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Carcinogenesis Advance Access published online on September 19, 2007
Carcinogenesis, doi:10.1093/carcin/bgm188
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Modes of Actions of Two Types of Antineoplastic Drugs, Dacarbazine and ACNU, to Induce Apoptosis

Masayuki Sanada1, Masumi Hidaka2, Yasumitsu Takagi1, Tomoko Y. Takano3, Yoshimichi Nakatsu2, Teruhisa Tsuzuki2 and Mutsuo Sekiguchi1,*

1 Department of Physiological Science and Molecular Biology, and Frontier Research Center, Fukuoka Dental College, Fukuoka, 814-0193, Japan
2 Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
3 Biomolecular Engineering Research Institute, Suita, 565-0874, Japan

* Corresponding author: Mutsuo Sekiguchi, Frontier Research Center, Fukuoka Dental College, Fukuoka 814-0193, Japan. Phone: 81-92-801-0411; Fax: 81-92-801-0685; E-mail: mseki{at}college.fdcnet.ac.jp

O6-methylguanine and O6-chloroethylguanine, which are the primary cytotoxic DNA lesions produced by dacarbazine and ACNU, respectively, can be repaired by O6-methylguanine-DNA methyltransferase, 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 dacabazine as well as with ACNU, the former being in MLH1-dependent while 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.

Key Words: apoptosis • alkylating drug • O6-alkylguanine • mismatch recognition • DNA repair enzyme

Received April 25, 2007; revised July 20, 2007; accepted August 13, 2007.


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