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Biotech / Medical : Kosan BioSciences -- KOSN -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (356)	9/26/2003 1:47:34 PM
From: Biomaven	Read Replies (1) \| Respond to of 933

Discovering the secrets of Hsp90 binding A ubiquitous antitumor drug target preferentially kills tumor cells due to target conformation \| By David Secko Geldanamycin is an antibiotic that binds to Hsp90 and inhibits its adenosine triphosphate binding and activity as a chaperone. A derivative of geldanamycin (GM) is the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG), which preferentially kills tumor cells and is in phase I clinical trials. Hsp90 is found in all cell types, but it has been unclear how the preferential killing of tumor cells by 17-AAG is accomplished. In the September 25 Nature, Adeela Kamal and colleagues at Conforma Therapeutics Corporation report that Hsp90 from tumor cells binds with higher affinity to 17-AAG and that this is due to Hsp90 being in multichaperone complexes in these cells. (Nature, 425:407-410, September 25, 2003) Kamal et al. performed competitive binding assays using increasing concentrations of 17-AAG to inhibit the binding of Hsp90 to GM-biotin and observed that Hsp90 from tumor cells had a 50% inhibitory concentration (IC50) of 6 nM compared with 400?600 nM for Hsp90 from control cells. Measurements comparing the binding of adenosine triphosphate (ATP) to Hsp90 also showed a lower IC50 for tumor Hsp90, revealing that Hsp90 in tumor cells had a significantly higher binding affinity for 17-AAG. Hsp90 assembles in multichaperone complexes by interacting with many cochaperone proteins (e.g., p23, Hop), and co-immunoprecipitation of Hsp90 demonstrated that Hsp90 from tumor cells is present in more of these complexes. Hsp90 tumor complexes also showed a higher ATPase activity (something that Hsp90 chaperone function is dependent on) that was inhibited by 17-AAG. In addition, in vitro reconstituted Hsp90 complexes showed an increased apparent affinity for 17-AAG?12 nM for Hsp90 alone rising to 600 nM when complexed. The authors then performed these experiments in mice and in clinical cancer and observed a similar pattern of 17-AAG binding to in vivo tumor Hsp90. ?Our data show that Hsp90 in tumor cells exists in a functionally distinct molecular form. [Hsp90 could be the] Achilles heel of tumor cells, driving the selective accumulation and bioactivity of pharmacological Hsp90 inhibitors, and making tumor Hsp90 a unique cancer target,? conclude the authors. Links for this article L. Neckers, Y.S. Lee, ?The rules of attraction,? Nature, 425:357-358, September 25, 2003. nature.com J.S. Isaacs et al., ?Heat shock protein 90 as a molecular target for cancer therapeutics,? Cancer Cell, 3:213-217, March 2003. [PubMed Abstract] A. Kamal et al., ?A high-affinity conformation of Hsp90 confers tumor selectivity on Hsp90 inhibitors,? Nature, 425:407-410, September 25, 2003. nature.com Conforma Therapeutics conformacorp.com K. Richter, J. Buchner, ?Hsp90: chaperoning signal transduction,? Journal of Cell Physiology, 188:281-290, September 2003. [PubMed Abstract] biomedcentral.com

To: scaram(o)uche who wrote (356)	10/3/2003 11:25:59 AM
From: tuck	Respond to of 933

[17-AAG and angiogenesis inhibitors] >>Published online before print October 2, 2003 Proc. Natl. Acad. Sci. USA, 10.1073/pnas.2031337100 Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors Paola de Candia , David B. Solit , Dilip Giri , Edi Brogi ¶, Peter M. Siegel , Adam B. Olshen \|\|, William J. Muller , Neal Rosen , and Robert Benezra * Program in Cell Biology, Departments of Medicine, \|\|Epidemiology and Biostatistics, and ¶Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; Department of Pathology, Lifespan Academic Medical Center, Rhode Island Hospital, Providence, RI 02903; and *McMaster Institute for Molecular Biology and Biotechnology, McMaster University, L8S 4L8 Hamilton, ON, Canada Edited by M. Judah Folkman, Harvard Medical School, Boston, MA, and approved August 11, 2003 (received for review March 7, 2003) Id proteins bind basic helix-loop-helix transcription factors and function as dominant negative inhibitors of gene expression. Id1 and Id3 are required for the recruitment of bone marrow-derived endothelial cell precursors and tumors transplanted into Id-deficient mice demonstrate impaired angiogenesis. Mouse mammary tumor virus-neu mice were bred with Id1-/-Id3+/- mice to ascertain the role of Id1 and Id3 in mammary tumorigenesis in a more physiologically relevant model. In mammary tumors from these mice, Id1 and Id3 expression was restricted to the vascular endothelium. Id1 and Id3 deficiency did not prevent or delay tumor formation but did alter tumor phenotype. The tumors that developed in the Id-deficient mice were larger and cystic with a viable rim of tumor cells surrounding a nonviable core of cellular debris. The Hsp90 chaperone protein is required for cellular survival under condition of environmental stress and for the stability of the neu oncogene. 17-Allylamino-17-demethoxygeldanamycin, an Hsp90 inhibitor, was used to treat these mice. Whereas 17-allylamino-17-demethoxygeldanamycin only modestly delayed the growth of established mammary tumors in WT mice for Id, tumor suppression was dramatically more effective in an Id1- or Id3-deficient background. These data suggest that tumorigenesis can occur in a background of defective angiogenesis but that tumors developing in such an environment may be especially sensitive to inhibitors of neu and stress-activated survival pathways. Thus angiogenesis inhibitors in combination with inhibitors of Hsp90 function should be evaluated for the treatment of advanced breast cancer.<< Cheers, Tuck