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937 Reversal of paclitaxel resistance: the potency of third-generation stony brook taxanes in ovarian cancer
  1. Marie Ehrlichova1,2,
  2. Alzbeta Spalenkova1,2,
  3. Karolina Seborova1,2,
  4. Tomas Sychra3,4,
  5. Lei Chen5,
  6. Hersh Bendale5,
  7. Iwao Ojima5,
  8. Pavel Soucek1,2 and
  9. Radka Vaclavikova1,2
  1. 1Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic
  2. 2Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
  3. 3Third Faculty of Medicine, Charles University, Prague, Czech Republic
  4. 4Department of Surgery, University Hospital Kralovske Vinohrady, Prague, Czech Republic
  5. 5Institute of Chemical Biology and Drug Discovery, Stony Brook University – State University of New York, Stony Brook, New York, USA


Introduction/Background In oncologic pharmacotherapy, taxanes are essential agents in the treatment of ovarian carcinoma, yet their efficacy is limited by the development of multidrug resistance. This study assessed novel taxane derivatives known as Stony Brook taxanes (SB-Ts) for their anticancer activity against ovarian carcinoma.

Methodology The viability of ovarian carcinoma cell lines (NCI-ADR/RES, SKOV-3, SKOV-3/R) was assessed using the CellTiter Blue Cell Viability Assay after 72 hours of incubation with paclitaxel (PTX), second-generation (SB-T-1214, SB-T-1216), and third-generation (SB-T-121402, SB-T-121605, SB-T-121606) agents. Cell-derived xenografts were created by subcutaneously injecting cells into immunodeficient mice. Once tumours were developed, the mice were treated with PTX, SB-T compounds, or a combination of both, twice a week.

Results Initial in vitro studies evaluated the cytotoxic efficacy of second-generation and third-generation SB-Ts on paclitaxel-sensitive and -resistant ovarian carcinoma cell lines. Of these, SB-T-121605 and SB-T-121606 were identified as potent agents and further subjected to in vivo validation using immunodeficient murine xenograft models, where they demonstrated enhanced tumour suppression compared to paclitaxel.

Further development led to the examination of biotinylated SB-T conjugates, designed to achieve targeted drug delivery to the tumour site, thereby potentially reducing off-target effects. These conjugates, when tested in vitro, showed increased cytotoxicity against ovarian carcinoma cells over paclitaxel alone.

Conclusion The investigation revealed that third-generation SB-Ts are efficient against ovarian cancer models, albeit with a toxicity threshold at doses ≥5 mg/kg. The current focus involves the study of biotinylated SB-T derivatives for their better therapeutic utility.

Disclosures This study was supported by grants from the Czech Science Foundation (no. 21–14082S), the Czech Ministry of Education, Youth and Sports (INTER-ACTION no. LUAUS23164), and the NIH, U.S.A. (R01 CA103314).

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