Electrochemical activation of chemotherapeutic prodrugs that mimic P450-catalyzed oxidation: proof-of-concept for a focal approach to chemical cancer treatment

The electrochemical oxidation of substrates cyclophosphamide and acetaminophen at Ti/RuO2 or (preferably) graphite anodes parallels P450-catalyzed oxidation in that both mechanisms involve transfer of an oxygen atom to the substrate. The aim of this work was to use this parallel to provide proof-of-concept for a localized approach to tumor chemotherapy using electrochemical oxidation to activate chemotherapeutic prodrugs ex situ. Cyclophosphamide and acetaminophen were electro-activated in batch and flow electrolytic cells and the products were tested against EMT6 mouse mammary adenocarcinoma cells. Cell viability was determined using a tetrazolium dye assay that monitored NADPH concentrations; microscopic examination showed consistent morphological differences between viable and nonviable cells. No cytotoxicity was observed in nonelectrolyzed control samples. The electrolyzed prodrugs demonstrated cytotoxicity up to the IC99 level at 5 mmol L-1 initial prodrug concentrations but not at 1 mmol L-1. The long-term objective of the work is to develop an ex situ electrochemical system for activating prodrugs to cause lethal toxicity to the cells of solid tumors, many of which lack sufficient P450s to bioactivate the toxicant themselves.