In vitro and in vivo characterization of XR11576, a novel, orally active, dual inhibitor of topoisomerase I and II.

Abstract

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 its in vitro and in vivo antitumor efficacy against a number of murine and human tumor models. XR11576 was a potent inhibitor of purified topoisomerase I and IIalpha, 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 vivo XR11576 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.

• Authors: Prakash Mistry, Alistair J Stewart, Wendy Dangerfield, Mark Baker, Chris Liddle, Douglas Bootle, Bettina Kofler, Deanne Laurie, William A Denny, Bruce Baguley, Peter A Charlton
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 13 Issue 1 Pg. 15-28 (Jan 2002) ISSN: 0959-4973 [Print] England
• PMID: 11914637 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 4-methoxybenzo(a)phenazine-11-carboxylic acid (2-(dimethylamino)-1-methylethyl)amide
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Enzyme Inhibitors
• Phenazines
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Body Weight (drug effects)
• Cell Survival (drug effects)
• Colonic Neoplasms (drug therapy, enzymology)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Enzyme Inhibitors (administration & dosage, pharmacokinetics, therapeutic use)
• Female
• Humans
• Injections, Intravenous
• Male
• Maximum Tolerated Dose
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms, Experimental (drug therapy, enzymology, pathology)
• Phenazines (administration & dosage, pharmacokinetics, therapeutic use)
• Rats
• Rats, Wistar
• Tissue Distribution
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors
• Tumor Cells, Cultured (drug effects)