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Potentiation of TNF-mediated cell killing by mitoxantrone. Relationship to DNA single-strand break formation.

Abstract：

:Tumor necrosis factor (TNF) is a pleiotropic cytokine that mediates different cellular responses including cytotoxicity, cytostasis, proliferation, differentiation and expression of specific genes. Recent studies have demonstrated that chemotherapeutic drugs that inhibit the nuclear enzyme DNA topoisomerase II synergize with TNF in tumor cell killing in vitro and in vivo. We now report that a combination of TNF and the topoisomerase II inhibitor Mitoxantrone produced dose-dependent synergistic cytotoxicity against the human ovarian cancer cell line A2774 in a clonogenic assay (1 hr treatment). This result was obtained with simultaneous administration of the drug and the cytokine under test, and is independent of modification of Mitoxantrone uptake. This combination is responsible for an evident augmentation of "cleavable complex" formation. From isolated nuclei, we have isolated also the topoisomerase II activity; we observed an increment when the cells were previously treated with TNF, 2.5 min before nuclear extraction. After 10-30 min of treatment with TNF, the topoisomerase II activity returned to normal values. If TNF is not given with but 30 min before Mitoxantrone, no potentiation of cytotoxicity or break induction is observed. These results suggest that specific timing of the association may be needed also when attempting to translate it to animals and humans.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Valenti M,Cimoli G,Mariani GL,Conte PF,Parodi S,Russo P

doi

10.1016/0006-2952(93)90468-c

subject

Has Abstract

pub_date

1993-10-05 00:00:00

pages

1199-206

issue

7

eissn

0006-2952

issn

1873-2968

pii

0006-2952(93)90468-C

journal_volume

46

pub_type

杂志文章

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