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Dofequidar

Description of dofequidar: Dofequidar (MS-209) is a quinolone-derived sphingomyelin synthase inhibitor that blocks P-glycoprotein and multidrug resistance-associated protein-1, is under development by Schering for the potential treatment of multidrug resistant tumors. By March 2003, phase II trials in breast cancer and non-small-cell lung cancer had been initiated.

Current developer: Mitsui Pharmaceuticals (Originator), Nihon Schering (Originator), Schering AG (Originator).

A substance that is being studied for its ability to make cancer cells respond better to chemotherapy drugs to which they have become resistant. It belongs to the family of drugs called quinolone antibiotics.

A synthetic quinoline derivative with multidrug resistance (MDR) modulating properties. Dofequidar fumarate, like many other MDR reversal agents, binds competitively to the drug-binding site of the transmembrane P-glycoprotein efflux pump (P-gp). Once bound to the P-gp efflux pump, dofequidar is transported out of transformed cells by a mechanism similar to that used by cytotoxic drugs, thereby blocking the efflux of these compounds from the cell. Inhibition of the efflux pump by this agent leads to a retention of the cytotoxic drug resulting in increased intracellular drug concentrations, thereby enhancing cytotoxicity. Dofequidar has demonstrated reversal of the MDR phenotype in those cells exposed to various chemotherapeutic agents, such as vinca alkaloids and anthracyclines.

1: Saeki T, Nomizu T, Toi M, Ito Y, Noguchi S, Kobayashi T, Asaga T, Minami H, Yamamoto N, Aogi K, Ikeda T, Ohashi Y, Sato W, Tsuruo T. Dofequidar fumarate (MS-209) in combination with cyclophosphamide, doxorubicin, and fluorouracil for patients with advanced or recurrent breast cancer. J Clin Oncol. 2007 Feb 1;25(4):411-7. Epub 2006 Dec 18. PubMed PMID: 17179098.

2: Robert J. MS-209 Schering. Curr Opin Investig Drugs. 2004 Dec;5(12):1340-7. Review. PubMed PMID: 15648956.

3: Tatsumi M, Tsuruo T, Nishimura T. Evaluation of MS-209, a novel multidrug-resistance-reversing agent, in tumour-bearing mice by technetium-99m-MIBI imaging. Eur J Nucl Med Mol Imaging. 2002 Mar;29(3):288-94. PubMed PMID: 12002701.

4: Kimura Y, Aoki J, Kohno M, Ooka H, Tsuruo T, Nakanishi O. P-glycoprotein inhibition by the multidrug resistance-reversing agent MS-209 enhances bioavailability and antitumor efficacy of orally administered paclitaxel. Cancer Chemother Pharmacol. 2002 Apr;49(4):322-8. Epub 2002 Feb 1. PubMed PMID: 11914912.

5: Naito M, Matsuba Y, Sato S, Hirata H, Tsuruo T. MS-209, a quinoline-type reversal agent, potentiates antitumor efficacy of docetaxel in multidrug-resistant solid tumor xenograft models. Clin Cancer Res. 2002 Feb;8(2):582-8. PubMed PMID: 11839680.

6: Nokihara H, Yano S, Nishioka Y, Hanibuchi M, Higasida T, Tsuruo T, Sone S. A new quinoline derivative MS-209 reverses multidrug resistance and inhibits multiorgan metastases by P-glycoprotein-expressing human small cell lung cancer cells. Jpn J Cancer Res. 2001 Jul;92(7):785-92. PubMed PMID: 11473730.

7: Suzuki T, Mabuchi K, Fukazawa N. Synthesis of glucuronides of multidrug resistance reversing drug MS-209. Bioorg Med Chem Lett. 1999 Mar 8;9(5):659-62. PubMed PMID: 10201824.

