title: (64)Cu-ATSM therapy targets regions with activated DNA repair and enrichment of CD133(+) cells in an HT-29 tumor model: Sensitization with a nucleic acid antimetabolite.
abstract: (64)Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) is a potential theranostic agent targeting the over-reduced state under hypoxia within tumors. Recent clinical Cu-ATSM positron emission tomography studies have revealed a correlation between uptake and poor prognosis; however, the reason is unclear. Here, using a human colon carcinoma HT-29 model, we demonstrated that the intratumoral (64)Cu-ATSM high-uptake regions exhibited malignant characteristics, such as upregulated DNA repair and elevated %CD133(+) cancer stem-like cells. Based on this evidence, we developed a strategy to enhance the efficacy of (64)Cu-ATSM internal radiotherapy (IRT) by inhibiting DNA repair with a nucleic acid (NA) antimetabolite. The results of the analyses showed upregulation of pathways related to DNA repair along with NA incorporation (bromodeoxyuridine uptake) and elevation of %CD133(+) cells in (64)Cu-ATSM high-uptake regions. In an in vivo(64)Cu-ATSM treatment study, co-administration of an NA antimetabolite and (64)Cu-ATSM synergistically inhibited tumor growth, with little toxicity, and effectively reduced %CD133(+) cells. (64)Cu-ATSM therapy targeted malignant tumor regions with activated DNA repair and high concentrations of CD133(+) cells in the HT-29 model. NA antimetabolite co-administration can be an effective approach to enhance the therapeutic effect of (64)Cu-ATSM IRT.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan. Electronic address: yukiey@nirs.go.jp.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yoshii
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Research Centre, Nihon Medi-Physics Co., Ltd., Chiba, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Division of Functional Imaging, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Yoshimoto
authors.affiliation: Biomedical Imaging Research Center, University of Fukui, Fukui, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kiyono
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujibayashi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D056831:Coordination Complexes; D003301:Copper Radioisotopes / Q000378:metabolism / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D005472:Fluorouracil / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D020411:Oligonucleotide Array Sequence Analysis; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology*; D000068437:Pemetrexed / Q000494:pharmacology; D010641:Phenotype; D019275:Radiopharmaceuticals / Q000378:metabolism / Q000627:therapeutic use*; D000068936:Theranostic Nanomedicine; D013866:Thioguanine / Q000494:pharmacology; D013882:Thiosemicarbazones / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D000964:Antimetabolites, Antineoplastic; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D009942:Organometallic Compounds; C000606023:PROM1 protein, human; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D000068437:Pemetrexed; D013866:Thioguanine; D005472:Fluorouracil
keywords: (64)Cu-ATSM; DNA repair; Hypoxia; Internal radiotherapy; Nucleic acid antimetabolite