Taxanes are widely used in the treatment of ovarian carcinomas. One of the main problems with conventional taxanes is the risk of development of multidrug resistance. New-generation synthetic experimental taxoids (Stony Brook Taxanes; SB-T) have shown promising effects against various resistant tumor models. The aim of our study was to compare the in vitro efficacy, intracellular content, and in vivo antitumor effect of clinically used paclitaxel (PTX) and SB-Ts from the previously tested second (SB-T-1214, SB-T-1216) and the newly synthesized third (SB-T-121402, SB-T-121605, and SB-T-121606) generation in PTX resistant ovarian carcinoma cells NCI/ADR-RES. The efficacy of the new SB-Ts was up to 50-times higher compared to PTX in NCI/ADR-RES cells in vitro. SB-T-121605 and SB-T-121606 induced cell cycle arrest in the G2/M phase much more effectively and their intracellular content was 10-15-times higher, when compared to PTX. Incorporation of SB-T-121605 and SB-T-121606 into therapeutic regimens containing PTX were effective in suppressing tumor growth in vivo in NCI/ADR-RES based mice xenografts at small doses (≤3 mg/kg), where their adverse effects were eliminated. In conclusion, new SB-T-121605 and SB-T-121606 analogs are promising candidates for the next phase of preclinical testing of their combination therapy with conventional taxanes in resistant ovarian carcinomas.

3rd Faculty of Medicine Charles University Prague Czech Republic

Department of Surgery University Hospital Kralovske Vinohrady and 3rd Faculty of Medicine Charles University Prague Czech Republic

Institute of Biotechnology of the Czech Academy of Sciences BIOCEV Research Center Vestec Czech Republic

Institute of Chemical Biology and Drug Discovery State University of New York at Stony Brook Stony Brook NY United States

Laboratory of Pharmacogenomics Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Toxicogenomics Unit National Institute of Public Health Prague Czech Republic

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Effect of substituents at the C3´, C3´N, C10 and C2-meta-benzoate positions of taxane derivatives on their activity against resistant cancer cells

Third-generation taxanes SB-T-121605 and SB-T-121606 are effective in pancreatic ductal adenocarcinoma