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362 Novel Stony Brook taxanes are efficacious in paclitaxel-resistant ovarian cancer models both in vitro and in vivo
  1. P Holý1,2,3,
  2. K Seborova1,3,
  3. A Spalenkova1,2,3,
  4. K Koucka1,3,
  5. M Ehrlichova1,3,
  6. C Wang4,
  7. I Ojima4,
  8. P Daniel5,
  9. K Balusikova5,
  10. M Jelinek5,
  11. J Kovar5,
  12. P Soucek1,3 and
  13. R Vaclavikova1,3
  1. 1Biomedical Center, Charles University Faculty of Medicine in Pilsen, Laboratory of Pharmacogenomics, Pilsen, Czech Republic
  2. 2Third Faculty of Medicine, Charles University, Prague, Czech Republic
  3. 3National Institute of Public Health, Prague, Toxicogenomics Unit, Prague, Czech Republic
  4. 4Institute of Chemical Biology and Drug Discovery – Stony Brook University – State University of New York, Stony Brook, NY, USA
  5. 5Third Faculty of Medicine, Charles University, Division of Cell and Molecular Biology, Prague, Czech Republic


Introduction/Background*Resistance of cancer cells to taxanes is a serious problem preventing successful therapy. Efforts are ongoing to synthesize novel taxanes efficacious against the resistant phenotype. Stony Brook taxanes (SB-Ts) have proven to have potential, but require further preclinical testing and more detailed study of their mechanism of action. Here, we aimed to evaluate the efficacy of several promising SB-Ts in resistant ovarian cancer models in vitro, and in vivo. We also studied the role of 3 candidate genes ABCC3, CPS1, and TRIP6 in SB-Ts cell death-inducing molecular mechanisms.

Methodology The NCI/ADR-RES ovarian cancer cell line was incubated with either paclitaxel or one of the second generation (SB-T-1214 and SB-T-1216) or third generation (SB-T-121402, SB-T-121605 and SB-T-121606) taxanes. Cell survival was measured as IC50 after 72 hours. Cell cycle analysis was performed using flow cytometry. Uptake of SB-Ts into cells was measured by HPLC. Female athymic mice Nude Crl: NU(NCr)-Foxn1nu (N=50) were used as the model organism for ovarian cancer by subcutaneous application of NCI/ADR-RES cells. In vivo efficacy of taxanes was measured after intraperitoneal application twice per week. Gene expression in tumour tissue was measured by RT-qPCR.

Result(s)*Compared to paclitaxel, NCI/ADR-RES cells showed 30x lower resistance to SB-T-1214, SB-T-1216, and SB-T-121402 and 50x lower to the 3rd generation taxanes SB-T-121605 and SB-T-121606. Cell cycle analysis showed the “1216” family to be more cytostatic than cytotoxic compared to “1214”. Uptake of SB-T-1216 and its derivatives into cells was 6-15.5x higher than for paclitaxel. Treatment of mice (groups of 5) with regimen combining paclitaxel and SB-T-121605/-06 significantly slowed tumour growth and even reduced tumour volume after several applications. Doses of SB-Ts higher than 3 mg/kg caused severe toxicity. Both SB-T-121605 and SB-T-121606, but not paclitaxel, led to significant decrease in CPS1 and ABCC3 expression in vitro and in case of CPS1 also in vivo.

Conclusion*Third generation taxanes SB-T-121605 and SB-T-121606 are highly effective in a paclitaxel-resistant ovarian carcinoma model both in vitro and in vivo and warrant further investigation. SB-T treatment led to deregulation of CPS1 and ABCC3 expression that seems to play a role in their efficacy.

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