Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies.

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Azarova AM, Lyu YL, Lin CP, Tsai YC, Lau JY, Wang JC, Liu LF

Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies.

Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11014-9. Epub 2007 Jun 19.

PubMed ID

17578914 [ View in PubMed

]

Abstract

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 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.

DrugBank Data that Cites this Article

Drugs

Etoposide

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Doxorubicin	DNA topoisomerase 2-alpha	Protein	Humans	Yes	Inhibitor	Details
Etoposide	DNA topoisomerase 2-beta	Protein	Humans	No	Inhibitor	Details

Drug Interactions

Drugs	Interaction
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Etoposide Atovaquone	The serum concentration of Etoposide can be increased when it is combined with Atovaquone.