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Biotech / Medical : Xenova (XNVA) -- Ignore unavailable to you. Want to Upgrade?

To: nigel bates who wrote (27)	2/19/2004 3:54:01 AM
From: tuck	Read Replies (1) \| Respond to of 173

[MOA for MLN 944 (XR5944] >>Mol Cancer Ther. 2004;3:47-58 © 2004 American Association for Cancer Research Biological characterization of MLN944: A potent DNA binding agent Darshan S. Sappal1, A. Kathleen McClendon5, James A. Fleming2, Vala Thoroddsen2, Kelly Connolly3, Corinne Reimer3, Ronald K. Blackman2, Christine E. Bulawa2, Neil Osheroff5,6, Peter Charlton4 and Laura A. Rudolph-Owen1 Departments of 1 Molecular and Cellular Oncology, 2 Applied Genomics, and 3 Cancer Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, MA; 4 Xenova, Ltd., Slough, United Kingdom; and Departments of 5 Biochemistry and 6 Medicine, Vanderbilt University School of Medicine, Nashville, TN Requests for Reprints: Darshan S. Sappal, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA 02140. Phone: (617) 551-3921; Fax: (617) 551-2902. E-mail: darshan.sappal@mpi.com MLN944 (XR5944) is a novel bis-phenazine that has demonstrated exceptional efficacy against a number of murine and human tumor models. The drug was reported originally as a dual topoisomerase I/II poison, but a precise mechanism of action for this compound remains to be determined. Several lines of evidence, including the marginal ability of MLN944 to stabilize topoisomerase-dependent cleavage, and the sustained potency of MLN944 in mammalian cells with reduced levels of both topoisomerases, suggest that other activities of the drug exist. In this study, we show that MLN944 intercalates into DNA, but has no effect on the catalytic activity of either topoisomerase I or II. MLN944 displays no significant ability to stimulate DNA scission mediated by either topoisomerase I or II compared with camptothecin or etoposide, respectively. In addition, yeast genetic models also point toward a topoisomerase-independent mechanism of action. To examine cell cycle effects, synchronized human HCT116 cells were treated with MLN944, doxorubicin, camptothecin, or a combination of the latter two to mimic a dual topoisomerase poison. MLN944 treatment was found to induce a G1 and G2 arrest in cells that is unlike the typical G2-M arrest noted with known topoisomerase poisons. Finally, transcriptional profiling analysis of xenograft tumors treated with MLN944 revealed clusters of regulated genes distinct from those observed in irinotecan hydrochloride (CPT-11)-treated tumors. Taken together, these findings suggest that the primary mechanism of action of MLN944 likely involves DNA binding and intercalation, but does not appear to involve topoisomerase inhibition. << Cheers, Tuck