Summary
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.
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References
Boesch, D., Gaveriaux, C., Jachez, B., Pourtier-Manzanedo, A., Bollinger, P. & Loor, F. (1991). In vivo circumvention of P-glycoprotein-mediated multidrug resistance of tumour cells with SDZ PSC 833. Cancer Res 51: 4226–4233.
Childs, S. & Ling, V. (1994). The MDR superfamily of genes and its biological implications. In Important Advances in Oncology, De Vita VT, Hellman S and Rosenberg SA (eds), pp. 21–36. Lippincott Co: Philadelphia
Colombo, T., Paz, O. G. & D’Incalci, M. (1996). Distribution and activity of doxorubicin combined with SDZ PSC 833 in mice with P388 and P388/DOX leukaemia. Br J Cancer 73: 866–871.
Cros, S., Guilbaud, N., Berlion, M., Dunn, T., Regnier, G., Dhainaut, A., Atassi, G. & Bizzari, J. P. (1992). In vivo evidence of complete circumvention of vincristine resistance by a new triazinoaminopiperidine derivative S9788 in P388/VCR leukaemia model. Cancer Chemother Pharmacol 30: 491–494.
Dale, I. L., Tuffley, W., Callaghan, R., Holmes, J. A., Martin, K., Luscombe, M., Mistry, P., Ryder, H., Stewart, A. J., Charlton, P., Twentyman, P. R. & Bevan, P. (1998). Reversal of P-glycoprotein (P-gp)-mediated multidrug resistance by XR9051, a novel diketopiperazine derivative. Br J Cancer 78: 885–892.
Dalton, W. S. (1994). Is p-glycoprotein a potential target for reversing clinical drug resistance?. Curr Opin Oncol 6: 595–600.
Dantzig, A. H., Shepard, R. L., Cao, J., Law, K. L., Ehlhardt, W. J., Baughman, T. M., Bumol, T. F. & Starling, J. J. (1996). Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979. Cancer Res 56: 4171–4179.
Ferry, D. R., Traunecker, H. & Kerr, D. J. (1996). Clinical trials of P-glycoprotein reversal in solid tumours. Eur J Cancer 32A: 1070–1081.
Germann, U. A. (1996). P-glycoprotein: a mediator of multidrug resistance in tumour cells. Eur J Cancer 32A: 927–944.
Gottesman, M. M. & Pastan, I. (1993). Biochemistry of multidrug resistance mediated by the multidrug transporter. Ann Rev Biochem 62: 385–427.
Hyafil, F., Vergely, C., Du Vignaud, P. & Grand-Perret, T. (1993). In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res 53: 4595–4602.
Johnson, R. K., Chitnis, M. P., Embrey, W. M. & Gregory, E. B. (1978). In vivo characteristics of resistance and cross-resistance of an adriamycin-resistant subline of P388 leukaemia. Cancer Treat Rep 62: 1535–1547.
Lum, B. L., Fisher, G. A., Brophy, N. A., Yahanda, A. M., Adler, K. M., Kaubisch, S., Halsey, J. & Sikic, B. I. (1993). Clinical trials of modulation of multidrug resistance. Pharmacokinetic and pharmacodynamic considerations. Cancer 72: 3502–3514.
Plumb, J. A., Wishart, G. C., Setanoians, A., Morrison, J. G., Hamilton, T. N., Bicknell, S. R. & Kaye, S. B. (1994). Identification of a multidrug resistance modulator with clinical potential by analysis of synergistic activity in vitro, toxicity in vivo and growth delay in a solid human tumour xenograft. Biochem Pharmacol 47: 257–266.
Sato, W., Fukazawa, N., Nakanishi, O., Baba, M., Suzuki, T., Yano, O., Naito, M. & Tsuruo, T. (1995). Reversal of multidrug resistance by a novel quinoline derivative, MS-209. Cancer Chemother Pharmacol 35: 271–277.
Shinoda, H., Inaba, M. & Tsuruo, T. (1989). In vivo circumvention of vincristine resistance in mice with P388 leukaemia using a novel compound AHC-52. Cancer Res 49: 1722–1726.
Spoelstra, E. C., Dekker, H., Schuurhuis, G. J., Broxterman, H. J. & Lankelma, J. (1991). P-glycoprotein efflux pump involved in the mechanism of intrinsic drug resistance in various colon cancer cell lines. Evidence for a saturation of active daunorubicin transport. Biochem Pharmacol 41: 349–359.
Tsuruo, T., Iida, H., Tsukagoshi, S. & Sakurai, Y. (1981). Overcoming of vincristine resistance in P388 leukaemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41: 1967–1972.
Twentyman, P. R., Fox, N. E., Wright, K. A. & Bleehen, N. M. (1986). Derivation and preliminary characterisation of adriamycin resistant lines of human lung cancer cells. Br J Cancer 53: 529–537.
Wacher, V. J., Wu, C. Y. & Benet, L. Z. (1995). Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 13: 129–134.
Yang, J-M, Goldenberg, S., Gottesman, M. M. & Hait, W. N. (1994). Characteristics of P388/VMDRC.04, a simple, sensitive model for studying P-glycoprotein antagonists. Cancer Res 54: 730–737.
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Mistry, P., Plumb, J., Eccles, S. et al. In vivo efficacy of XR9051, a potent modulator of P-glycoprotein mediated multidrug resistance. Br J Cancer 79, 1672–1678 (1999). https://doi.org/10.1038/sj.bjc.6690267
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DOI: https://doi.org/10.1038/sj.bjc.6690267
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