity1139 appears to be based solely on protein levels rather than enzyme kinetics. Consequentially, @entity5878 can occupy a central role in @entity1139 metabolic activation since it is often highly overexpressed in @entity5 cells. Although a good correlation has been observed in cell lines between @entity5878 expression and aerobic @entity137 , this does not hold consistently in vivo for any single bioreductive enzyme, suggesting revision of the enzyme-directed hypothesis as originally formulated.
