In vivo efficacy of XR9051, a potent modulator of P-glycoprotein mediated multidrug resistance.
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.
Mistry
P
P
Xenova Ltd, Slough, UK.
Plumb
J
J
Eccles
S
S
Watson
S
S
Dale
I
I
Ryder
H
H
Box
G
G
Charlton
P
P
Templeton
D
D
Bevan
P B
PB
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D001597:Benzylidene Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007408:Intestinal Absorption; D007546:Isoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D044005:Tetrahydroisoquinolines; D014183:Transplantation, Heterologous
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001597:Benzylidene Compounds; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C118656:XR 9051