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(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.

(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.:
http:--linkinghub.elsevier.com-ihub-imag Related Articles

(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.

Cancer Lett. 2016 ;376(1):74-82

Authors: Yoshii Y, Furukawa T, Matsumoto H, Yoshimoto M, Kiyono Y, Zhang MR, Fujibayashi Y, Saga T

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.

PMID: 26996296 [PubMed - in process]

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