Regular Article

British Journal of Cancer (1999) 79, 1672–1678. doi:10.1038/sj.bjc.6690267 www.bjcancer.com
Published online 12 March 1999

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

P Mistry1, J Plumb2, S Eccles3, S Watson4, I Dale1, H Ryder1, G Box3, P Charlton1, D Templeton1 and P B Bevan1

  1. 1Xenova Ltd, 240 Bath Road, Slough, SL1 4EF, UK
  2. 2CRC Department of Oncology, University of Glasgow, Glasgow, G61 1BD, UK
  3. 3Institute of Cancer Research, Sutton, SM2 5NG, UK
  4. 4Cancer Studies Unit, University of Nottingham, Nottingham, NG7 2UH,UK

Received 14 April 1998; Revised 27 July 1998; Accepted 7 August 1998.

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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.

Keywords:

multidrug resistance, P-glycoprotein, XR9051, resistance modulators

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