Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies

Anna M. Azarova, Yi Lisa Lyu, Chao P. Lin, Yuan Chin Tsai, J. Y N Lau, James C. Wang, Leroy F. Liu

研究成果: 雜誌貢獻文章

180 引文 (Scopus)

摘要

Drugs that target DNA topoisomerase II (Top2), including etoposide (VP-16), doxorubicin, and mitoxantrone, are among the most effective anticancer drugs in clinical use. However, Top2-based chemotherapy has been associated with higher incidences of secondary malignancies, notably the development of acute myeloid leukemia in VP-16-treated patients. This association is suggestive of a link between carcinogenesis and Top2-mediated DNA damage. We show here that VP-16-induced carcinogenesis involves mainly the β rather than the α isozyme of Top2. In a mouse skin carcinogenesis model, the incidence of VP-16-induced melanomas in the skin of 7,12-dimethylbenz[a]anthracene-treated mice is found to be significantly higher in TOP2β+ than in skin-specific top2β-knockout mice. Furthermore, VP-16-induced DNA sequence rearrangements and double-strand breaks (DSBs) are found to be Top2β-dependent and preventable by cotreatment with a proteasome inhibitor, suggesting the importance of proteasomal degradation of the Top2β-DNA cleavage complexes in VP-16-induced DNA sequence rearrangements. VP-16 cytotoxicity in transformed cells expressing both Top2 isozymes is, however, found to be primarily Top2α-dependent. These results point to the importance of developing Top2α-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies.
原文英語
頁(從 - 到)11014-11019
頁數6
期刊Proceedings of the National Academy of Sciences of the United States of America
104
發行號26
DOIs
出版狀態已發佈 - 六月 26 2007
對外發佈Yes

指紋

Type II DNA Topoisomerase
Etoposide
Isoenzymes
Drug Therapy
Neoplasms
Carcinogenesis
Gene Rearrangement
Skin
Pharmaceutical Preparations
Mitoxantrone
DNA Cleavage
Proteasome Inhibitors
Incidence
Acute Myeloid Leukemia
Knockout Mice
Doxorubicin
DNA Damage
Melanoma

ASJC Scopus subject areas

  • General
  • Genetics

引用此文

Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. / Azarova, Anna M.; Lyu, Yi Lisa; Lin, Chao P.; Tsai, Yuan Chin; Lau, J. Y N; Wang, James C.; Liu, Leroy F.

於: Proceedings of the National Academy of Sciences of the United States of America, 卷 104, 編號 26, 26.06.2007, p. 11014-11019.

研究成果: 雜誌貢獻文章

Azarova, Anna M. ; Lyu, Yi Lisa ; Lin, Chao P. ; Tsai, Yuan Chin ; Lau, J. Y N ; Wang, James C. ; Liu, Leroy F. / Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. 於: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; 卷 104, 編號 26. 頁 11014-11019.
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AB - Drugs that target DNA topoisomerase II (Top2), including etoposide (VP-16), doxorubicin, and mitoxantrone, are among the most effective anticancer drugs in clinical use. However, Top2-based chemotherapy has been associated with higher incidences of secondary malignancies, notably the development of acute myeloid leukemia in VP-16-treated patients. This association is suggestive of a link between carcinogenesis and Top2-mediated DNA damage. We show here that VP-16-induced carcinogenesis involves mainly the β rather than the α isozyme of Top2. In a mouse skin carcinogenesis model, the incidence of VP-16-induced melanomas in the skin of 7,12-dimethylbenz[a]anthracene-treated mice is found to be significantly higher in TOP2β+ than in skin-specific top2β-knockout mice. Furthermore, VP-16-induced DNA sequence rearrangements and double-strand breaks (DSBs) are found to be Top2β-dependent and preventable by cotreatment with a proteasome inhibitor, suggesting the importance of proteasomal degradation of the Top2β-DNA cleavage complexes in VP-16-induced DNA sequence rearrangements. VP-16 cytotoxicity in transformed cells expressing both Top2 isozymes is, however, found to be primarily Top2α-dependent. These results point to the importance of developing Top2α-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies.

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