Geldanamycin is a benzoquinone ansamycin antibiotic that binds to Hsp90 (Heat Shock Protein 90) and alters its function. Geldanamycin induces the degradation of proteins that are mutated in tumor cells such as v-Src, Bcr-Abl and p53 preferentially over their normal cellular counterparts. This effect is mediated via HSP90. Despite its potent antitumor potential, geldanamycin presents several major drawbacks as a compound candidate (namely, hepatotoxicity) that have led to the development of geldanamycin analogues, in particular analogues containing a derivatisation at the 17 position:17-AAG,17-DMAG.
|Cell lines||A2780 human ovarian cell line|
|Preparation method||Treating exponentially growing cells with Geldanamycin and assessing at various times DNA synthesis by incorporation of bromodeoxyuridine (BrdUrd) and flow cytometric analysis. No marked difference in total cell number is noted during this time course for treated and untreated cultures. BrdUrd (10 μM) is incorporated over a 4-h incubation period at 37 °C and cells are harvested and fixed in 70% ethanol. After denaturation of the DNA with 2 N HC1, incubating cells with an anti-BrdUrd mouse monoclonal antibody followed by a fluorescein isothiocyanate (FITC)-linked goat anti-mouse IgG. Staining cells for 30 minutes at room temperature with propidium iodide and analysing by flow cytometry using a Coulter EPICS Profile Analyzer.|
|Incubation time||3 hours|
|Animal models||FRE/erbB-2 tumors in nu/nu mice|
|Formulation||Geldana50 mg/kgmycin is dissolved in DMSO.|
|Administration||Administered via i.p.|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: ≥ 19 mg/mL|
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