Pharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allylamino, 17-demethoxygeldanamycin in human ovarian cancer xenograft models.
OBJECTIVE
To establish the pharmacokinetic and pharmacodynamic profile of the heat shock protein 90 (HSP90) inhibitor 17-allylamino, 17-demethoxygeldanamycin (17-AAG) in ovarian cancer xenograft models.


METHODS
The effects of 17-AAG on growth inhibition and the expression of pharmacodynamic biomarkers c-RAF-1, CDK4, and HSP70 were studied in human ovarian cancer cell lines A2780 and CH1. Corresponding experiments were conducted with established tumor xenografts. The variability and specificity of pharmacodynamic markers in human peripheral blood lymphocytes (PBL) were studied.


RESULTS
The IC50 values of 17-AAG in A2780 and CH1 cells were 18.3 nmol/L (SD, 2.3) and 410.1 nmol/L (SD, 9.4), respectively. Pharmacodynamic changes indicative of HSP90 inhibition were demonstrable at greater than or equal the IC50 concentration in both cell lines. Xenograft experiments confirmed tumor growth inhibition in vivo. Peak concentrations of 17-AAG achieved in A2780 and CH1 tumors were 15.6 and 16.5 micromol/L, respectively, and there was no significant difference between day 1 and 11 pharmacokinetic profiles. Reversible changes in pharmacodynamic biomarkers were shown in tumor and murine PBLs in both xenograft models. Expression of pharmacodynamic markers varied between human PBLs from different human volunteers but not within the same individual. Pharmacodynamic biomarker changes consistent with HSP90 inhibition were shown in human PBLs exposed ex vivo to 17-AAG but not to selected cytotoxic drugs.


CONCLUSIONS
Pharmacokinetic-pharmacodynamic relationships were established for 17-AAG. This information formed the basis of a pharmacokinetic-pharmacodynamic-driven phase I trial.
Banerji
Udai
U
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, United Kingdom.
Walton
Michael
M
Raynaud
Florence
F
Grimshaw
Rachel
R
Kelland
Lloyd
L
Valenti
Melani
M
Judson
Ian
I
Workman
Paul
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016227:Benzoquinones; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D016227:Benzoquinones; D015415:Biomarkers; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017828:Rifabutin; C112765:tanespimycin; D019908:Proto-Oncogene Proteins c-raf; D051358:Cyclin-Dependent Kinase 4