Effect of Pyrazoloacridine (NSC 366140) on DNA topoisomerases I and II

Alex Adjei, Martin Charron, Eric K. Rowinsky, Phyllis A. Svingen, Jennifer Miller, Joel M Reid, Judith Sebolt-Leopold, Matthew M. Ames, Scott H Kaufmann

Research output: Contribution to journalArticle

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Abstract

Pyrazoloacridine (PA), an acridine congener with an unknown mechanism of action, has shown selective activity against solid tumor cells, cytotoxicity in noncycling and hypoxic cells, and promising antitumor activity in Phase I clinical trials. In the present study, the effect of PA on topoisomerase (topo) activity was evaluated using yeast strains lacking functional topo I or II, mammalian cell nuclear extracts, purified samples of mammalian topo I and topo II, and intact mammalian tissue culture cells. Clonogenic assays revealed that PA cytotoxicity in yeast strains was unaffected by selective loss of topo I or topo II activity. On the other hand, enzyme assays revealed that 2-4 μM PA abolished the catalytic activity of both topo I and topo II in vitro. In contrast to topotecan and etoposide, PA did not stabilize covalent topo-DNA complexes. Instead, PA inhibited topotecan-induced stabilization of covalent topo I-DNA complexes and etoposide-induced stabilization of topo II-DNA complexes in vitro and in intact cells. Consistent with these results, colony-forming assays indicated that short- term PA exposure inhibited the cytotoxicity of topotecan and etoposide, whereas prolonged PA exposure was itself toxic to these cells. Accumulation studies revealed that PA was concentrated as much as 250-fold in drug- treated cells, resulting in intranuclear concentrations that far exceeded those required to inhibit topo I and topo II. Collectively, these results not only suggest that PA can target both topo I and topo II at clinically achievable concentrations but also indicate that its mechanism is distinct from topo I and topo II poisons presently licensed for clinical use.

Original languageEnglish (US)
Pages (from-to)683-691
Number of pages9
JournalClinical Cancer Research
Volume4
Issue number3
StatePublished - 1998

Fingerprint

NSC 366140
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Topotecan
Etoposide
Poisons
Yeasts
Acridines
Clinical Trials, Phase I
Enzyme Assays

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Effect of Pyrazoloacridine (NSC 366140) on DNA topoisomerases I and II. / Adjei, Alex; Charron, Martin; Rowinsky, Eric K.; Svingen, Phyllis A.; Miller, Jennifer; Reid, Joel M; Sebolt-Leopold, Judith; Ames, Matthew M.; Kaufmann, Scott H.

In: Clinical Cancer Research, Vol. 4, No. 3, 1998, p. 683-691.

Research output: Contribution to journalArticle

Adjei, A, Charron, M, Rowinsky, EK, Svingen, PA, Miller, J, Reid, JM, Sebolt-Leopold, J, Ames, MM & Kaufmann, SH 1998, 'Effect of Pyrazoloacridine (NSC 366140) on DNA topoisomerases I and II', Clinical Cancer Research, vol. 4, no. 3, pp. 683-691.
Adjei A, Charron M, Rowinsky EK, Svingen PA, Miller J, Reid JM et al. Effect of Pyrazoloacridine (NSC 366140) on DNA topoisomerases I and II. Clinical Cancer Research. 1998;4(3):683-691.
Adjei, Alex ; Charron, Martin ; Rowinsky, Eric K. ; Svingen, Phyllis A. ; Miller, Jennifer ; Reid, Joel M ; Sebolt-Leopold, Judith ; Ames, Matthew M. ; Kaufmann, Scott H. / Effect of Pyrazoloacridine (NSC 366140) on DNA topoisomerases I and II. In: Clinical Cancer Research. 1998 ; Vol. 4, No. 3. pp. 683-691.
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