Cytotoxic mechanism of XK469: Resistance of topoisomerase IIβ knockout cells and inhibition of topoisomerase I Journal Article
| Authors: | Snapka, R. M.; Gao, H.; Grabowski, D. R.; Brill, D.; Chan, K. K.; Li, L.; Li, G. C.; Ganapathi, R. |
| Article Title: | Cytotoxic mechanism of XK469: Resistance of topoisomerase IIβ knockout cells and inhibition of topoisomerase I |
| Abstract: | Topoisomerase IIβ knockout mouse cells (β-/-) were found to have only slight resistance to m-AMSA, a dual topoisomerase IIα-IIβ poison, as compared to wild-type cells (ν+/+) during 1 h or 3 day exposures to the drug. In contrast, the β-/- cells were greater than threefold resistant to XK469, a selective topoisomerase IIβ poison during three day drug exposures (β+/+ IC50=175 μM, β-/- IC50=581 μM). Short term (1 h) exposure to XK469 was not cytotoxic to either β-/- or β+/+ cells, suggesting that anticancer therapy with XK469 may be more efficacious if systemic levels can be prolonged. During studies on topoisomerase activity in nuclear extracts of the β+/+ and β-/- cells, we found evidence that XK469 is a weak topoisomerase I catalytic inhibitor. The high IC50 for topoisomerase I inhibition (2 mM) suggests that topoisomerase I is not a significant target for XK469 cytotoxicity. © 2001 Academic Press. |
| Keywords: | controlled study; unclassified drug; dna-binding proteins; drug efficacy; nonhuman; antineoplastic agents; antineoplastic agent; animal cell; mouse; animals; mice; mice, knockout; enzyme inhibition; embryo; dose-response relationship, drug; tumor cells, cultured; enzyme activity; time factors; dna; drug mechanism; drug cytotoxicity; amsacrine; dna topoisomerase inhibitor; dna topoisomerase (atp hydrolysing); ic 50; inhibitory concentration 50; knockout mouse; dna topoisomerases, type ii; drug exposure; dna topoisomerase; dna topoisomerases, type i; cross-linking reagents; poison; humans; priority journal; article; quinoxaline derivative; xk 469; quinoxalines |
| Journal Title: | Biochemical and Biophysical Research Communications |
| Volume: | 280 |
| Issue: | 4 |
| ISSN: | 0006-291X |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 2001-02-02 |
| Start Page: | 1155 |
| End Page: | 1160 |
| Language: | English |
| DOI: | 10.1006/bbrc.2001.4249 |
| PUBMED: | 11162648 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work