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

Br J Cancer. 1999 Apr;79(11-12):1672-8. doi: 10.1038/sj.bjc.6690267.


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)phe nyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-pipera zinylidene)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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Animals
  • Benzylidene Compounds / pharmacokinetics
  • Benzylidene Compounds / pharmacology*
  • Colonic Neoplasms / drug therapy
  • Drug Resistance, Multiple*
  • Drug Screening Assays, Antitumor
  • Humans
  • Intestinal Absorption
  • Isoquinolines / pharmacokinetics
  • Isoquinolines / pharmacology*
  • Leukemia, Experimental / drug therapy
  • Mice
  • Tetrahydroisoquinolines*
  • Transplantation, Heterologous


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Benzylidene Compounds
  • Isoquinolines
  • Tetrahydroisoquinolines
  • XR 9051