Zosuquidar trihydrochloride: Multidrug resistance modulator, P-glycoprotein (MDR-1) inhibitor

Drugs of the Future

Volumn 28, Issue 2, 2003, Pages 125-136

  Sorbera, L A ^a   Castaner J ^a   Silvestre, J S ^a   Bayes M ^a  

^a PROUS SCIENCE   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BIRICODAR DICITRATE; BUFURALOL; CYCLOPHOSPHAMIDE; CYCLOSPORIN; CYTARABINE; DAUNORUBICIN; DICLOFENAC; DOCETAXEL; DOXORUBICIN; ELACRIDAR; ETOPOSIDE; GLYCOPROTEIN P; MIDAZOLAM; MS 073; NAVELBINE; PACLITAXEL; PHENACETIN; PREDNISONE; RESERPINE; TACROLIMUS; TAMOXIFEN; TARIQUIDAR; TOREMIFENE; TRIFLUOPERAZINE; UNCLASSIFIED DRUG; VERAPAMIL; VINCRISTINE; YOHIMBINE; ZOSUQUIDAR;

AGITATION; ARTHRALGIA; ATAXIA; BINDING AFFINITY; CANCER; CELL MEMBRANE; CEREBELLUM DISEASE; CLINICAL TRIAL; CONFUSION; CONSTIPATION; DOSE RESPONSE; DRUG ACTIVITY; DRUG BLOOD LEVEL; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG MECHANISM; DRUG METABOLISM; DRUG POTENTIATION; DRUG SAFETY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TOLERABILITY; EFFUSION; ENERGY; FATIGUE; FEVER; HALLUCINATION; HUMAN; MULTIDRUG RESISTANCE; MYALGIA; NEUROTOXICITY; NEUTROPENIA; PROTEIN EXPRESSION; REVIEW; STOMATITIS; TREMOR;

EID: 0038035675     PISSN: 03778282     EISSN: None     Source Type: Journal    
DOI: 10.1358/dof.2003.028.02.719469     Document Type: Review

References (80)

1. Pfister, J.R., Makra, F., Muehldorf, A.V., Wu, H., Nelson, J.T., Cheung, P., Bruno, N.A., Casey, S.M., Zutshi, N., Slate, D.L. Methanodibenzosuberylpiperazines as potent multidrug resistance reversal agents. Bioorg Med Chem Lett 1995, 5: 2473-6.
2. Pfister, J.R., Slate, D.L. (Syntex USA). 10,11-Methanodibenzosuberane derivs. used as chemosensitizing agents. EP 0695293, EP 0866063, JP 1996509223, WO 9424107.
3. Vo, D., Wolowyk, M.W., Knaus, E.E. Synthesis and cardioselective β-adrenergic antagonist activity of quinolyloxypropanolamines. Drug Des Discov 1992, 9: 69-78.
4. Huff, B.E., Le Tourneau, M.E., Wilson, T.M., Bush, J.K., Reutzel-Edens, S.M. (Eli Lilly and Company). Process for preparing 10,11-methanobenzosuberane derivs. EP 1189887, JP 2003501421, WO 0075121.
5. Astleford, B.A., Barnett, C.J., Kobierski, M.E., Wilson, T.M. (Eli Lilly and Company). Process for preparing a 10,11-methanodibenzosuberane deriv. EP 1198462, WO 0075132.
6. Gottesman, M.M., Pastan, I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 1993, 62: 385-427.
7. Ruetz, S., Gros, P. Functional expression of P-glycoproteins in secretory vesicles. J Biol Chem 1994, 269: 12277-84.
8. Bosch, I., Croop, J. P-glycoprotein multidrug resistance and cancer. Biochim Biophys Acta 1996, 1288: F37-54.
9. Thiebaut, F., Tsuruo, T., Hamada, H., Gottesman, M.M., Pastan, I., Willingham, M.C. Cellular localization of the multidrugresistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 1987, 84: 7735-8.
