PMID: 9533538May 14, 1998Paper

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

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
A A AdjeiS H Kaufmann

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 microM 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. A...Continue Reading

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