ENHANCEMENT OF PACLITAXEL ACTIVITY AGAINST HORMONE-REFRACTORY PROSTATE-CANCER CELLS IN-VITRO AND IN-VIVO BY QUINACRINE

Cytoplasmic phospholipase A(2) (PLA(2)) is known to be phosphorylated and activated by MAP kinase (Lin et al 1993, Cell 72: 269-278), an imp ortant downstream component of signal transduction, whereas paclitaxel has been shown to inhibit isoprenylation of ras proteins (Danesi et a l 1995, Mol Pharmacol 47: 1106-1111). Given that quinacrine (Q), a PLA (2) inhibitor, and paclitaxel (P) might act at different sites in the cell signalling pathway, our aim was to test whether they were synergi stic in combination against prostate cancer cells. Cell viability of P C-3, PC-3M and DU145 cells in 96 - well plates was assessed 96 h after drugs were added concurrently. Using Chou analysis, we demonstrated s ynergy for the combination against all three cell lines. Further, syne rgy was present under both conservative (mutually nonexclusive) and no n-conservative (mutually exclusive) models. Studies in the nude mouse xenograft model support the finding of synergy in vitro. In DU145-bear ing mice, Q (50 mg kg(-1)) and P (0.5 mg kg(-1)) given daily for 12 co nsecutive days, either concurrently or sequentially, was more effectiv e than either drug alone, at twice the dose intensity. In an enzyme-li nked immunosorbent (ELISA) apoptosis assay, arachidonic acid was able to partially reverse Q- and P-induced apoptosis, suggesting PLA(2) pat hway involvement. Finally, the combination of lovastatin, another inhi bitor of ras isoprenylation, and quinacrine had synergistic inhibitory effects on the growth of PC-3 cells in vitro, suggesting that the com bination of these two classes of compounds might serve as an attractiv e therapeutic approach for prostate cancer.