Abstract
Abstract Purpose: Patients with advanced urothelial carcinoma (UC) are treated with cisplatin-based chemotherapy. Polo-like kinase 1 (PLK1) inhibitors (e.g. volasertib) have been shown to be effective in patients with refractory UC (AACR-NCI-EORTC Meeting 2008 abstr 36). We studied the combined cytotoxic effects of volasertib and cisplatin in UC cells in vitro. Materials and methods: The cytotoxicity of the two agents either alone or in combination were studied against UC cell lines with different genetic background: T24 (HRAS mutation), RT4, J82 (FGFR3 mutation), and BFTCC909 (TP53 mutation), using the sulforhodamine B colorimetric assay. Schedule-dependence of the two-drug combination was assayed using 3 different treatment schedules: concurrent and 2 sequential exposures. We examined the effects of volasertib on cell-cycle progression in unsynchronized UC cells by determining the DNA content. Results: The volasertib IC50s of T24, RT4, J82, and BFTCC909 were 13.4±0.13, 54.0±10.6, 14.1±1.3 and 62.4±4.46 nM, respectively and the cisplatin IC50s of the four cells were 2776±361, 8767±1018, 6270±1240 and >10000 nM, respectively. With the median-effect analysis, the combined effects of the two agents when given concurrently were sub-additive in the low fraction affected (Fa) range (0.1-0.3) and additive in the median to high Fa range (0.4-1.0) for the four cells. The combined cytotoxicity was more synergistic if volasertib was given 24 hours earlier than cisplatin. The effects were less synergistic if cisplatin was given prior to volasertib. This phenomenon was seen in all four cells. UC cells in media with 50 nM volasertib arrested in G2/M and showed synchronization 24 hr after release. Conclusions: In our UC cell model, the combined effects may be optimized by sequential use of the two agents, preferably volasertib given 24 hours before cisplatin. Volasertib-treated UC cells arrested in G2/M and showed synchronization which may maximally sensitize UC cells to cisplatin. Our results have clinical implications for the treatment of UC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3725. doi:1538-7445.AM2012-3725
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