10. Cordon-Cardo, C., O'Brien, J.P., Boccia, J., Casals, D., Bertino, J.R., Melamed, M.R. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 1990, 38: 1277-87.
11. Schinkel, A.H., Mayer, U., Wagenaar, E. et al. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl. Acad Sci USA 1997, 94: 4028-33.
12. Rao, V., Dahlheimer, J.L., Bardgett, M.E., Snyder, A.Z., Piwnica-Worms, D. MDR1 Pgp mediates the blood-cerebrospinal fluid permeability barrier in choroid plexus epithelium. Proc Am Assoc Cancer Res 1998, 39: Abst 517.
13. van Helvoort, A., Smith, A.J., Sprong, H., Fritzsche, I., Schinkel, A.H., Borst, P., van Meer, G. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 1996, 87: 507-17.
14. Bosch, I., Dunussi-Joannopoulos, K., Wu, R.L., Furlong, S.T., Croop, J. Phosphatidylcholine and phosphatidylethanolamine behave as substrates of the human MDR1 P-glycoprotein. Biochemistry 1997, 36: 5685-94.
15. Bezombes, C., Maestre, N., Laurent, G., Levade, T., Bettaieb, A., Jaffrezou, J.P. Restoration of TNF-α-induced ceramide generation and apoptosis in resistant human leukemia KG1a cells by the P-glycoprotein blocker PSC833. FASEB J 1998, 12: 101-9.
16. Lange, Y., Steck, T.L. Cholesterol homeostasis. Modulation by amphiphiles. J Biol Chem 1994, 269: 29371-4.
17. Luker, G.D., Nilsson, K.R., Covey, D.F., Piwnica-Worms, D. Multidrug resistance (MDR1) P-glycoprotein enhances esterification of plasma membrane cholesterol. J Biol Chem 1999, 274: 6979-91.
18. Sandor, V., Foto, T., Bates, S.E. Future perspectives for the development of P-glycoprotein modulators. Drug Resist Updates 1998, 1: 190-200.
19. Tsuruo, T., Iida, H., Tsukagoshi, S., Sakurai, Y. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 1981, 41: 1967-72.
20. Lum, B.L., Fisher, G.A., Brophy, N.A., Yahanda, A.M., Adler, K.M., Kaubisch, S., Halsey, J., Sikic, B.I. Clinical trials of modulation of multidrug resistance. Pharmacokinetic and pharmacodynamic considerations. Cancer 1993, 72: 3502-14.
21. Goldstein, L.J. Clinical reversal of drug resistance. Curr Probl Cancer 1995, 19: 65-124.
22. Shustik, C., Dalton, W., Gros, P. P-glycoprotein-mediated multidrug resistance in tumor cells: Biochemistry, clinical relevance and modulation. Mol Aspects Med 1995, 16: 1-78.
23. Johnson, W.W. P-glycoprotein-mediated efflux as a major factor in the variance of absorption and distribution of drugs: Modulation of chemotherapy resistance. Methods Find Exp Clin Pharmacol 2002, 24: 501-14.
24. Slate, D.L., Bruno, N.A., Casey, S.M., Zutshi, N., Garvin, L.J., Wu, H., Pfister, J.R. RS-33295-198: A novel, potent modulator of P-glycoprotein-mediated multidrug resistance. Anticancer Res 1995, 15: 811-4.
25. Dantzig, A.H., Law, K.L., Cao, J., Starling, J.J. Reversal of multidrug resistance by the P-glycoprotein modulator, LY335979, from the bench to the clinic. Curr Med Chem 2001, 8: 39-50.
26. Starling, J.J., Shepard, R.L., Cao, J. et al. Pharmacological characterization of LY335979: A potent cyclopropyldibenzosuberane modulator of P-glycoprotein. Adv Enzyme Regul 1997, 37: 335-47.
27. Dantzig, A.H., Shepard, R.L., Cao, J., Law, K.L., Ehlhardt, W.J., Baughman, T.M., Bumol, T.F., Starling, J.J. Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979. Cancer Res 1996, 56: 4171-9.
