PAK-104P, a pyridine analogue, reverses paclitaxel and doxorubicin resistance in cell lines and nude mice bearing xenografts that overexpress the multidrug resistance protein

• Published in: Clinical cancer research 1996-02, Vol.2 (2), p.369-377
• Main Authors: VANHOEFER, U, SHOUSONG CAO, MINDERMAN, H, TOTH, K, SCHEPER, R. J, SLOVAK, M. L, RUSTUM, Y. M
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; ATP-Binding Cassette Transporters - physiology; Biological and medical sciences; Chemotherapy; Cyclic P-Oxides - pharmacology; Doxorubicin - pharmacokinetics; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Glutathione - analysis; Humans; Medical sciences; Mice; Mice, Nude; Multidrug Resistance-Associated Proteins; Neoplasm Transplantation; Nicotinic Acids - pharmacology; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Sarcoma, Experimental - drug therapy; Transplantation, Heterologous; Tumor Cells, Cultured
• ISSN: 1078-0432; 1557-3265

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.