SNS-595 Mechanism
The integrity of normal cells and tissues is maintained by two exquisitely regulated processes—cell division or replication, and cell death or apoptosis. There are four phases to cell division: G1, S, G2, and M. During G1 phase, the cell grows and commits to division, at which point it enters S phase. During S phase, DNA is replicated so that at the end of the phase the cell contains duplicate copies of each chromosome. The cell checks that the chromosomes have been reproduced reliably. If not, a normal cell arrests at this point and undergoes apoptosis. Cancer cells often escape the quality control mechanisms or 'checkpoints' designed to detect defective replication. After S phase, the cell enters G2 phase and grows to ready itself for M phase. In M phase, the cell undergoes mitosis, the process by which the duplicated chromosomes are pulled to opposite sides of the nucleus and the cell completes division into two daughter cells.
SNS-595 targets replication during S phase, inducing an irreversible G2 arrest and rapid cell death. SNS-595 has a mechanism of action that includes inhibition of an enzyme called Topoisomerase II as well as other activities that contribute to its anti-cancer effects. During replication, Topoisomerase II helps chromosomal DNA unwind so that it can be copied. SNS-595 traps Topoisomerase II bound to the DNA, causing the DNA to break. As a result, the cell fails to repair its damaged DNA and undergoes programmed cell death. We know that SNS-595 has additional targets beyond Topoisomerase II, because if we manipulate cells and knock out this enzyme, SNS-595 can still kill the cancer cell. SNS-595 acts only on cells that are dividing, thus sparing most normal tissues while attacking the cancer. SNS-595 is being tested in Phase 1 and Phase 2 trials in patients with advanced acute hematologic malignancies and ovarian cancers.
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| HCT-116 colorectal cancer cells treated with control vehicle for 8 hr. No DNA damage foci are detectable. | HCT-116 colorectal cancer cells treated with SNS-595 for 8 hr. DNA damage foci were detected with antibody to gammaH2AX. |
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HCT-116 colorectal cancer cells treated with SNS-595 for 8 hr. DNA damage foci were detected with antibody to pATM. Cells were imaged using an Arrayscan® for quantitation. |