28. Dantzig, A.H., Shepard, R.L., Law, K.L., Tabas, L., Pratt, S., Gillespie, J.S., Binkley, S.N., Kuhfeld, M.T., Starling, J.J., Wrighton, S.A. Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein and effect on cytochrome P-450 activities. J Pharmacol Exp Ther 1999, 290: 854-62.
29. Lehne, G., Moerkrid, L., den Boer, M., Rugstad, H.E. Diverse effects of P-glycoprotein inhibitory agents on human leukemia cells expressing the multidrug resistance protein (MRP). Int J Clin Pharmacol Ther 2000, 38: 187-95.
30. Lehne, G., De Angelis, P., den Boer, M., Rugstad, H.E. Growth inhibition, cytokinesis failure and apoptosis of multidrug-resistant leukemia cells after treatment with P-glycoprotein inhibitory agents. Leukemia 1999, 13: 768-78.
31. Shepard, R.L., Cao, J., Starling, J.J., Dantzig, A.H. Modulation of P-glycoprotein but not MRP1- or BCRP-mediated drug resistance by LY335979. Int J Cancer 2003, 103: 121-5.
32. Green, L.J., Marder, P., Slapak, C.A. Modulation by LY335979 of P-glycoprotein function in multidrug-resistant cell lines and human natural killer cells. Biochem Pharmacol 2001, 61: 1393-9.
33. Baughman, T.M., Ehlhardt, W.J., Cao, J., Law, K.L., Starling, J.J. The effect of LY335979 on plasma levels of doxorubicin, etoposide and Taxol in mouse and rat. 7th North Am Issx Meet (Oct. 20-24, San Diego) 1996, Abst 269.
34. Wacher, V.J., Wu, C.Y., Benet, L.Z. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: Implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995, 13: 129-34.
35. Ehlhardt, W.J., Woodland, J.M., Baughman, T.M., Vandenbranden, M., Wrighton, S.A., Kroin, J.S., Norman, B.H., Maple, S.R. Liquid chromatography/nuclear magnetic resonance spectroscopy and liquid chromatography/mass spectrometry identification of novel metabolites of the multidrug resistance modulator LY335979 in rat bile and human liver microsomal incubations. Drug Metab Dispos 1998, 26: 42-51.
36. Truex, L.L., Zimmermann, J., Luffer-Atlas, D., Reddy, V. Effects of co-administered LY335979 on vinorelbine pharmacokinetics and pharmacodynamics in beagle dogs. Proc Am Assoc Cancer Res 2001, 42: Abst 5105.
37. Reddy, V.R., Buben, J.A., Truex, L.L., Brown, D.E., Fletcher, D.J., Zimmerman, J.L., Vahle, J.L. The toxicity and pharmacokinetic interaction of LY335979, an inhibitor of P-glycoprotein, with doxorubicin in beagle dogs. Proc Am Assoc Cancer Res 1998, 39: Abst 511.
38. Rubin, E.H., de Alwis, D.P., Pouliquen, I. et al. A phase I trial of a potent P-glycoprotein inhibitor, zosuquidar.3HCl trihydrochloride (LY335979), administered orally in combination with doxorubicin in patients with advanced malignancies. Clin Cancer Res 2002, 8: 3710-7.
39. Fracasso, P.M., Tan, B.R., Arquette, M.A. et al. A phase I and pharmacokinetic study of docetaxel and LY335979 in patients with advanced maligancies. Proc Am Soc Clin Oncol 2000, 19: Abst 701.
40. Moore, M.J., Siu, L.L., Oza, A., MacLean, M., Fisher, B., Jordan, C., Slapak, C., Seymour, L. A phase I study of vinorelbine plus multidrug resistance (MDR) inhibitor LY 335979 in patients with advanced solid tumors. Clin Cancer Res 2000, 6(Suppl.): Abst 190.
