Hypersensitivity in DNA mismatch repair-deficient colon carcinoma cells to DNA polymerase reaction inhibitors

Takahashi, Tomonori; Min, Zhenghua; Uchida, Iichiro; Arita, Michitsune; Watanabe, Yoh; Koi, Minoru; Hemmi, Hiromichi

doi:10.1016/j.canlet.2004.07.044

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Volume 220, Issue 1 , Pages 85-93, 18 March 2005

Hypersensitivity in DNA mismatch repair-deficient colon carcinoma cells to DNA polymerase reaction inhibitors

Tomonori Takahashi
- Department of Molecular Biology, Faculty of Medicine, Toho University, 5-21-16 Ohmori-Nishi, Ohta-Ku, Tokyo 143-8540, Japan
Zhenghua Min
- Department of Molecular Biology, Faculty of Medicine, Toho University, 5-21-16 Ohmori-Nishi, Ohta-Ku, Tokyo 143-8540, Japan
Iichiro Uchida
- Department of Molecular Biology, Faculty of Medicine, Toho University, 5-21-16 Ohmori-Nishi, Ohta-Ku, Tokyo 143-8540, Japan
Michitsune Arita
- Department of Molecular Biology, Faculty of Medicine, Toho University, 5-21-16 Ohmori-Nishi, Ohta-Ku, Tokyo 143-8540, Japan
Yoh Watanabe
- Department of Obstetrics and Gynecology, Kinki University School of Medicine, Osaka, Japan
Minoru Koi
- Department of Biological Sciences, Brunel Institute of Cancer Genetics and Pharmacogenomics, Brunel University, Uxbridge, Middlesex, UK
Hiromichi Hemmi
- Department of Molecular Biology, Faculty of Medicine, Toho University, 5-21-16 Ohmori-Nishi, Ohta-Ku, Tokyo 143-8540, Japan
- Corresponding author. Tel.: +81 3 3762 4151; fax: +81 3 3764 6923.

Received 9 June 2004; accepted 15 July 2004.

Abstract

We studied the cytotoxic effects of various DNA replication inhibitors on MMR-deficient and -proficient colon carcinoma cell lines. DNA polymerase (pol) inhibitors including aphidicolin and gemcitabine, and hydroxyurea were more toxic (1.7 to 2.8-fold) to hMLH1-deficient HCT116 than to hMLH1-proficient HCT116+ch3. Similarly, pol inhibitors were more toxic to hMSH2-deficient LoVo than to hMSH2-proficient LoVo+ch2. In contrast, DNA topoisomerase I inhibitors, such as CPT-11, SN-38, and topotecan, were more toxic to MMR-proficient cells. Our results suggest that MMR-deficient colon carcinoma cells are hypersensitive to inhibitors of the pol reaction.

Keywords: DNA mismatch repair, Colon carcinoma, DNA polymerase, DNA replication, Hypersensitive