Acquisition of resistance to antitumor alkylating agent ACNU: a possible target of positron emission tomography monitoring

Kawai, Hideya; Toyohara, Jun; Kado, Hirotsugu; Nakagawa, Takao; Takamatsu, Shinji; Furukawa, Takako; Yonekura, Yoshiharu; Kubota, Toshihiko; Fujibayashi, Yasuhisa

doi:10.1016/j.nucmedbio.2005.10.002

« Previous Next »Nuclear Medicine and Biology
Volume 33, Issue 1 , Pages 29-35, January 2006

Acquisition of resistance to antitumor alkylating agent ACNU: a possible target of positron emission tomography monitoring

Hideya Kawai
- Department of Neurosurgery, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
- Research Institute of Brain and Blood Vessels, Akita 010-0874, Japan
Jun Toyohara
- Radiopharmaceutical Chemistry Section, Department of Medical Imaging, National Institute of Radiological Sciences, Chiba 263-8555, Japan
- Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193, Japan
Hirotsugu Kado
- Research Institute of Brain and Blood Vessels, Akita 010-0874, Japan
Takao Nakagawa
- Department of Neurosurgery, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
Shinji Takamatsu
- Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193, Japan
Takako Furukawa
- Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193, Japan
Yoshiharu Yonekura
- Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193, Japan
Toshihiko Kubota
- Department of Neurosurgery, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
Yasuhisa Fujibayashi
- Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193, Japan
- Corresponding author. Tel.: +81 776 61 8430; fax: +81 776 61 8170.

Received 2 August 2005; received in revised form 2 October 2005; accepted 4 October 2005.

Abstract

Early detection of tumor response to chemotherapy is of great importance for appropriate treatment of tumors. In this study, characteristics of two positron emission tomography (PET) tracers, [¹⁸F]2-fluoro-2-deoxy-d-glucose (FDG) and[¹⁸F]3′-fluoro-3′-deoxy-thymidine (FLT), in the early detection of tumor cell response as well as tolerance development to chemotherapy was compared using rat C6 glioma cells and 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosoureahydrochloride (ACNU). ACNU is an alkylating agent known to induce drug resistance through expression of O⁶-methylguanine-deoxyribonucleic acid methyl transferase (O⁶-MGMT). We established an ACNU-resistant C6 glioma cell line (C6/ACNU) and investigated the effect of ACNU on the uptake of FLT and FDG. In C6 cells, DNA synthesis presented as [³H]thymidine ([³H]Thd) incorporation into DNA was quickly suppressed by ACNU. In C6/ACNU cells, the suppression was recovered promptly, indicating that DNA alkylation occurs initially but highly expressed O⁶-MGMT repairs DNA, leading to the recovery of DNA synthesis. The patterns of FLT uptake in C6 and C6/ACNU were difficult to distinguish in the very early stage of the treatment, though it was reported that FLT uptake well correlated with proliferation in certain conditions. FDG uptake showed different patterns between the resistant and control cells, with significantly decreased uptake in C6 cells and unchanged uptake in C6/ACNU cells at 18–24 h after the treatment. Though difficult to be directly translated into clinical situation, the present study will provide a base to develop an appropriate protocol to assess tumor response to treatment by PET and to design effective treatment plans.

Keywords: Drug resistance, Glioma, Thymidine, PET, FLT, FDG