Carcinogenesis Advance Access originally published online on September 19, 2007
Carcinogenesis 2007 28(12):2657-2663; doi:10.1093/carcin/bgm188
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Modes of actions of two types of anti-neoplastic drugs, dacarbazine and ACNU, to induce apoptosis
1 Department of Physiological Science and Molecular Biology
2 Frontier Research Center, Fukuoka Dental College, Fukuoka 814-0193, Japan
3 Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
4 Biomolecular Engineering Research Institute, Suita 565-0874, Japan
* To whom correspondence should be addressed. Tel: +81 92 801 0411; Fax: +81 92 801 0685; Email: mseki{at}college.fdcnet.ac.jp
O6-Methylguanine and O6-chloroethylguanine, which are the primary cytotoxic DNA lesions produced by 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (dacarbazine) and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), respectively, can be repaired by O6-methylguanine-DNA methyltransferase (MGMT), coded by the MGMT gene. However, the two types of drugs exhibit different effects on cells defective in both MGMT and MLH1 functions, the latter being related to the cellular activity to recognize mismatched bases of DNA for inducing apoptosis. Human cells deficient in both MGMT and MLH1 are resistant to the killing effect of dacarbazine and exhibit an increased mutant frequency after treatment with dacarbazine. On the other hand, these doubly deficient cells are sensitive to the killing action of ACNU and there is no significant increase in ACNU-induced mutant frequency. A mismatch recognition complex, composed of MSH2, MSH6, MLH1, PMS2 and PCNA, is formed after exposing MGMT-deficient cells to dacarbazine, but not in cells treated with ACNU. In contrast, the phosphorylation of Chk1 efficiently occurs in cells treated with dacarbazine as well as with ACNU, the former being in MLH1-dependent manner, whereas the latter in MLH1-independent manner. Therefore, the signals delivered from different sources would merge at the step of Chk1 activation or at an earlier step, and the subsequent process leading to apoptosis appears to be common.
Abbreviations: ACNU, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea; dacarbazine, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide; D-MEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; MGMT, O6-methylguanine-DNA methyltransferase; SDS–PAGE, sodium dodecyl sulfate–polyacrylamide gel electrophoresis; siRNA, small interference RNA; 6-TG, 6-thioguanine
Received April 25, 2007; revised July 20, 2007; accepted August 13, 2007.