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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.

 

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