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

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.

• Authors: Wataru Ichikawa, Akio Ooyama, Etsuko Toda, Yoshikazu Sugimoto, Toshinori Oka, Takehiro Takahashi, Michio Shimizu, Yasutsuna Sasaki, Renzo Hirayama
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 58 Issue 6 Pg. 794-801 (Dec 2006) ISSN: 0344-5704 [Print] Germany
• PMID: 16528528 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Suppressor Protein p53
• Ferredoxin-NADP Reductase
• Leucovorin
• Fluorouracil

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Colorectal Neoplasms (drug therapy, enzymology, genetics, pathology)
• DNA Mutational Analysis
• Ferredoxin-NADP Reductase (genetics)
• Fluorouracil (administration & dosage)
• Frameshift Mutation (genetics)
• Gene Expression (genetics)
• Gene Expression Regulation, Enzymologic (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• Leucovorin (administration & dosage)
• Middle Aged
• Mutation, Missense (genetics)
• Neoplasm Metastasis
• Prognosis
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Analysis
• Treatment Outcome
• Tumor Suppressor Protein p53 (genetics)