Annals of Oncology 14:1169-1176, 2003
© 2003 European Society for Medical Oncology
Review Article |
The Hsp90 chaperone complex as a novel target for cancer therapy
Division Medical Oncology, Department of Biochemistry and Molecular Biology, Division of Developmental Oncology Research and Mayo Graduate School, Rochester, MN 55905, USA
Received 12 February 2003; accepted 11 March 2003
Abstract
Background:
Heat shock protein 90 (Hsp90) is responsible for chaperoning proteins involved in cell signaling, proliferation and survival. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is an anticancer agent currently in phase I trials in the USA and UK. It represents a class of drugs, the benzoquinone ansamycin antibiotics, capable of binding and disrupting the function of Hsp90, leading to the depletion of multiple oncogenic client proteins.
Materials and methods:
Studies were identified through a PubMed search, review of bibliographies of relevant articles and review of abstracts from national meetings.
Results:
Preclinical studies have demonstrated that disruption of many client proteins chaperoned by Hsp90 is achievable and associated with significant growth inhibition, both in vitro and in tumor xenografts. Following an overview of the mechanism of action of ansamycin antibiotics and the pathways they disrupt, we review the current clinical status of 17-AAG, and discuss future directions for combinations of traditional antineoplastics with 17-AAG.
Conclusions:
17-AAG represents a class of drugs capable of affecting multiple targets in the signal transduction pathway involved in tumor cell proliferation and survival. Early results from phase I studies indicate that 17-AAG administration results in an acceptable toxicity profile while achieving in vivo disruption of client proteins.
Key words: 17-AAG, heat shock protein, Hsp90
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