Basic and Translational ScienceDemethylating Agent 5-Aza-2′-Deoxycytidine Enhances Susceptibility of Bladder Transitional Cell Carcinoma to Cisplatin
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Cell Lines and Agents
We used bladder transitional cell carcinoma cell lines: RT112 (wild-type p53), 253J (wild-type p53), TCCSUP (mutant p53) and T24 (p53 −/−). All cell lines were cultured in complete medium and maintained as monolayers and incubated in a humidified atmosphere containing 5% CO2 at 37°C.
We purchased DAC, paclitaxel (PTX), VBL, and 5-fluorouracil (5-FU) from Sigma Aldrich Japan (Tokyo, Japan); CDDP and ADM were purchased from Nippon Kayaku (Tokyo, Japan) and Kyowa Hakko Kogyo (Tokyo, Japan),
Synergistic Growth Suppression by DAC and CDDP
5-Aza-2′-deoxycytidine (Fig. 1A) and five chemotherapeutic agents (data not shown) each caused dosage-dependent cell growth suppression of TCC cells. DAC could increase the susceptibility of TCC cells to CDDP (Fig. 1B and C, results for RT112 and TCCSUP), and combined treatment with DAC and CDDP caused synergistic growth suppression in all TCC cell lines examined in a p53-independent manner, as shown by isobolographic analysis (Fig. 1D). However, synergy of DAC and PTX, 5-FU, VBL, and ADM was
Comment
Promising new antitumor agents usually appear as our understanding of oncogenesis advances. Although decitabine (Dacogen), a pharmacological form of DAC, has only been approved for use against hematopoietic malignancies at present, it also showed clinical efficacy in the treatment of metastatic lung carcinoma.5 Since 2004, studies concerning combination chemotherapy of DAC and chemotherapeutic agents have been performed, and the results suggested that DAC increased the cytotoxicity of
Conclusions
We observed synergistic growth suppression by DAC and CDDP in TCC cell lines, and the synergy of the two agents was independent of p53 status. This suggests that DAC might enhance the efficacy of CDDP against TCC, and combination chemotherapy with DAC and CDDP might become a new clinical therapeutic strategy to overcome TCC.
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This research was supported by a grant from Ministry of Education, Culture, Sports, Science and Technology, Japan.