41. Schellens, J.H.N., Kruytzer, M.F., Vasey, P.A., Harris, A.L., Deplanque, G., Burgess, M., deAlwis, D., O'Callahan, M., Kaye, S.B., Beijnen, J.H. Phase I and pharmacologic study of the P-glycoprotein (P-gp) inhibitor L-335979 (LY) and paclitaxel (P) in patients with solid tumors. Proc Am Assoc Cancer Res 2001, 42: Abst 2882.
42. Tura, S., Morschhauser, F., Zinzani, P., Sloots, L., Burgess, M., Dumontet, C. A phase I trial of the P-glycoprotein (P-gp) inhibitor zosuquidar (LY335979) and CHOP chemotherapy in patients with non-Hodgkin's lymphoma. Blood 2001, 98(11, Part 2): Abst 4734.
43. Gerrard, G., Ganeshaguru, K., Baker, R., Potter, M., Prentice, H.G., Burgess, M., Herbert, L., McCullough, H., Mehta, A.B. Preliminary pharmacodynamic analysis on a phase 1 study of the P-gp inhibitor zosuquidar (LY335979) given by short intravenous infusion in combination with daunorubicin and cytarabine in AML patients. 7th Congr Eur Hematol Assoc (June 6-9, Florence) 2002, Abst 0566.
44. Cripe, L.D., Tallman, M., Karanes, C., List, A.F., Kinney, P.A., Burgess, M.F., Slapak, C.A. A phase II trial of zosuquidar (LY335979), a modulator of P-glycoprotein (PgP9 activity, plus daunorubicin and high-dose cytarabine in patients with newlydiagnosed secondary acute myelod leukemia (AML), refractory anemia with excess blasts in transformation (RAEB-t) or relapsed/refractory AML. Blood 2001, 98(11, Part 1): Abst 2492.
45. Green, L., Cripe, L.D., Tallman, M.S., Karanes, C., List, A.F., Slapak, C.A., Marder, P. Blockade of P-gp function in acute myeloid leukemia bone marrow cells after zosuquidar (LY335979) administration. Blood 2001, 98(11, Part 2): Abst 4399.
46. Ma, L., Cripe, L.D., Tallman, M.S., Karanes, C., List, A.F., Jordan, C.L., Slapak, C.A. Genetic polymorphism of the MDR1 gene in patients with acute myeloid leukemia (AML) treated with zosuquidar (LY335979), daunorubicin, and cytarabine. Blood 2001, 98(11, Part 2): Abst 4411.
47. www.clinicaltrials.gov.
48. Germann, U.A., Shlyakhter, D., Mason, V.S., Zelle, R.E., Duffy, J.P., Galullo, V., Armistead, D.M., Saunders, J.O., Boger, J., Harding, M.W. Cellular and biochemical characterization of VX-710 as a chemosensitizer: Reversal of P-glycoprotein-mediated multidrug resistance in vitro. Anticancer Drugs 1997, 8: 125-40.
49. Mistry, P., Stewart, A.J., Dangerfield, W., Okiji, S., Liddle, C., Bootle, D., Plumb, J.A., Templeton, D., Charlton, P. In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Res 2001, 61: 749-58.
50. Martin, C., Berridge, G., Mistry, P., Higgins, C., Charlton, P., Callaghan, R. The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein. Br J Pharmacol 1999, 128: 403-11.
51. Traunecker, H.C.L., Stevens, M.C., Kerr, D.J., Ferry, D.R. The acridonecarboxamide GF120918 potently reverses P-glycoprotein-mediated resistance in human sarcoma MES-Dx5 cells. Br J Cancer 1999, 81: 942-51.
52. Mellows, G., Norris, D., Waterfall, J. The effect of XR9576 (tariquidar), a specific P-glycoprotein inhibitor, on cytochrome P450 activities in human liver microsomes. Proc Am Assoc Cancer Res 2002, 43: Abst 4714.
