Controlled Administration of Penicillamine Reduces Radiation Exposure in Critical Organs during 64Cu-ATSM Internal Radiotherapy: A Novel Strategy for Liver Protection

Abstract

Purpose 64Cu-diacetyl-bis (N 4-methylthiosemicarbazone) (64Cu-ATSM) is a promising theranostic agent that targets hypoxic regions in tumors related to malignant characteristics. Its diagnostic usefulness has been recognized in clinical studies. Internal radiotherapy (IRT) with 64Cu-ATSM is reportedly effective in preclinical studies; however, for clinical applications, improvements to reduce radiation exposure in non-target organs, particularly the liver, are required. We developed a strategy to reduce radiation doses to critical organs while preserving tumor radiation doses by controlled administration of copper chelator penicillamine during 64Cu-ATSM IRT.MethodsBiodistribution was evaluated in HT-29 tumor-bearing mice injected with 64Cu-ATSM (185 kBq) with or without oral penicillamine administration. The appropriate injection interval between 64Cu-ATSM and penicillamine was determined. Then, the optimal penicillamine administration schedule was selected from single (100, 300, and 500 mg/kg) and fractionated doses (100 mg/kg×3 at 1- or 2-h intervals from 1 h after 64Cu-ATSM injection). PET imaging was performed to confirm the effect of penicillamine with a therapeutic 64Cu-ATSM dose (37 MBq). Dosimetry analysis was performed to estimate human absorbed doses.ResultsPenicillamine reduced 64Cu accumulation in the liver and small intestine. Tumor uptake was not affected by penicillamine administration at 1 h after 64Cu-ATSM injection, when radioactivity was almost cleared from the blood and tumor uptake had plateaued. Of the single doses, 300 mg/kg was most effective. Fractionated administration at 2-h intervals further decreased liver accumulation at later time points. PET indicated that penicillamine acts similarly with the therapeutic 64Cu-ATSM dose. Dosimetry demonstrated that appropriately scheduled penicillamine administration reduced radiation doses to critical organs (liver, ovaries, and red marrow) below tolerance levels. Laxatives reduced radiation doses to the large intestine.ConclusionsWe developed a novel strategy to reduce radiation exposure in critical organs during 64Cu-ATSM IRT, thus promoting its clinical applications. This method could be beneficial for other 64Cu-labeled compounds.

Focus on the Controversial Aspects of 64Cu-ATSM in Tumoral Hypoxia Mapping by PET Imaging

“…The mechanism of radiolabeled Cu-ATSM accumulation in hypoxic tumor area was currently under investigation but it was well-known than there was a high physiological accumulation of free 64 Cu in non-target organ and the liver was reported to be the principal dose-limiting organ ( 26 ). To reduce the liver absorbed dose, Yoshii et al showed that the use of a copper chelator like penicillamine could reduce liver absorbed dose (increase of free copper renal clearance) but have no effect on the Cu-ATSM tumor accumulation ( 27 ).…”

“…From this physiological metabolism of copper, it appears than free copper present a negative impact on the PET image information of 64 Cu-ATSM. Nevertheless, this impact could be decreased by the co-administration of d -penicillamine, which will permit to accelerate the elimination of free copper without impact on the 64 Cu-ATSM tumor fixation ( 27 ).…”

64Cu-ATSM internal radiotherapy to treat tumors with bevacizumab-induced vascular decrease and hypoxia in human colon carcinoma xenografts

“…The mice were intravenously injected with 64 Cu-ATSM (37 MBq) or saline (day 21) and continued to be treated with bevacizumab (bevacizumab+ 64 Cu-ATSM group or bevacizumab alone). The dose of 64 Cu-ATSM (37 MBq) used in this study was decided based on toxicity and dosimetry analyses of previous studies, which demonstrated that the dosage results in no significant body weight loss and suggested not to administer radiation doses on the dose-limiting organs beyond the tolerance level [ 16 , 26 , 30 ]. For comparison, groups without bevacizumab treatment were also examined: 64 Cu-ATSM (37 MBq) on day 21 ( 64 Cu-ATSM alone-day 21 group); 64 Cu-ATSM (37 MBq) on day 7, on which day tumor size was similar to that in the bevacizumab-treated mice on day 21 ( 64 Cu-ATSM alone-day 7 group); saline instead of 64 Cu-ATSM (day 21) (control group).…”

“…Our in vivo treatment study showed that administration of 37 MBq of 64 Cu-ATSM had a therapeutic effect against bevacizumab-treated tumors without noticeably increased toxicity levels. We have previously demonstrated that 37 MBq of 64 Cu-ATSM was an appropriate dosage for treatment in mice, since it did not cause significant body weight loss and hematotoxicity [ 16 , 26 , 30 ]. In addition, we have estimated the human dosimetry of 64 Cu-ATSM based on the time-series biodistribution data in normal organs and tumors using mice bearing HT-29 tumors [ 16 , 30 ].…”

Menkes disease: Oral administration of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) rescues the macular mouse

“…Administration of penicillamine reduces intestinal copper accumulation during internal radiotherapy with 64 CuBTSC. 39 Thus, combined administration of penicillamine with CuGTSM may reduce copper overload in the ileum. In addition, dietary copper supplementation combined with zinc reduced the incidence and severity of diarrhea, which may applicable to CuGTSM treatment.…”