Synergy of Interferon-α and 5-Fluorouracil in Human Renal Cell Carcinoma Requires p53 Activity

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• 作者：Donghao Shang ; Noriyuki Ito ; Jun Watanabe ; Yasuo Awakura ; Hiroyuki Nishiyama ; Toshiyuki Kamoto ; Osamu Ogawa
• 关键词：5-Fluorouracil ; Interferon-α ; p53 ; Renal cell carcinoma ; Synergy
• 刊名：European Urology
• 出版年：2007
• 出版时间：October 2007
• 年：2007
• 卷：52
• 期：4
• 页码：1131-1139
• 全文大小：1920 K

文摘

Immunochemical therapy combining cytokines and chemotherapeutic agents is expected to be effective for treating advanced renal cell carcinoma (RCC). We investigated the mechanism underlying the synergism of interferon-α (IFN-α) and 5-fluorouracil (5-FU) and the effect of p53 status on the synergy of the combined therapy in RCC cell lines.

Methods

The synergy of IFN-α and 5-FU was analyzed by isobolographic analysis in five RCC cell lines. The effect of combined treatment on apoptosis induction was measured by flow cytometric analysis, Hoechst staining, and caspase activity assay; PCNA expression was investigated by Western blotting to examine the effect of combined treatment on the antiproliferative effect.

Results

We demonstrated synergy of IFN-α and 5-FU in five RCC cell lines with wild-type p53. IFN-α suppressed the proliferation of RCC cells via G1 or G2/M cell cycle arrest without inducing apoptosis, whereas 5-FU induced apoptosis in a dosage-dependent manner. IFN-α enhanced the apoptosis of RCC cells induced by 5-FU, whereas 5-FU did not increase the antiproliferative effect of IFN-α. However, the synergistic inhibition by IFN-α and 5-FU was abolished when the cell lines were transfected with p53 dominant-negative vector.

Conclusions

The synergy of IFN-α and 5-FU requires p53 activity, suggesting that p53 status may serve as a predictive factor for response to the combination therapy. Because metastatic RCC frequently has p53 mutations, therapy restoring p53 may markedly improve the response rate of immunochemical therapy combining IFN-α and 5-FU.