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01.12.2011 | Original Article

Sorafenib augments cytotoxic effect of S-1 in vitro and in vivo through TS suppression

verfasst von: Ario Takeuchi, Masaki Shiota, Katsunori Tatsugami, Akira Yokomizo, Masatoshi Eto, Junichi Inokuchi, Kentaro Kuroiwa, Keijiro Kiyoshima, Seiji Naito

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 6/2011

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Abstract

Purpose

Sorafenib, a multikinase and tyrosine-kinase inhibitor, has anti-tumor activity in patients with advanced renal cell carcinoma (RCC). Recently, we reported that S-1 was active and well tolerated for the treatment of cytokine-refractory metastatic RCC. Therefore, we hypothesized that S-1 might be a good candidate for combination therapy with molecular targeting agents. In this study, we examined the mechanisms underlying for the synergism between S-1 and Sorafenib for RCC treatment in vitro and in tumor-bearing murine models.

Methods

Human RCC cell lines were used for the in vitro cell proliferation assay. ACHN and 786-O tumors were subcutaneously transplanted into NCr-nu/nu-mice. Mice were treated with S-1 and/or Sorafenib, and tumor growth and side effects were monitored.

Results

Synergistic anti-proliferative effects of Sorafenib and S-1 were clearly demonstrated in ACHN and 786-O cell lines in vitro due to the suppression of TS and E2F-1 expression. In the NCr-nu/nu model, the synergistic anti-tumor effects of S-1 and Sorafenib were again clearly seen, indicating direct synergistic effects of each drug on tumor growth.

Conclusions

Our results demonstrate the synergistic activity of S-1 and Sorafenib and provided the rationale for combination therapy with S-1 and Sorafenib for the treatment of patients with advanced RCC.

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Titel: Sorafenib augments cytotoxic effect of S-1 in vitro and in vivo through TS suppression
verfasst von: Ario Takeuchi
Masaki Shiota
Katsunori Tatsugami
Akira Yokomizo
Masatoshi Eto
Junichi Inokuchi
Kentaro Kuroiwa
Keijiro Kiyoshima
Seiji Naito
Publikationsdatum: 01.12.2011
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 6/2011
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1660-6

Springer Medizin

Sorafenib augments cytotoxic effect of S-1 in vitro and in vivo through TS suppression