New multidrug-resistance-reversing drugs, MS-209 and SDZ PSC 833

Abstract

The emergence of multidrug resistance (MDR) is a major problem in cancer chemotherapy. Many compounds have been developed to reverse MDR, and some of them are undergoing clinical trials. Among them, MS-209, a novel quinoline derivative, is one of the most potent MDR-reversing agents: MS-209 at 3 microM effectively reverses MDR in various cell lines in vitro. MS-209 directly interacts with P-glycoprotein (Pgp) and inhibits Pgp-mediated drug transport. Oral administration of MS-209 combined with anticancer drugs significantly increases the life span of mice bearing MDR tumor cells without causing serious side effects. SDZ PSC 833, a non-immunosuppressive analogue of cyclosporin A (CsA), is another potent MDR-reversing drug. Interestingly, the MDR-reversing activity of SDZ PSC 833 is enhanced in vitro and in vivo by MRK-16, a monoclonal antibody that recognizes an extracellular epitope of Pgp. Since MRK-16 promotes immune responses to MDR tumor cells expressing Pgp, the combined use of MRK-16, SDZ PSC 833, and antitumor drugs could be an effective therapeutic modality to reverse MDR.