161-Ho + IUdR: Optimized Photon Activation Therapy

Abstract

The radiosensitizing pharmaceutical iododeoxyuridine (IUdR) has been around since the 1950’s, but has never reached full efficacy due to a lack of practical activation radiation source in the suitable energy range. We have successfully created and characterized radioactive holmium as a solution to this dilemma. The spectrum consists primarily of dysprosium K x-rays of 45 and 52 keV from the decay of holmium-161; radiation just above the K-edge of iodine (33 keV) has been shown to be of optimal energy for photon activation therapy of this drug. This study compares survival of human colorectal cancer (HT-29) cells with and without exposure to IUdR and subsequent irradiation with Cs-137, 300 kVp x-rays, I-125 seeds, and radioactive holmium. In our analysis, we isolate mechanisms of dose enhancement from each other as well as from the mechanisms of radiosensitivity, and in doing so, extract information about fundamental physical processes of DNA breakage. Through this independent formalism and a phenomenological assay of cell survival, we make conclusions about the lethality of DNA dSBs that agree with the literature. Furthermore, we have developed an objective protocol to analyze sensitization effects that obviates an arbitrary choice of measurement criteria. Sensitization values from holmium irradiation reported here are by far the greatest given the uptake of our drug, even on a notably radioresistant cell line. Most importantly, since holmium is a feasible material for brachytherapy implants, the full efficacy of this combination therapy, which has gone unexploited for 60 years, can finally be realized. Our results suggest that in vivo studies and clinical trials of IUdR photon activation with holmium brachytherapy have the potential to save lives and therefore merit consideration.