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• W2600413252 abstract "5907 The microtubule stabilizing drug Paclitaxel is a valuable drug against a wide range of tumors. Despite its value as an anti-cancer agent, paclitaxel has two features that hamper its applicability: its low aqueous solubility, and the development of drug resistance mediated by the overexpression of the P-glycoprotein and the presence of beta-tubulin mutations. Epothilones have similar mechanisms of action to paclitaxel, but are more water soluble, are a poorer substrate for the P-glycoprotein and have a simpler molecular architecture for total synthesis and analog optimization. Recently we (Y.S.C.) synthesized epothilone analogs dEpoB and 26-trifluoro-9,10-dehydro-12,13-desoxyepothilone B (Fludelone). All tested human tumor cell lines (colon, breast and ovarian) were highly sensitive to Fludelone, with IC50s between 1-20nM in the XTT-test. The IC50 of Fludelone was lower than that of dEpoB in every case. Ovarian cancer cell lines were particularly sensitive to Fludelone which possessed a ∼8-fold greater anti-tumor activity than dEpoB. Both drugs caused tumor cells to arrest in G2M phase and rapidly induced apoptosis and beta-tubulin increase. Normal bone marrow stromal cells showed a comparable, relative resistance to both these compounds, indicating a safe therapeutic window and a potential therapeutic advantage of Fludelone over dEpoB. Fetal human lung fibroblasts (MRC-5) were sensitive to dEpoB and Fludelone, but a therapeutic window was still evident with Fludelone. In our Xenograft model we injected 1-5x107 Ovcar3, ovarian cancer cells, transduced with a HSV-TK/eGFP/Luciferase triple fusion gene, intraperitoneally into NOD-SCID mice (to study tumor growth in the physiological niche for ovarian cancer). To monitor tumor growth and location of metastases, whole animal imaging by luciferase bioluminescence was performed at three points: (1) 5-10 days post tumor injection and prior to drug treatment, (2) after 10 drug administrations and (3) at the terminal stage. Fludelone was administered 3 times weekly by intraperitoneal injection. Minor and reversible body weight loss was observed with Fludelone. A tumor reduction of 90% after ten dosages was achieved, matching Taxol controls and with greatly prolonged survival. By using in vivo19F NMR signal from Fludelone as an indicator of efficient tumor tissue uptake we were able to (1) estimate the time after injection at which the tumor tissue concentration is maximum (between 4 and 5 hours ) and (2) establish the optimal in vivo drug dosage for maximum uptake and retention (50-100 mg/kg) . To elucidate possible differences between dEpoB and Fludelone action on Ovcar3 cells we conducted micro array analysis and selective gene modulation in the NFkB pathway. Given the large therapeutic window of Fludelone compared to dEpoB, Fludelone is a promising epothilone analog for ovarian cancer treatment." @default.
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• W2600413252 date "2005-05-01" @default.
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• W2600413252 title "Fludelone, an optimized epothilone for ovarian cancer treatment" @default.
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