Copper-64-Diacetyl-Bis(N4-Methylthiosemicarbazone): An Agent for Radiotherapy

• Published in: Proceedings of the National Academy of Sciences - PNAS 2001-01, Vol.98 (3), p.1206-1211
• Main Authors: Lewis, Jason S., Laforest, Richard, Buettner, Thomas L., Song, Sheng-Kwei, Fujibayashi, Yasuhisa, Connett, Judith M., Welch, Michael J.
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Brachytherapy - methods; Cell Hypoxia; Cells; Colorectal cancer; Colorectal Neoplasms - radiotherapy; Coordination Complexes; Copper Radioisotopes - pharmacokinetics; Copper Radioisotopes - therapeutic use; Copper Radioisotopes - toxicity; Cricetinae; Dosage; Dose Fractionation, Radiation; Hamsters; Humans; Hydralazine - therapeutic use; Hypoxia; Imaging; Injections; Intestine, Large - drug effects; Intestine, Large - pathology; Kidney - drug effects; Kidney - pathology; Large intestine; Liver - drug effects; Liver - pathology; Male; Medical treatment; Mesocricetus; Organometallic Compounds - pharmacokinetics; Organometallic Compounds - therapeutic use; Organometallic Compounds - toxicity; Positron emission tomography; Radiotherapy; Radiotherapy Dosage; Therapy; Thiosemicarbazones - pharmacokinetics; Thiosemicarbazones - therapeutic use; Thiosemicarbazones - toxicity; Tissue Distribution; Tomography, Emission-Computed; Transplantation, Heterologous; Tumor burden; Tumors; Weight Loss
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.98.3.1206

Systemic administration of hypoxia-selective64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) has increased significantly the survival time of hamsters bearing human GW39 colon cancer tumors. Radiotherapy experiments were performed in animals bearing either 7-day-old (0.5-1.0 g) or 15-day-old (1.5-2.0 g) tumors. Studies compared animals treated with a single dose of 0, 4, 6, 7, 8, or 10 mCi of64Cu-ATSM (1 Ci = 37 GBq) with or without the vasodilator hydralazine. A multiple dose regimen of 3 x 4 mCi at 72-h intervals was studied also. Single doses of >6 mCi of64Cu-ATSM and the dose-fractionation protocol significantly increased the survival time of the hamsters compared with controls. The highest dose, 10 mCi of64Cu-ATSM, increased survival to 135 days in 50% of animals bearing 7-day-old tumors, 6-fold longer than control animals' survival (20 days), with only transient leucopenia and thrombocytopenia but no overt toxicity. Human absorbed doses were calculated from hamster biodistribution; the dose-critical organs were the lower large intestine (1.43 ± 0.19 rad/mCi) and upper large intestine (1.20 ± 0.38 rad/mCi). High-resolution MRI and positron-emission tomography using a therapeutic administration of 10 mCi were used to monitor tumor volume and morphology and to assess tumor dosimetry accurately, giving a tumor dose of 81 ± 7.5 rad/mCi.64Cu-ATSM has increased the survival time of tumor-bearing animals significantly with no acute toxicity and thus is a promising agent for radiotherapy.