Cytosolic/microsomal redox pathway: a reductive retention mechanism of a PET-oncology tracer, Cu-pyruvaldehyde-bis(N-4-methylthiosemicarbazone) (Cu-PTSM)

Objective: To clarify the retention mechanism of a PET imaging agent Cu-pyr uvaldehyde-bis(N-4-methylthiosemicarbazone) (Cu-62-PTSM) in tumor cells, re ductive metabolism of non-radioactive Cu-PTSM in five cultured tumor cell l ines, a tumor specimen and non-tumor tissues in vitro was evaluated by elec tron spin resonance spectrometry (ESR). Results: In the brain, mitochondrial electron transport enzyme reduced Cu-P TSM specifically. On the other hand, Cu-PTSM was not reduced in tumor mitoc hondria. The mitochondrial electron transport enzyme in tumor cells was not damaged, but NADH was considered to be depleted. In compensation for that, the tumor cells acquired complementary reduction activity in the microsome /cytosol. The reduction was enzymatic and NADH-dependent, possibly similar to the activation mechanism of bioreductive anticancer drugs. Conclusion: Cu-PTSM and its derivatives are considered to be used as a mark er for microsome/cytosol redox ability in PET oncology, although the physio logical role of the redox enzyme system in tumor cells has not been clarifi ed. The change in electron (NADH) flow in tumor cells might be a mechanism supporting aerobic glycolysis in tumor cells.