This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Utsugi, T. Articles by Hanna, N. Search for Related Content PubMed PubMed Citation Articles by Utsugi, T. Articles by Hanna, N.

Potentiation of Topoisomerase Inhibitor-induced DNA Strand Breakage and Cytotoxicity by Tumor Necrosis Factor: Enhancement of Topoisomerase Activity as a Mechanism of Potentiation

Departments of Immunology [T. U., N. H.] and Molecular Pharmacology [M. R. M., C. K. M.], Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406-0939

A combination of tumor necrosis factor (TNF) and the topoisomerase I inhibitor, camptothecin, or the topoisomerase II inhibitors, teniposide and amsacrine, produced dose-dependent synergistic cytotoxicity against the murine L929 fibrosarcoma cells. Similar synergy was not observed with a combination of TNF and bleomycin. To define the role of TNF in the augmentation of tumor cell killing by topoisomerase I or II inhibitors, the effect of TNF on the production of enzyme-linked DNA strand breaks induced in cells by topoisomerase inhibitors was investigated. L929 cells incubated for 1 h with the topoisomerase inhibitors contained protein-linked strand breaks. In contrast, TNF alone did not induce DNA strand breakage. However, when cells were incubated simultaneously with TNF and camptothecin, amsacrine, Adriamycin, actinomycin D, teniposide, or etoposide, increased numbers of strand breaks were produced. Preincubation of the cells with TNF for 30 min or 3 h before the addition of camptothecin or etoposide resulted in no more strand breaks than that observed in cells incubated with the drugs alone. TNF treatment of L929 cells produced a rapid and transient increase in specific activity of extractable topoisomerases I and II. These increases were maximum at 2–5 min of TNF treatment and by 30 min the activities of extractable enzymes were equal to or less than those detected in extracts from untreated cell controls. The transient nature of the increase in extractable topoisomerase activity may explain the kinetics and significance of the order of addition of TNF and inhibitors for maximal synergistic activity. These data are consistent also with a role for topoisomerase-linked DNA lesions in the TNF-mediated potentiation of killing of L929 cells by topoisomerase inhibitors.

¹ To whom correspondence should be addressed.

Received 1/26/89. Revised 11/16/89.

This article has been cited by other articles:

				E.-J. Yeo, J.-H. Ryu, Y.-S. Chun, Y.-S. Cho, I.-J. Jang, H. Cho, J. Kim, M.-S. Kim, and J.-W. Park YC-1 Induces S Cell Cycle Arrest and Apoptosis by Activating Checkpoint Kinases. Cancer Res., June 15, 2006; 66(12): 6345 - 6352. [Abstract] [Full Text] [PDF]