Continuous Wave Electron Paramagnetic Resonance Imaging

Division Of Basic Sciences - Nci

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Abstract

TH-302 is a binary chemotherapeutic drug which has a 2-nitroimidazole moiety covalently linked to a DNA alkylating nitrogen mustard moiety. The 2-nitroimidazole moiety undergoes bioreduction by intracellular reduction. In the presence of oxygen, the drug is reoxidized to original state but in hypoxic conditions, the drug undergoes fragmentation and releases the alkylating nitrogen mustard inflicting selective hypoxic cytotoxicity. We studied the redox-cycling behavior of TH-302 using EPR spin trapping with DMPO as the spin trap to monitor the superoxide radical produced during redox cycling of TH-302 when exposed to activating enzymes, in the presence of different concentrations of dissolved oxygen. Using superoxide flux as an orthogonal indicator of DNA alkylating effects of TH-302, we found quantitatively that this process can occur at pO2 levels < 5 mmHg beyond which redox-cycling predominates. The cellular studies evaluating the hypoxic cytotoxicity also were in agreement with the in vitro EPR studies.