Reversal of Multidrug Resistance by the P-Glycoprotein Modulator, LY335979, from the Bench to the Clinic

• Published in: Current medicinal chemistry Vol. 8; no. 1; pp. 39 - 50
• Main Authors: DANTZIG, A. H, LAW, K. L, CAO, J, STARLING, J. J
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Schiphol Bentham Science Publishers Ltd 01.01.2001; Bentham Science
• Subjects: Animals; Antineoplastic agents; ATP; ATP Binding Cassette Transporter, Subfamily B - drug effects; ATP Binding Cassette Transporter, Subfamily B - genetics; Biological and medical sciences; Chemotherapy; Cytochrome; Dibenzocycloheptenes - pharmacology; Dibenzocycloheptenes - therapeutic use; Drug Resistance, Multiple - genetics; Drug Resistance, Neoplasm - genetics; Humans; Leukemia; Medical sciences; Neoplasms - drug therapy; Neoplasms - genetics; Pharmacokinetics; Pharmacology. Drug treatments; Quinolines - pharmacology; Quinolines - therapeutic use; Tumors; Antineoplastic agent; Drug combination; Modulator; Vinblastine; Taxol; P Glycoprotein; Etoposide; Quinoline derivatives; Tetracyclic compound; Doxorubicin; Biological activity; Podophyllotoxine derivatives; Alkaloid; Hydroxyether; Synthetic product; Multiple resistance; Taxane derivatives; Anthracyclins; Aromatic compound; Drug interaction; Piperazine derivatives
• ISSN: 0929-8673; 1875-533X
• DOI: 10.2174/0929867013373903

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 responsible for the removal from the cell of several anticancer agents including doxorubicin. Modulators can inhibit these transporters. LY335979 is among the most potent modulators of Pgp with a Ki 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 implanted with Pgp-expressing murine leukemia (P388/ADR) when administered in combination with either daunorubicin, doxorubicin or etoposide. Coadministration of LY335979 with paclitaxel compared to paclitaxel alone significantly reduced the tumor mass of the Pgp-expressing UCLAP3.003VLB 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 significant effect on the pharmacokinetics of these anticancer agents. This may be 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 of Pgp in multidrug resistance. LY335979 is currently in clinical trials.