This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sappal, D. S. Articles by Rudolph-Owen, L. A. Search for Related Content PubMed PubMed Citation Articles by Sappal, D. S. Articles by Rudolph-Owen, L. A.

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{at}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.

Grant support: N.Osheroff is supported by NIH grant GM33944. A.K.McClendon is a trainee under National Institutes of Health Grant 5 T32 CA09582.

Note: Present address of P.Charlton: Vertex Pharmaceuticals, Ltd., Abingdon, Oxfordshire, United Kingdom. Present address of L.A. Rudolf-Owen: Eisai Research Institute, Andover, MA.

Received 8/27/03; revised 10/10/03; accepted 10/23/03.

This article has been cited by other articles:

				C. Punchihewa, A. De Alba, N. Sidell, and D. Yang XR5944: A potent inhibitor of estrogen receptors Mol. Cancer Ther., January 1, 2007; 6(1): 213 - 219. [Abstract] [Full Text] [PDF]

				P. Luo, Q. He, X. He, Y. Hu, W. Lu, Y. Cheng, and B. Yang Potent antitumor activity of 10-methoxy-9-nitrocamptothecin. Mol. Cancer Ther., April 1, 2006; 5(4): 962 - 968. [Abstract] [Full Text] [PDF]

				T. Kosakowska-Cholody, W. M. Cholody, A. Monks, B. A. Woynarowska, and C. J. Michejda WMC-79, a potent agent against colon cancers, induces apoptosis through a p53-dependent pathway Mol. Cancer Ther., October 1, 2005; 4(10): 1617 - 1627. [Abstract] [Full Text] [PDF]

				S. A. Byers, B. Schafer, D. S. Sappal, J. Brown, and D. H. Price The antiproliferative agent MLN944 preferentially inhibits transcription Mol. Cancer Ther., August 1, 2005; 4(8): 1260 - 1267. [Abstract] [Full Text] [PDF]

				F. Di Nicolantonio, L. A. Knight, P. A. Whitehouse, S. J. Mercer, S. Sharma, P. A. Charlton, D. Norris, and I. A. Cree The ex vivo characterization of XR5944 (MLN944) against a panel of human clinical tumor samples Mol. Cancer Ther., December 1, 2004; 3(12): 1631 - 1637. [Abstract] [Full Text] [PDF]

				J. Dai, C. Punchihewa, P. Mistry, A. T. Ooi, and D. Yang Novel DNA Bis-intercalation by MLN944, a Potent Clinical Bisphenazine Anticancer Drug J. Biol. Chem., October 29, 2004; 279(44): 46096 - 46103. [Abstract] [Full Text] [PDF]