PAK-104P, A PYRIDINE ANALOG, REVERSES PACLITAXEL AND DOXORUBICIN RESISTANCE IN CELL-LINES AND NUDE-MICE BEARING XENOGRAFTS THAT OVEREXPRESSTHE MULTIDRUG-RESISTANCE PROTEIN

Multidrug resistance (MDR) is considered multifactorial and has been a ssociated with overexpression of the multidrug resistance protein (MRP ), However, effective compounds for reversal of MRP-related MDR are li mited, In the present study, the modulatory activity of the novel pyri dine analogue PAK-104P on MRP-mediated resistance to doxorubicin and p aclitaxel was investigated in two doxorubicin-selected human tumor cel l lines [HT1080/DR4 (sarcoma) and HL60/ADR (leukemia)] and compared wi th the nonimmunosuppressive cyclosporine analogue PSC-833. In cell lin es 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-104 P (1 and 5 mu M), the reversal of doxorubicin resistance was significa nt but partial in HT1080/DR4 and HL60/ADR cells (dose-modifying factor for 5.0 mu M 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 cytomet ry analysis demonstrated that PAK-104P was effective in restoring cell ular doxorubicin concentrations in resistant cells to levels comparabl e 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 a dministered in combination with PAK-104P, documenting improvement in t he therapeutic index of these agents, In addition to reversing P-glyco protein-mediated MDR, the pyridine analogue PAK-104P provides an examp le of an effective in vivo modulator of MRP-mediated MDR.