EP018/#324 The efficacy and molecular mechanisms of MDR-reversal agents (stony brook taxanes) in resistant ovarian carcinoma models

Objectives

Taxane resistance is a serious problem in the successful treatment of ovarian carcinoma. New generations of taxane analogs (Stony Brook taxanes; SB-Ts) seem to be effective against resistant solid tumors. Our aim was to estimate in vitro and in vivo efficacy of SB-Ts in comparison to paclitaxel and discover underlying changes of gene expression profile connected with the treatment of taxanes.

Methods

NCI/ADR-RES and SKOV-3/PCT-RES human ovarian cancer cell lines were used as multidrug-resistant model. The efficacy of taxanes was compared via assessment of IC₅₀ values. Flow cytometry was used for analysis of cell cycle changes. In vivo efficacy of taxanes was measured after intraperitoneal application of paclitaxel alone (10 mg/kg) or combined with SB-Ts (1–5 mg/kg) twice a week in resistant ovarian cell line-derived xenograft (CDX) models. Gene expression profiles were followed by quantitative real-time PCR in CDX tumors.

Results

In vitro experiments revealed the third generation SB-Ts – SB-T-121605 and SB-T-121606 as the most effective. In vivo, both SB-Ts effectively suppressed tumor growth at low doses (<3 mg/kg) in combination with paclitaxel, limiting their adverse effects. Treatment of SB-Ts also led to significant deregulation of many genes involved in resistance.

Conclusions

SB-T-121605 and SB-T-121606 are promising candidates for further studies, aimed at development of novel therapeutics for therapy of resistant ovarian tumors. Supported by projects of the Czech Science Foundation no. 21–14082S, the Czech Ministry of Education, Youth and Sports: INTER-ACTION, project no. LTAUSA19032, and the National Institutes of Health (NIH), U.S.A. grant R01 CA103314.