53. Gerrard, G., Ganeshaguru, K., Baker, R., Potter, M., Prentice, H.G., Burgess, M., Herbert, L., McCullough, H., Mehta, A.B. A phase I study of a P-gp inhibitor zosuquidar (LY 335979), given by short intravenous infusion in combination with daunorubicin and cytarabine in AML/MDS patients. Blood 2001, 98(11, Part 2): Abst 4398.
54. Green, L., Marder, P., Skerjanec, A., Rubin, E., Sandler, A., Slapak, C. P-glycoprotein targeted pharmacological activity detected during clinical evaluations of LY335979. Proc Am Assoc Cancer Res 1999, 40: Abst 437.
55. Skerjanec, A., Sandler, A., Green, L., Marder, P., Kuan, S., Chaudhary, A., Slapak, C. A phase I dose-escalating trial of LY335979, a potent multidrug-resistance modulator. Farm Vestn 1999, 50: 292-3.
56. Choo, E.F., Leake, B., Wandel, C., Imamura, H., Wood, A.J., Wilkinson, G.R., Kim, R.B. Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos 2000, 28: 655-60.
57. Fontaine, M., Yang, H., Elmquist, W.F. The effect of LY-335979, a novel P-glycoprotein inhibitor, on the permeability of mannitol across the blood-brain and blood-CSF barriers: An in vivo microdiaslysis study in freely-moving rats. Pharm Res 1997, 14(11, Suppl.): Abst 2364.
58. Sun, H., Elmquist, W.F. The effect of LY-335979, a novel P-glycoprotein inhibitor, on the free fraction of quinidine in rat plasma. Pharm Res 1997, 14(11, Suppl.): Abst 3293.
59. Starling, J.J., Law, K.L., Shepard, R.L., Cao, J., Bumol, T.F., Dantzig, A.H. LY335979, a potent cyclopropyldibenzosuberane inhibitor of P-glycoprotein, significantly reverses taxol resistance in a multidrug resistant human non-small cell lung carcinoma nude mouse xenograft model. Proc Am Assoc Cancer Res 1996, 37: Abst 2264.
60. Slapak, C.A., Dahlheimer, J., Piwnica-Worms, D. Reversal of multidrug resistance with LY335979: Functional analysis of P-glycoprotein-mediated transport activity and its modulation in vivo. J Clin Pharmacol 2001, 41: 29S-38S.
61. Kurumboor, S.K., Miller, D.W., Elmquist, W.F. Effect of LY335979 on the brain distribution of doxorubicin in wild-type and P-glycoprotein deficient mice. Proc Am Assoc Cancer Res 1999, 40: Abst 4370.
62. van der Sandt, I.C.J., Gaillard, P.J., Voorwinden, H.H., de Boer, A.G., Breimer, D.D. P-glycoprotein inhibition leads to enhanced disruptive effects by anti-microtubule cytostatics at in vitro bloodbrain barrier. Pharm Res 2001, 18: 587-92.
63. Shepard, R.L., Law, K.L., Starling, J.J., Dantzig, A.H. Modulation of navelbine and mitoxantrone resistance by the P-glycoprotein modulator, LY335979. Proc Am Assoc Cancer Res 2000, 41: Abst 1703.
64. Shepard, R.L., Slate, D.L., Pfister, J., Cao, J., Starling, J.J., Dantzig, A.H. Evaluation of a highly potent modulator of multidrug resistance (MDR), RS33295-198. Proc Am Assoc Cancer Res 1995, 36: Abst 2051.
65. Shepard, R.L., Dantzig, A.H. The affinity of P-glycoprotein (Pgp) differs for stereoisomers of the potent modulator LY335979. Proc Am Assoc Cancer Res 1996, 37: Abst 2272.
66. Dantzig, A.H., Shepard, R.L., Law, K.L., Tabas, L., Gillespie, J., Binkley, S., Starling, J.J., Wrighton, S. Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein and effect on cytochrome P450 activities. 10th NCI-EORTC Symp New Drugs Cancer Ther (June 16-19, Amsterdam) 1998, Abst 555.
