Reversal of multidrug resistance by the P-glycoprotein modulator, LY335979, from the bench to the clinic

Multidrug resistance may be conferred by P-glycoprotein (Pgp, ABCB1) or the multidrug resistance associated protein (MRP). These membrane proteins are members of the ATP binding cassette transporter superfamily and are respon sible for the removal from the cell of several anticancer agents including doxorubicin. Modulators can inhibit these transporters. LY335979 is among t he most potent modulators of Pgp with a K-i of 59 nM. LY335979 is selective for Pgp, and does not modulate MRP-mediated resistance by MRP1 (ABCC1) and MRP2 (ABCC2). LY335979 significantly enhanced the survival of mice implant ed with Pgp-expressing murine leukemia (P388/ADR) when administered in comb ination with either daunorubicin, doxorubicin or etoposide. Coadministratio n of LY335979 with paclitaxel compared to paclitaxel alone significantly re duced the tumor mass of the Pgp-expressing UCLA-P3.003VLB lung carcinoma in a xenograph model and delayed the development of tumors in mice implanted with the parental drug-sensitive UCLA-P3 tumor. LY335979 was without signif icant effect on the pharmacokinetics of these anticancer agents. This may b e due impart to its poor inhibition of four major cytochrome P450 isozymes important in metabolizing doxorubicin and other oncolytics. The selectivity and potency of this modulator allows the clinical evaluation of the role o f Pgp in multidrug resistance. LY335979 is currently in clinical trials.