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Gene expression of ferredoxin reductase predicts outcome in patients with metastatic colorectal cancer treated by 5-fluorouracil plus leucovorin

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Abstract

Purpose: Ferredoxin reductase (FDXR) is a putative contributor to p53-mediated apoptosis from 5-fluorouracil (5-FU) through the generation of oxidative stress in the mitochondria. However, the influence of FDXR gene expression levels on the outcome of 5-FU chemotherapy has been relatively little studied. The aim of this study is to investigate the association between FDXR gene expressions and the clinical outcome when treated by 5-FU chemotherapy, as well as the correlation of FDXR gene expressions and p53 mutation. Methods: Pre-chemotherapeutic fresh frozen samples of 33 patients with metastatic colorectal cancer, who received bolus 5-FU and leucovorin (LV) as first line chemotherapy, were studied. FDXR gene expression and p53 mutation were evaluated by real-time RT-PCR and direct sequencing, respectively. Results: FDXR gene expression was significantly higher in responding tumors compared with non-responding ones (P=0.0379). Patients with FDXR values above the cutoff value of 13.52 had a statistically longer survival than those with FDXR gene expressions below the cutoff value (P=0.0148). The 9 tumors with wild-type p53 had statistically higher FDXR gene expressions than the 14 tumors with mutant-type p53 which had sequence alterations within the “hot spot” codons, the L2–L3 loops, or frameshift (P=0.0463). Conclusions: FDXR gene expression did not affect clinical outcome in patients with wild-type p53 tumors, whereas, among patients with p53 mutant-type tumors, patients with tumors with low FDXR gene expression had a worse outcome than those with a high FDXR gene expression (P=0.0200). FDXR gene expression, which is regulated at least in part by p53, is associated with both response and survival when metastatic colorectal cancer is treated with 5-FU plus LV. In addition, analysis of p53 mutation combined with FDXR gene expression might be useful in estimating the outcome in 5-FU-treated patients.

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Acknowledgment

The authors are indebted to Prof. J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript, and Mr. Nobutaka Samejima for preparing the article. This work was supported, in part, by a Grant-in-Aid for Scientific Research from Ministry of Education, Culture, Sports and Technology.

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Authors and Affiliations

  1. Department of General and Digestive Surgery, Saitama Medical School, 38, Moro-Hongo, Moroyama, Iruma, 350-049, Saitama, Japan

    Wataru Ichikawa, Takehiro Takahashi & Renzo Hirayama

  2. Optimal Medication Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima, 771-0194, Tokushima, Japan

    Akio Ooyama, Etsuko Toda, Yoshikazu Sugimoto & Toshinori Oka

  3. Department of Pathology, Saitama Medical School, 38, Moro-Hongo, Moroyama, Iruma, 350-049, Saitama, Japan

    Michio Shimizu

  4. Department of Clinical Oncology, Saitama Medical School, 38, Moro-Hongo, Moroyama, Iruma, 350-049, Saitama, Japan

    Yasutsuna Sasaki

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  1. Wataru Ichikawa
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  2. Akio Ooyama
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  4. Yoshikazu Sugimoto
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  9. Renzo Hirayama
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Correspondence to Wataru Ichikawa.

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Ichikawa, W., Ooyama, A., Toda, E. et al. Gene expression of ferredoxin reductase predicts outcome in patients with metastatic colorectal cancer treated by 5-fluorouracil plus leucovorin. Cancer Chemother Pharmacol 58, 794–801 (2006). https://doi.org/10.1007/s00280-006-0217-6

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  • DOI: https://doi.org/10.1007/s00280-006-0217-6

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