67. Norman, B.H., Kroin, J.S., Dantzig, A.H., Shepard, R.L., Cao, J., Winter, M.A., Bell, M.G., Starling, J.J. Structure activity relationship (SAR) studies of cyclopropyldibenzosubarane inhibitors of P-glycoprotein and their effects on multidrug resistance in vitro and in vivo. 9th NCI-EORTC Symp New Drugs Cancer Ther (March 12-15, Amsterdam) 1996, Abst 414.
68. Ekins, S., Kim, R.B., Leake, B.F. et al. Three-dimensional quantitative structure-activity relationships of inhibitors of P-glycoprotein. Mol Pharmacol 2002, 61: 964-73.
69. Ekins, S., Kim, R.B., Leake, B.F. et al. Application of threedimensional quantitative structure-activity relationships of P-glycoprotein inhibitors and substrates. Mol Pharmacol 2002, 61: 974-81.
70. Liu, L., Nussbaum, M.A. Systematic screening approach for chiral separations of basic compounds by capillary electrophoresis with modified cyclodextrins. J Pharm Biomed Anal 1999, 19: 679-94.
71. Ekins, S., Bravi, G., Binkley, S., Gillespie, J.S., Ring, B.J., Wikel, J.H., Wrighton, S.A. Three- and four-dimensional quantitative structure activity relationship analyses of cytochrome P-450 3A4 inhibitors. J Pharmacol Exp Ther 1999, 290: 429-38.
72. Ekins, S., Bravi, G., Binkley, S., Gillespie, J.S., Ring, B.J., Wikel, J.H., Wrighton, S.A. Three- and four-dimensional-quantitative structure activity relationship (3D/4D QSAR) analyses of CYP2C9 inhibitors. Drug Metab Dispos 2000, 28: 994-1002.
73. Baron, J.M., Goh, L.B., Yao, D., Wolf, C.R., Friedberg, T. Modulation of P450 CYP3A4-dependent metabolism by P-glycoprotein: Implications for P450 phenotyping. J Pharmacol Exp Ther 2001, 296: 351-8.
74. Sun, H., Bungay, P.M., Elmquist, W.F. Effect of capillary efflux transport inhibition on the determination of probe recovery during in vivo microdialysis in the brain. J Pharmacol Exp Ther 2001, 297: 991-1000.
75. van der Sandt, I.C., Vos, C.M., Nabulsi, L., Blom-Roosemalen, M.C., Voorwinden, H.H., de Boer, A.G., Breimer, D.D. Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood-brain barrier. AIDS 2001, 15: 483-91.
76. Florea, B.I., van der Sandt, I.C., Schrier, S.M., Kooiman, K., Deryckere, K., de Boer A.G., Junginger, H.E., Borchard, G. Evidence of P-glycoprotein mediated apical to basolateral transport of flunisolide in human broncho-tracheal epithelial cells (Calu-3). Br J Pharmacol 2001, 134: 1555-63.
77. Molnár, L., Keseru, G.M. A neural network based virtual screening of cytochrome P450 3A4 inhibitors. Bioorg Med Chem Lett 2002, 12: 419-21.
78. de Alwis, D.P., Pouliquen, I., Burgess, M., Green, L., Chaudhary, A., Jordan, C., Slapak, C., Sandler, A. A phase I dose escalating study of LY335979, a novel Pgp modulator-administered intravenously in combination with doxorubicin. Proc Am Soc Clin Oncol 2001, 20(Part 1): Abst 284.
79. Sweeney, C., Sandler, A., Gordon, M. et al. Continuous intravenous infusion of LY335979, a P-glycoprotein modulator, administered in combination with doxorubicin: Results of a phase I dose-escalating trial. Proc Am Soc Clin Oncol 1999, 18: Abst 703.
80. Rubin, E., Zamek, R., Medina, M. et al. A phase I trial of LY335979, a potent multidrug-resistance modulator, administered orally in combination with doxorubicin. Proc Am Soc Clin Oncol 1999, 18: Abst 705.