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Biotech / Medical : Xenova (XNVA)

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To: nigel bates who started this subject	11/19/2003 5:02:35 AM
From: nigel bates	of 173

Xenova Group: Research Elucidates Tumour Therapy Action Wednesday November 19, 3:55 am ET Edited Press Release LONDON -(Dow Jones)- Xenova Group said Wednesday that recent research supports the conclusion that XR5944 is a novel DNA/RNA targeting agent and that its mechanism of action is distinct from current cytotoxic agents. XR5944 is currently in Phase I clinical development in patients with advanced solid tumours. Xenova announced the publication of four abstracts relating to new research into the mechanism of action of its novel cytotoxic agent XR5944 (MLN944) at the meeting of the annual AACR-NCI-EORTC International Conference held in Boston. Preclinical studies have shown XR5944 to be a highly active and potent cytotoxic agent. XR5944 was previously thought to exert its cytotoxic action by dual inhibition of topoisomerases I and II. However, evidence now suggests that XR5944 has a different mechanism of action. For example, it has been shown that XR5944 maintains its cytotoxicity in yeast cells deficient in topoisomerases (Fleming et al; Proceedings of the 94th AACR 2003). Moreover, XR5944 arrests human tumour cell lines in both the G1 and G2 phases of the cell cycle, in contrast to topoisomerase inhibitors which arrest at the S/G2 phase (Freathy et al; Proceedings of the 94th AACR 2003). Although not active against topoisomerases, recent biochemical studies suggest that the anti-tumour activity of XR5944 does involve nucleic acid binding and intercalation into DNA (Sappal et al. Mol Cancer Therapeutics in press). The new studies reported in Boston have further investigated the mechanism of action of XR5944. Blackman et al reported yeast functional genomics studies with XR5944 suggesting a pattern indicative of alterations in cellular RNA synthesis and metabolism. Pulse labelling experiments confirmed inhibition of cellular RNA synthesis which appeared to result from inhibition of RNA polymerases I and II. Byers et al reported studies on the effect of XR5944 on RNA polymerase II. They tested XR5944 for its ability to inhibit the kinase activity of positive transcription elongation factor b (P-TEFb). XR5944 did not inhibit the kinase activity of P-TEFb in vitro; however treatment of cells with XR5944 caused a shift in the large predominantly inactive form of P-TEFb to the small active form. They propose that the increased sensitivity of cancer cells to XR5944 is through modifications in their P-TEFb environment. Yang et al have reported results of NMR structural binding studies which suggest XR5944 bis-intercalates and binds through the major groove of DNA. Sappal et al measured the primary effects of XR5944 treatment on DNA, RNA and protein synthesis in human tumour cell lines. By measuring the incorporation of radiolabeled precursors after short-term exposure to XR5944, the data showed inhibition of RNA synthesis at concentrations consistent with growth inhibition. A modest reduction in DNA synthesis was also observed at higher XR5944 concentrations. These results are consistent with a mechanism of action for XR5944 that involves DNA binding and inhibition of RNA synthesis. David Oxlade, Chief Executive of Xenova, said: "We are delighted with the progress made in elucidating the mechanism by which XR5944 achieves its highly potent cancer cell killing effect and we look forward to further developments that will clearly differentiate XR5944 from other drugs being developed to improve the treatment of cancer patients." ...

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