Role of Topoisomerase II in Mediating Epipodophyllotoxin-induced DNA Cleavage

Warren Ross, Bonnie Glisson, Jack Yalowich, Tom Rowe, Leroy Liu

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476 引文 斯高帕斯(Scopus)


Epipodophyllotoxins are an important new dass of anticancer agents which include the compounds VM-26 (teniposide) and VP-16 (etoposide).The mechanism of action of these drugs appears to involve production of DNA single- and double-strand breaks by virtue of a temperature-sensitive interaction between drug and a heat-labile intranuclear component. We now report evidence indicating that type II topoisomerase is the likely intracellular target for the DNA strand-breaking effects of the epipodophyllotoxins. Both VM-26 and VP-16 stimulate site-specific DNA cleavage by a highly purified calf thymus type II topoisomerase. VM-26 is 5- to 10-fold more potent than VP-16 in this assay, a difference that is also seen when DNA strand breaks are assayed in isolated nuclei of mouse leukemia cells following drug exposure. Furthermore, a similar potency difference exists with respect to cytotoxicity. Equilibrium dialysis experiments using [3H]VP-16 indicate that the drug does not bind to DNA. Thus, we suggest that the epipodophyllotoxins exert their anticancer effects by ‘poisoning’ type II topoisomerase without binding to DNA. In this regard, their actions may be analogous to those of nalidixic acid in bacteria.

頁(從 - 到)5857-5860
期刊Cancer Research
出版狀態已發佈 - 12月 1 1984

ASJC Scopus subject areas

  • 腫瘤科
  • 癌症研究


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