Role of Topoisomerase II in Mediating Epipodophyllotoxin-induced DNA Cleavage

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

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Abstract

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.

Original languageEnglish
Pages (from-to)5857-5860
Number of pages4
JournalCancer Research
Volume44
Publication statusPublished - Dec 1 1984
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ross, W., Glisson, B., Yalowich, J., Rowe, T., & Liu, L-F. (1984). Role of Topoisomerase II in Mediating Epipodophyllotoxin-induced DNA Cleavage. Cancer Research, 44, 5857-5860.