Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies.
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.
Azarova
Anna M
AM
Department of Pharmacology, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA.
Lyu
Yi Lisa
YL
Lin
Chao-Po
CP
Tsai
Yuan-Chin
YC
Lau
Johnson Yiu-Nam
JY
Wang
James C
JC
Liu
Leroy F
LF
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000502:physiology*; D004195:Disease Models, Animal; D015195:Drug Design; D005047:Etoposide / Q000009:adverse effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D018345:Mice, Knockout; D016609:Neoplasms, Second Primary / Q000139:chemically induced* / Q000188:drug therapy / Q000209:etiology; D011480:Protease Inhibitors / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D007527:Isoenzymes; D011480:Protease Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004250:DNA Topoisomerases, Type II