The Hsp90 chaperone complex as a novel target for cancer therapy.
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.


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.
Goetz
M P
MP
Division Medical Oncology, Department of Biochemistry, Mayo Graduate School, Rochester, MN 55905, USA.
Toft
D O
DO
Ames
M M
MM
Erlichman
C
C
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016227:Benzoquinones; D017321:Clinical Trials, Phase I as Topic; D004195:Disease Models, Animal; D005260:Female; D005544:Forecasting; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D011809:Quinones / Q000494:pharmacology / Q000627:therapeutic use; D012106:Research; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D017828:Rifabutin; C112765:tanespimycin; C001277:geldanamycin