Versipelostatin: Unfolding an Unsweetened Death

Extract

The classical basis for successful cancer chemotherapeutic regimens has been the induction of tumor shrinkage, or response, in animal models of cancer, usually mice bearing syngeneic or xenografted human tumors. Historically, agents that had activity in a high proportion of such models had a statistically increased likelihood of demonstrating value in Phase II clinical efficacy trials in humans ( 1 ) . Based on such behavior, Phase III trials could be planned to assess utility in prolonging survival. The antiproliferative mechanisms of successful conventional cytotoxic compounds in most cases ultimately involve apoptosis, or programmed cell death, with concomitant decrease in clonogenic potential of cells from treated tumors.

During the past 15 years, a number of cellular pathways leading to tumor cell apoptosis have been defined. DNA-damaging agents appear capable of activating a range of proapoptotic cellular responses ( 2 ) . For example, in cells with an intact p53 tumor suppressor gene, DNA damage is sensed by pathways initiated by DNA-dependent protein kinase, ataxia and telangiectasia–mutated (ATM) kinase, and ataxia telangiectasia–related (ATR) kinase, depending on the nature of the damage. The p53 protein is then phosphorylated and activated, whereupon it has several proapoptotic transcriptional effects, including increases in expression of PUMA and noxa. These proteins in turn modulate the mitochondrial threshold for release of the caspase activators APAF1 and cytochrome c, which are also regulated by the bcl2-related families of pro- and antiapoptotic proteins.