The phase I clinical compound SNS-595 acts during S-phase and causes a sustained G2 arrest

Proc Amer Assoc Cancer Res, Volume 46, 2005 2293 Although recent research has identified cancer therapies with non-cytotoxic mechanisms, there is still a need to discover and develop the next generation of cytotoxics with strong activities, manageable toxicities, and novel mechanisms of action. SNS-595 is a first-in-class naphthyridine compound that demonstrates potent cytotoxic activity as well as robust antineoplastic activity in several syngeneic and human xenograft tumor models, and is currently in phase I clinical trials for solid tumors. In vitro, SNS-595 has been observed to induce G2 cell cycle arrest and subsequent apoptosis in various cancer cells, including many multi-drug resistant lines. The effect of SNS-595 on cell cycle progression and checkpoint stimulation has been characterized and compared to the effects of a number of therapeutically relevant cell cycle modulators (cisplatin, docetaxol, gemcitabine, etoposide, doxorubicin, irinotecan, bleomycin, and mitomycin C). Cell cycle progression was analyzed using both DNA content and the cell cycle markers cyclins A, B, and E. In asynchronous populations, SNS-595 treatment causeed a full G2 arrest in all cell lines tested. This arrest was accompanied by rapid apoptosis as determined by DNA fragmentation. In synchronized cell populations treated with SNS-595, cells cycled normally until they reached S phase, which was 30% longer than in untreated cells. Checkpoint markers (chk kinases, cdc25 phosphatases, cdc2, and p21) appeared rapidly upon entering S phase, and the cells eventually reached a sustained and irreversible arrest with 4N DNA content. SNS-595 is shown to be distinct from the other G2 arrestors tested in that it causes p21 expression early in S phase and a significant S-phase lag. SNS-595 is also differentiable from other S-phase active compounds in showing a definitive arrest at G2 as opposed to a varied G1/S/G2 arrest profile. Further research into the stimulation of checkpoint and apoptotic pathways by SNS-595 will lead to a more detailed understanding of this compound’s potent anticancer activity.