2285

SNS-595, currently in phase I trials, is a novel cell cycle modulator with potent activity against various tumor models. SNS-595 treated cells have been shown to undergo rapid and cell-cycle dependent apoptosis. Further characterization of the kinetics and mechanism of apoptosis in SNS-595-treated cells was conducted and compared to the activities of eight clinically relevant cytotoxics (cisplatin, docetaxel, etoposide, gemcitabine, doxorubicin, irinotecan, bleomycin, and mitomycin C). The relationship between the cell cycle and apoptosis was studied in both asynchronous and synchronous cell populations using several markers of p53-dependent and independent pathways (including p53, p73, c-Abl, and p21). In an asynchronous cell population, SNS-595 caused half maximal caspase-3 activation within 5 hrs of exposure, two times faster than the other cytotoxics studied. Cells synchronized at G1/S and treated with SNS-595 displayed a steep increase in caspase-3 activation as the cells enter S phase. SNS-595 did not activate caspase-3 during M or G1 phases of the cell cycle, nor was caspase-3 activated in non-cycling cells. These results are consistent with cell cycle analysis indicating an S-phase lag, S-phase checkpoint activation, and G2 arrest following SNS-595 treatment. Analysis of the signaling pathways stimulated by SNS-595 indicate that apoptosis is stimulated through p53-independent and dependent mechanisms. In contrast to comparator compounds, SNS-595 stimulates p21 expression and caspase-3 activation rapidly (within 30 minutes) after p53 phosphorylation. Thus, SNS-595 stimulates the apoptotic cascade and subsequent cell death only when dosed during DNA synthesis; apoptosis follows stimulation of the p53, p73 and cell cycle checkpoint pathways. These distinctive cell cycle and apoptotic effects of SNS-595 will lead to further insight into the mechanism of action of this potent and novel cytotoxic compound.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]

American Association for Cancer Research
2005