Zalypsis® is a novel anti-cancer agent that is structurally related to the natural marine-derived compounds jorumycin and the family of renieramycins. Zalypsis® is currently in Phase I trials in patients with advanced solid tumors and lymphoma. We have begun to examine the mechanism of action of this novel compound, initially focusing on its effect on cell growth and cell cycle, as well as DNA damage and RNA synthesis. Treatment of human colorectal carcinoma SW620 cells with Zalypsis® led to a potent cytotoxic response. At 24 hours, cells were arrested in S-phase, followed by apoptosis. Moreover, Zalypsis® was able to inhibit both RNA and DNA synthesis in vitro; importantly, Zalypsis® was also shown to inhibit transcriptional activation of the MDR1 gene in vitro, with minimal effect on constitutive MDR1 expression. To pursue the observation that Zalypsis® specifically inhibited transcriptional activation, we have begun to examine the role of transcription factors and chromatin modifiers that have been shown to play critical roles in transcriptional activation. We now report that the expression of poly (ADP- Ribose) Polymerase-1 (PARP-1), a protein involved in the detection of single-stranded DNA breaks as well as in transcriptional activation, influences cellular response to Zalypsis®. Specifically, mouse embryonic fibroblasts (MEFs) null for PARP expression were found to be significantly more sensitive to treatment with Zalypsis® than their wild-type counterparts. Whether this increased sensitivity is indicative of an effect of Zalypsis on PARP-mediated DNA damage repair or PARP-mediated transcription is currently under investigation. Nevertheless, these results indicate that Zalypsis® is a potent anti-cancer agent that has an unusual impact on transcriptional activation. That PARP knockout cells are more sensitive to treatment with Zalypsis® than their wild-type counterparts suggests a possible role of PARP in the mechanism of action of this compound, and suggests that PARP expression may influence Zalypsis® efficacy in vivo.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA