Anna M Azarova, Yi Lisa Lyu, Chao-Po Lin, Yuan-Chin Tsai, Johnson Yiu-Nam Lau, James C Wang, Leroy F Liu
Department of Pharmacology, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA.
Proceedings of the National Academy of Sciences of the United States of America 2007 Jun 26Drugs 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 TOP2beta(+) than in skin-specific top2beta-knockout mice. Furthermore, VP-16-induced DNA sequence rearrangements and double-strand breaks (DSBs) are found to be Top2beta-dependent and preventable by cotreatment with a proteasome inhibitor, suggesting the importance of proteasomal degradation of the Top2beta-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 Top2alpha-dependent. These results point to the importance of developing Top2alpha-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies.
Anna M Azarova, Yi Lisa Lyu, Chao-Po Lin, Yuan-Chin Tsai, Johnson Yiu-Nam Lau, James C Wang, Leroy F Liu. Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. Proceedings of the National Academy of Sciences of the United States of America. 2007 Jun 26;104(26):11014-9
PMID: 17578914
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