Cu(II)-ATSM continues to be investigated, both in the laboratory and in the clinic, as a tumor hypoxia imaging agent. However, meaningful interpretation of these images requires a more complete understanding of the mechanism by which the tracer is trapped within the cell. Cu(II)-ATSM is a simple molecule and its biochemical interaction with cells is similarly simple, mainly based upon redox chemistry. Here we suggest that the trapping mechanism is biphasic. The first phase is a reduction/oxidation cycle involving thiols and molecular oxygen. This can be followed by interaction with proteins in the mitochondria leading to more permanent retention of the tracer. The uptake mechanism is complicated by this second step because of the changes in the cell resulting from hypoxia, such as an increase in nicotinamide adenine dinucleotide (NADH) redox state and differences in cellular biochemistry and cell proteomes. These changes may lead to differences in the extent of trapping and retention of the (64)Cu in different cell types. For example, copper uptake might be increased in cells with lower pH due to the lower stability of metal bis(thiosemicarbazones) under acidic conditions. Reaction rates with cellular reductants also vary with pH, which differs between cellular organelles. For Cu(II)-ATSM to reach its full potential, more complete characterization of the mechanism of cellular trapping in different cell types is required.
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