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Biotech / Medical : Millennium Pharmaceuticals, Inc. (MLNM) -- Ignore unavailable to you. Want to Upgrade?

To: Icebrg who wrote (1702)	7/3/2003 12:36:49 PM
From: Icebrg	Read Replies (1) \| Respond to of 3044

Using yeast to probe the mechanism of action of MLN944 (XR5944), a novel bis-phenazine with potent anti-tumor activity James A. Fleming, Ronald K. Blackman, Vala Thoroddsen, Laura Rudolph-Owen, Peter Charlton, Chris Bulawa. Millennium Pharmaceuticals, Cambridge, MA; Xenova Ltd, Slough, UK. MLN944 (XR5944) has demonstrated in vitro and in vivo anti-tumor efficacy against a number of murine and human tumor models. Previously, biochemical analysis suggested that MLN944 could act through a mechanism which includes the dual inhibition of Topoisomerase I and II (Anti-Cancer Drugs 2001; 12: 359-367). In the current study, we use classical genetics and functional genomics to investigate the cellular mechanism of action of MLN944 in the yeast Saccharomyces cerevisiae. Several lines of evidence suggest that MLN944 impacts the cell by a mechanism distinct from that of topoisomerase inhibition. In this study, we demonstrate that MLN944 does not have altered efficacy in yeast strains with altered levels of Topoisomerase I, II or III activity. Further, the potency of the compound appears unchanged in mutant strains unable to repair double strand DNA breaks. Previously tested topoisomerase inhibitors such as camptothecin and etoposide show altered sensitivities in these diagnostic assays. The functional genomics data from this study also appear to differentiate MLN944 from known topoisomerase inhibitors. Transcript profiling of MLN944-treated cells shows up-regulated expression of RNA polymerase subunits, as well as genes involved in rRNA processing. Also, genes involved in nitrogen metabolism are perturbed, suggesting that nutrient availability or sensing may be affected by drug treatment. Importantly, DNA damage response genes appear to be unaffected by MLN944 treatment. In another genome-wide analysis, a systematic survey of yeast strains individually mutant for each yeast gene uncovers a number of strains sensitive to MLN944. Of note, strains with mutations in ribosomal proteins, genes involved in RNA processing or RNA polymerase functions, and genes involved in nutrient availability have increased sensitivity to MLN944, compared to strains without these mutations, consistent with the profiling results described above. Conclusion: Our data suggest that the primary cellular target of MLN944 is not topoisomerase function and suggest that MLN944 may work via a novel mechanism of action. Additional experiments in yeast and human cells are currently underway to elucidate this mechanism. aacr03.agora.com