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Mol Cancer Ther. 2003 Feb;2(2):123-9
Comment in: Mol Cancer Ther. 2003 Feb;2(2):131-8.
17AAG low target binding affinity and potent cell activity--finding an
explanation.
Chiosis G, Huezo H, Rosen N, Mimnaugh E, Whitesell L, Neckers L.
Program in Cell Biology and Department of Medicine, Memorial Sloan-Kettering
Cancer Center, New York, New York 10021, USA. chiosisg@mskcc.org
The ansamycin geldanamycin (GM) and its derivative, 17AAG, now in early clinical
trials in cancer patients, have potent activity against several cancer cells at
low nanomolar concentrations. The main target of these drugs is the molecular
chaperone heat shock protein 90. Contrary to the high antitumor potency, the
affinity of these drugs for the chaperone was determined to be approximately 1
microM. We propose that this difference can partly be explained by the
physicochemical characteristics of the ansamycins. GM and 17AAG accumulate in
cells, producing higher intracellular concentrations than expected. We conclude
that although apparent activity for ansamycins can be seen at low nanomolar
concentration, their real activity correlates with the heat shock protein 90
binding affinity and is in the low micromolar concentration range. We suggest
that in the clinic, micromolar concentrations of 17AAG must accumulate in the
tumor cells to achieve antitumor effects in patients comparable with ones
achieved in tissue culture settings.
PMID: 12589029
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