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

被引:25
作者
Mistry, P
Plumb, J
Eccles, S
Watson, S
Dale, I
Ryder, H
Box, G
Charlton, P
Templeton, D
Bevan, PB
机构
[1] Xenova Ltd, Slough SL1 4EF, Berks, England
[2] Univ Glasgow, CRC, Dept Oncol, Glasgow G61 1BD, Lanark, Scotland
[3] Inst Canc Res, Sutton SM2 5NG, Surrey, England
[4] Univ Nottingham, Canc Studies Unit, Nottingham NG7 2UH, England
关键词
multidrug resistance; P-glycoprotein; XR9051; resistance modulators;
D O I
10.1038/sj.bjc.6690267
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:1672 / 1678
页数:7
相关论文
共 22 条
[1]  
BOESCH D, 1991, CANCER RES, V51, P4226
[2]  
Childs S, 1994, Important Adv Oncol, P21
[3]   Distribution and activity of doxorubicin combined with SDZ PSC 833 in mice with P388 and P388/DOX leukaemia [J].
Colombo, T ;
Paz, OG ;
DIncalci, M .
BRITISH JOURNAL OF CANCER, 1996, 73 (07) :866-871
[4]   INVIVO EVIDENCE OF COMPLETE CIRCUMVENTION OF VINCRISTINE RESISTANCE BY A NEW TRIAZINOAMINOPIPERIDINE DERIVATIVE S-9788 IN P388/VCR LEUKEMIA MODEL [J].
CROS, S ;
GUILBAUD, N ;
BERLION, M ;
DUNN, T ;
REGNIER, G ;
DHAINAUT, A ;
ATASSI, G ;
BIZZARI, JP .
CANCER CHEMOTHERAPY AND PHARMACOLOGY, 1992, 30 (06) :491-494
[5]   Reversal of P-glycoprotein-mediated multidrug resistance by XR9051, a novel diketopiperazine derivative [J].
Dale, IL ;
Tuffley, W ;
Callaghan, R ;
Holmes, JA ;
Martin, K ;
Luscombe, M ;
Mistry, P ;
Ryder, H ;
Stewart, AJ ;
Charlton, P ;
Twentyman, PR ;
Bevan, P .
BRITISH JOURNAL OF CANCER, 1998, 78 (07) :885-892
[6]  
Dalton William S., 1994, Current Opinion in Oncology, V6, P595, DOI 10.1097/00001622-199411000-00011
[7]  
Dantzig AH, 1996, CANCER RES, V56, P4171
[8]   Clinical trials of P-glycoprotein reversal in solid tumours [J].
Ferry, DR ;
Traunecker, H ;
Kerr, DJ .
EUROPEAN JOURNAL OF CANCER, 1996, 32A (06) :1070-1081
[9]   P-glycoprotein - A mediator of multidrug resistance in tumour cells [J].
Germann, UA .
EUROPEAN JOURNAL OF CANCER, 1996, 32A (06) :927-944
[10]   BIOCHEMISTRY OF MULTIDRUG-RESISTANCE MEDIATED BY THE MULTIDRUG TRANSPORTER [J].
GOTTESMAN, MM ;
PASTAN, I .
ANNUAL REVIEW OF BIOCHEMISTRY, 1993, 62 :385-427