title: PAK-104P, a pyridine analogue, reverses paclitaxel and doxorubicin resistance in cell lines and nude mice bearing xenografts that overexpress the multidrug resistance protein.
abstract: Multidrug resistance (MDR) is considered multifactorial and has been associated with overexpression of the multidrug resistance protein (MRP). However, effective compounds for reversal of MRP-related MDR are limited. In the present study, the modulatory activity of the novel pyridine analogue PAK-104P on MRP-mediated resistance to doxorubicin and paclitaxel was investigated in two doxorubicin-selected human tumor cell lines [HT1080/DR4 (sarcoma) and HL60/ADR (leukemia)] and compared with the nonimmunosuppressive cyclosporine analogue PSC-833. In cell lines HT1080/DR4 (MRP/lung resistance-related protein phenotype) and HL60/ADR (MRP phenotype), doxorubicin resistance was significantly higher (250-fold and 180-fold, respectively) than that to paclitaxel (6-fold and 9-fold, respectively). With noncytotoxic concentrations of PAK-104P (1 and 5 microM), the reversal of doxorubicin resistance was significant but partial in HT1080/DR4 and HL60/ADR cells (dose-modifying factor for 5.0 microM PAK-104P, 25.0 and 31.2, respectively), whereas complete reversal of paclitaxel resistance was achieved in HL60/ADR cells. In contrast, PSC-833 modulation of doxorubicin and paclitaxel resistance was modest. Cellular drug uptake and retention studies by flow cytometry analysis demonstrated that PAK-104P was effective in restoring cellular doxorubicin concentrations in resistant cells to levels comparable to those obtained in parental cells. In athymic nude mice, PAK-104P significantly potentiated the therapeutic efficacy of doxorubicin and paclitaxel against resistant HT1080/DR4 xenografts. Of significance is that the maximum tolerated doses of doxorubicin and paclitaxel were administered in combination with PAK-104P, documenting improvement in the therapeutic index of these agents. In addition to reversing P-glycoprotein-mediated MDR, the pyridine analogue PAK-104P provides an example of an effective in vivo modulator of MRP-mediated MDR.
authors.affiliation: Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: U
authors.initials: U
authors.lastname: Vanhoefer
authors.forename: S
authors.initials: S
authors.lastname: Cao
authors.forename: H
authors.initials: H
authors.lastname: Minderman
authors.forename: K
authors.initials: K
authors.lastname: Tóth
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: M L
authors.initials: ML
authors.lastname: Slovak
authors.forename: Y M
authors.initials: YM
authors.lastname: Rustum
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003498:Cyclic P-Oxides / Q000494:pharmacology*; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000032:analysis; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009368:Neoplasm Transplantation; D009539:Nicotinic Acids / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D012513:Sarcoma, Experimental / Q000188:drug therapy; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D003498:Cyclic P-Oxides; D004317:Doxorubicin; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009539:Nicotinic Acids; D017239:Paclitaxel; C103821:PAK 104P