Modes of actions of two types of anti-neoplastic drugs, dacarbazine and ACNU, to induce apoptosis

Masayuki Sanada, Masumi Hidaka, Yasumitsu Takagi, Tomoko Y. Takano, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Mutsuo Sekiguchi

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2657-2663
Number of pages7
JournalCarcinogenesis
Volume28
Issue number12
DOIs
Publication statusPublished - Dec 1 2007

Fingerprint

Nimustine
Dacarbazine
Methyltransferases
Apoptosis
DNA
Pharmaceutical Preparations
Proliferating Cell Nuclear Antigen
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Sanada, M., Hidaka, M., Takagi, Y., Takano, T. Y., Nakatsu, Y., Tsuzuki, T., & Sekiguchi, M. (2007). Modes of actions of two types of anti-neoplastic drugs, dacarbazine and ACNU, to induce apoptosis. Carcinogenesis, 28(12), 2657-2663. https://doi.org/10.1093/carcin/bgm188

Modes of actions of two types of anti-neoplastic drugs, dacarbazine and ACNU, to induce apoptosis. / Sanada, Masayuki; Hidaka, Masumi; Takagi, Yasumitsu; Takano, Tomoko Y.; Nakatsu, Yoshimichi; Tsuzuki, Teruhisa; Sekiguchi, Mutsuo.

In: Carcinogenesis, Vol. 28, No. 12, 01.12.2007, p. 2657-2663.

Research output: Contribution to journalArticle

Sanada, M, Hidaka, M, Takagi, Y, Takano, TY, Nakatsu, Y, Tsuzuki, T & Sekiguchi, M 2007, 'Modes of actions of two types of anti-neoplastic drugs, dacarbazine and ACNU, to induce apoptosis', Carcinogenesis, vol. 28, no. 12, pp. 2657-2663. https://doi.org/10.1093/carcin/bgm188
Sanada, Masayuki ; Hidaka, Masumi ; Takagi, Yasumitsu ; Takano, Tomoko Y. ; Nakatsu, Yoshimichi ; Tsuzuki, Teruhisa ; Sekiguchi, Mutsuo. / Modes of actions of two types of anti-neoplastic drugs, dacarbazine and ACNU, to induce apoptosis. In: Carcinogenesis. 2007 ; Vol. 28, No. 12. pp. 2657-2663.
@article{12139101446d4d909fa75eecea444d8d,
title = "Modes of actions of two types of anti-neoplastic drugs, dacarbazine and ACNU, to induce apoptosis",
abstract = "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.",
author = "Masayuki Sanada and Masumi Hidaka and Yasumitsu Takagi and Takano, {Tomoko Y.} and Yoshimichi Nakatsu and Teruhisa Tsuzuki and Mutsuo Sekiguchi",
year = "2007",
month = "12",
day = "1",
doi = "10.1093/carcin/bgm188",
language = "English",
volume = "28",
pages = "2657--2663",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "12",

}

TY - JOUR

T1 - Modes of actions of two types of anti-neoplastic drugs, dacarbazine and ACNU, to induce apoptosis

AU - Sanada, Masayuki

AU - Hidaka, Masumi

AU - Takagi, Yasumitsu

AU - Takano, Tomoko Y.

AU - Nakatsu, Yoshimichi

AU - Tsuzuki, Teruhisa

AU - Sekiguchi, Mutsuo

PY - 2007/12/1

Y1 - 2007/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=36949008827&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36949008827&partnerID=8YFLogxK

U2 - 10.1093/carcin/bgm188

DO - 10.1093/carcin/bgm188

M3 - Article

VL - 28

SP - 2657

EP - 2663

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 12

ER -