In vitroandin vivocharacterization of XR11576, a novel, orally active, dual inhibitor of topoisomerase I and II
作者:
Prakash Mistry,
Alistair Stewart,
Wendy Dangerfield,
Mark Baker,
Chris Liddle,
Douglas Bootle,
Bettina Kofler,
Deanne Laurie,
William Denny,
Bruce Baguley,
Peter Charlton,
期刊:
Anti-Cancer Drugs
(OVID Available online 2002)
卷期:
Volume 13,
issue 1
页码: 15-28
ISSN:0959-4973
年代: 2002
出版商: OVID
关键词: Antitumor agent;dual topoisomerase I and II poison;pharmacokinetics;XR11576
数据来源: OVID
摘要:
XR11576, a novel phenazine, was developed as an inhibitor of both topoisomerase I and II. This study characterized the ability of XR11576 to inhibit both enzymes, and determined itsin vitroandin vivoantitumor efficacy against a number of murine and human tumor models. XR11576 was a potent inhibitor of purified topoisomerase I and II&agr;, and exhibited similar potency for both enzymes. The compound stabilized enzyme–DNA cleavable complexes indicating that it acted as a topoisomerase poison. The DNA cleavage patterns obtained with XR11576 were different from those induced by camptothecin and etoposide, which are topoisomerase I and II poisons, respectively. XR11576 demonstrated potent cytotoxic activity against a variety of human and murine tumor cell lines (IC50=6–47 nM). Its activity profile was comparable to or better than that of many widely used anticancer drugs. Moreover, XR11576 was unaffected by multidrug resistance (MDR) mediated by overexpression of either P-glycoprotein or MDR-associated protein, or by down-regulation of topoisomerase II. The latter property supports the dual inhibitory mechanism of action of the compound. XR11576 exhibited a similar pharmacokinetic profile in mice and rats after either i.v. or p.o. administration.In vivoXR11576 showed marked efficacy against a number of tumors including sensitive (H69/P) and multidrug-resistant (H69/LX4) small cell lung cancer and the relatively refractory MC26 and HT29 colon carcinomas following i.v. and p.o. administration. The efficacy of XR11576 was at least comparable to that of TAS-103, originally proposed as a dual inhibitor of topoisomerase I and II. These results suggest that XR11576 is a promising new antitumor agent with oral and i.v. activity, and warrants further development.
点击下载:
PDF
(480KB)
返 回