8: Nakamura T, Oka M, Aizawa K, Soda H, Fukuda M, Terashi K, Ikeda K, Mizuta Y, Noguchi Y, Kimura Y, Tsuruo T, Kohno S. Direct interaction between a quinoline derivative, MS-209, and multidrug resistance protein (MRP) in human gastric cancer cells. Biochem Biophys Res Commun. 1999 Feb 24;255(3):618-24. PubMed PMID: 10049760.

9: Shrivastava P, Hanibuchi M, Yano S, Parajuli P, Tsuruo T, Sone S. Circumvention of multidrug resistance by a quinoline derivative, MS-209, in multidrug-resistant human small-cell lung cancer cells and its synergistic interaction with cyclosporin A or verapamil. Cancer Chemother Pharmacol. 1998;42(6):483-90. PubMed PMID: 9788575.

10: Takeshita H, Kusuzaki K, Tsuji Y, Hirata M, Hashiguchi S, Nakamura S, Murata H, Ashihara T, Hirasawa Y. Avoidance of doxorubicin resistance in osteosarcoma cells using a new quinoline derivative, MS-209. Anticancer Res. 1998 Mar-Apr;18(2A):739-42. PubMed PMID: 9615713.

11: Naito M, Nakanishi O, Tsuruo T. [Overcoming of multidrug resistance by a newly synthesized quinoline compound, MS-209]. Nihon Rinsho. 1997 May;55(5):1122-7. Review. Japanese. PubMed PMID: 9155163.

12: Wang YH, Motoji T, Motomura S, Shiozaki H, Tsuruo T, Mizoguchi H. Recovery of drug sensitivity by MS-209, a new multidrug resistance-reversing agent, on acute myelogenous leukaemic blasts and K562 cells resistant to adriamycin cell line. Eur J Haematol. 1997 Mar;58(3):186-94. PubMed PMID: 9150713.

13: Germann UA, Ford PJ, Shlyakhter D, Mason VS, Harding MW. Chemosensitization and drug accumulation effects of VX-710, verapamil, cyclosporin A, MS-209 and GF120918 in multidrug resistant HL60/ADR cells expressing the multidrug resistance-associated protein MRP. Anticancer Drugs. 1997 Feb;8(2):141-55. PubMed PMID: 9073310.

14: Naito M, Tsuruo T. New multidrug-resistance-reversing drugs, MS-209 and SDZ PSC 833. Cancer Chemother Pharmacol. 1997;40 Suppl:S20-4. PubMed PMID: 9272129.

15: Narasaki F, Oka M, Fukuda M, Nakano R, Ikeda K, Takatani H, Terashi K, Soda H, Yano O, Nakamura T, Doyle LA, Tsuruo T, Kohno S. A novel quinoline derivative, MS-209, overcomes drug resistance of human lung cancer cells expressing the multidrug resistance-associated protein (MRP) gene. Cancer Chemother Pharmacol. 1997;40(5):425-32. PubMed PMID: 9272120.

16: Nakanishi O, Baba M, Saito A, Yamashita T, Sato W, Abe H, Fukazawa N, Suzuki T, Sato S, Naito M, Tsuruo T. Potentiation of the antitumor activity by a novel quinoline compound, MS-209, in multidrug-resistant solid tumor cell lines. Oncol Res. 1997;9(2):61-9. PubMed PMID: 9167187.

17: Sato W, Fukazawa N, Nakanishi O, Baba M, Suzuki T, Yano O, Naito M, Tsuruo T. Reversal of multidrug resistance by a novel quinoline derivative, MS-209. Cancer Chemother Pharmacol. 1995;35(4):271-7. PubMed PMID: 7828268.

18: Baba M, Nakanishi O, Sato W, Saito A, Miyama Y, Yano O, Shimada S, Fukazawa N, Naito M, Tsuruo T. Relationship between multidrug resistant gene expression and multidrug resistant-reversing effect of MS-209 in various tumor cells. Cancer Chemother Pharmacol. 1995;36(5):361-7. PubMed PMID: 7634376.