Abstract
17-allylamino, 17-demethoxygeldanamycin (17AAG; NSC 330507) is the first modulator of heat shock protein 90 (Hsp90) to enter clinical trials. Hsp90 serves a chaperone role to properly fold and deliver client proteins to appropriate intracellular locations. Interest in Hsp90 modulators for the experimental therapeutics of cancer has arisen based on pre-clinical evaluations suggesting that Hsp90 client proteins regulate signaling pathways critical to the molecular economy of many types of tumors, including oncogene signaling, cyclin-dependent kinase activation, steroid hormone receptors, and mediators of invasion and metastasis. Thus, Hsp90-directed agents could affect molecules upon which tumors depend for their proliferation and survival. Initial clinical studies have therefore sought to incorporate assessment of these endpoints into initial clinical evaluations. Three schedules of administration have been supported for initial evaluation in Phase I studies sponsored by the National Cancer Institute (NCI) or supported by NCI and sponsored by Cancer Research UK. In the daily times five schedule, a recommended Phase II dose (RPTD) of 40 mg / m2 has been reached, while once weekly or three of four weekly schedules are defining RPTDs of 295 and 308 mg / m2. Toxicity is tolerable and appears dominated by hepatic, gastrointestinal, and constitutional symptoms. Concentrations of drug at peak of ∼1700-3000 nM are concordant with concentrations predictive of useful outcomes in pre-clinical model systems. Evidence of modulation of Hsp90 partner molecules has been obtained in both surrogate and some tumor compartments. These very early results encourage additional clinical evaluations of 17AAG and related molecules.
Keywords: 17-Allylamino, 17AAG, oncogene, cyclin-dependent kinase
Current Cancer Drug Targets
Title: Clinical Development of 17-Allylamino, 17-Demethoxygeldanamycin
Volume: 3 Issue: 5
Author(s): Edward A. Sausville, Joseph E. Tomaszewski and Percy Ivy
Affiliation:
Keywords: 17-Allylamino, 17AAG, oncogene, cyclin-dependent kinase
Abstract: 17-allylamino, 17-demethoxygeldanamycin (17AAG; NSC 330507) is the first modulator of heat shock protein 90 (Hsp90) to enter clinical trials. Hsp90 serves a chaperone role to properly fold and deliver client proteins to appropriate intracellular locations. Interest in Hsp90 modulators for the experimental therapeutics of cancer has arisen based on pre-clinical evaluations suggesting that Hsp90 client proteins regulate signaling pathways critical to the molecular economy of many types of tumors, including oncogene signaling, cyclin-dependent kinase activation, steroid hormone receptors, and mediators of invasion and metastasis. Thus, Hsp90-directed agents could affect molecules upon which tumors depend for their proliferation and survival. Initial clinical studies have therefore sought to incorporate assessment of these endpoints into initial clinical evaluations. Three schedules of administration have been supported for initial evaluation in Phase I studies sponsored by the National Cancer Institute (NCI) or supported by NCI and sponsored by Cancer Research UK. In the daily times five schedule, a recommended Phase II dose (RPTD) of 40 mg / m2 has been reached, while once weekly or three of four weekly schedules are defining RPTDs of 295 and 308 mg / m2. Toxicity is tolerable and appears dominated by hepatic, gastrointestinal, and constitutional symptoms. Concentrations of drug at peak of ∼1700-3000 nM are concordant with concentrations predictive of useful outcomes in pre-clinical model systems. Evidence of modulation of Hsp90 partner molecules has been obtained in both surrogate and some tumor compartments. These very early results encourage additional clinical evaluations of 17AAG and related molecules.
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Sausville A. Edward, Tomaszewski E. Joseph and Ivy Percy, Clinical Development of 17-Allylamino, 17-Demethoxygeldanamycin, Current Cancer Drug Targets 2003; 3 (5) . https://dx.doi.org/10.2174/1568009033481831
DOI https://dx.doi.org/10.2174/1568009033481831 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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