¹National Cancer Institute, NIH, Bethesda, MD, USA

²Department of Medicine, New York Medical College, Valhalla, NY, USA

Correspondence to: M V Blagosklonny, NIH, Bldg 10, R 12 N 226, Bethesda, MD 20892, USA; Fax: 301 402 0172

Geldanamycin (GA), herbimycin A and radicicol bind heat-shock protein-90 (Hsp90) and destabilize its client proteins including v-Src, Bcr-Abl, Raf-1, ErbB2, some growth factor receptors and steroid receptors. Thus, Hsp90-active agents induce ubiquitination and proteasomal degradation of numerous oncoproteins. Depending on the cellular context, HSP90-active agents cause growth arrest, differentiation and apoptosis, or can prevent apoptosis. HSP-active agents are undergoing clinical trials. Like targets of most chemotherapeutics, Hsp90 is not a cancer-specific protein. By attacking a nonspecific target, HSP-90-active compounds still may preferentially kill certain tumor cells. How can this be achieved? How can therapeutic potentials be exploited? This article starts the discussion.

Leukemia (2002) 16, 455-462. DOI: 10.1038/sj/leu/2402415

molecular therapeutics; geldanamycin; oncogenes; heat shock proteins