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. 1999 Apr;79(11-12):1672–1678. doi: 10.1038/sj.bjc.6690267

In vivo efficacy of XR9051, a potent modulator of P-glycoprotein mediated multidrug resistance

P Mistry 1, J Plumb 2, S Eccles 3, S Watson 4, I Dale 1, H Ryder 1, G Box 3, P Charlton 1, D Templeton 1, P B Bevan 1
PMCID: PMC2362811  PMID: 10206276

Abstract

Overexpression of P-glycoprotein (P-gp) is a potential cause of multidrug resistance (MDR) in tumours. We have previously reported that XR9051 (N-(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide) is a potent and specific inhibitor of P-gp, which reverses drug resistance in several murine and human MDR cell lines. In this study we have evaluated the in vivo efficacy of this novel modulator in a panel of murine and human tumour models and examined its pharmacokinetic profile. Efficacy studies in mice bearing MDR syngeneic tumours (P388/DX Johnson, MC26) or human tumour xenografts (A2780AD, CH1/DOXr, H69/LX) demonstrated that co-administration of XR9051 significantly potentiated the anti-tumour activity of a range of cytotoxic drugs. This modulatory activity was observed following parenteral and oral co-administration of XR9051. In addition, the combination schedules were well-tolerated. Following intravenous administration in mice, XR9051 is rapidly distributed and accumulates in tumours and other tissues. In addition, the compound is well-absorbed after oral administration. These data suggest that XR9051 has the potential for reversing clinical MDR mediated by P-glycoprotien. © 1999 Cancer Research Campaign

Keywords: multidrug resistance, P-glycoprotein, XR9051, resistance modulators

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Selected References

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