Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies

被引:239
作者
Azarova, Anna M.
Lyu, Yi Lisa
Lin, Chao-Po
Tsai, Yuan-Chin
Lau, Johnson Yiu-Nam
Wang, James C.
Liu, Leroy F.
机构
[1] Univ Med & Dent New Jersey, Dept Pharmacol, Piscataway, NJ 08854 USA
[2] Avagenex Pharmaceut, Princeton Jct, NJ 08550 USA
[3] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA
关键词
DNA rearrangements; melanoma; skin-specific topoisomerase II beta-knockout; tumor cell killing; carcinogenesis;
D O I
10.1073/pnas.0704002104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
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 beta rather than the alpha 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 TOP2 beta(+) than in skin-specific top2 beta-knockout mice. Furthermore, VP-16-induced DNA sequence rearrangements and double-strand breaks (DSBs) are found to be Top2 beta-dependent and preventable by cotreatment with a proteasome inhibitor, suggesting the importance of proteasomal degradation of the Top2 beta-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 Top2 alpha-dependent. These results point to the importance of developing Top2 alpha-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies.
引用
收藏
页码:11014 / 11019
页数:6
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