Gene expression of ferredoxin reductase predicts outcome in patients with metastatic colorectal cancer treated by 5-fluorouracil plus leucovorin.
OBJECTIVE
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.
Ichikawa
Wataru
W
Department of General and Digestive Surgery, Saitama Medical School, 38, Moro-Hongo, Moroyama, Iruma, 350-049, Saitama, Japan. wataru@saitama-med.ac.jp
Ooyama
Akio
A
Toda
Etsuko
E
Sugimoto
Yoshikazu
Y
Oka
Toshinori
T
Takahashi
Takehiro
T
Shimizu
Michio
M
Sasaki
Yasutsuna
Y
Hirayama
Renzo
R
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005472:Fluorouracil / Q000008:administration & dosage; D016368:Frameshift Mutation / Q000235:genetics; D015870:Gene Expression / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D009362:Neoplasm Metastasis; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D016159:Tumor Suppressor Protein p53; D005287:Ferredoxin-NADP Reductase; D002955:Leucovorin; D005472:Fluorouracil