Hypersensitivity in DNA mismatch repair-deficient colon carcinoma cells to DNA polymerase reaction inhibitors.
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.
Takahashi
Tomonori
T
Department of Molecular Biology, Faculty of Medicine, Toho University, 5-21-16 Ohmori-Nishi, Ohta-Ku, Tokyo 143-8540, Japan.
Min
Zhenghua
Z
Uchida
Iichiro
I
Arita
Michitsune
M
Watanabe
Yoh
Y
Koi
Minoru
M
Hemmi
Hiromichi
H
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology; D016590:Aphidicolin / Q000494:pharmacology; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D003110:Colonic Neoplasms / Q000235:genetics*; D004260:DNA Repair; D045325:HCT116 Cells; D006801:Humans; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D016590:Aphidicolin; D000070957:MutL Protein Homolog 1