Prognostic impact of orotate phosphoribosyl transferase among 5‐fluorouracil metabolic enzymes in resectable colorectal cancers treated by oral 5‐fluorouracil‐based adjuvant chemotherapy

Ochiai, Takumi; Nishimura, Kazuhiko; Noguchi, Hideyo; Kitajima, Masayuki; Tsukada, Akira; Watanabe, Emiko; Nagaoka, Isao; Futagawa, Shunji

doi:10.1002/ijc.21779

Cited by 29 publications

(19 citation statements)

References 21 publications

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“…To our knowledge, the present study was the first clinical report using immunohistochemistry, to demonstrate the clinical significance of the OPRT expression in a relatively large number of cancer patients treated with UFT. In fact, a recent clinical study also revealed a positive OPRT activity to be associated with a better prognosis in resectable colorectal cancer patients treated with oral 5-FU (Ochiai et al, 2006).…”

Section: Discussionmentioning

confidence: 98%

Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT

et al. 2006

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The sensitivity to 5-fluorouracil (5-FU) has been reported to be associated with target molecule thymidylate synthase (TS), fluoropyrimidine-metabolising enzymes such as orotate phosphoribosyltransferase (OPRT), and dihydropyrimidine dehydrogenase (DPD). We performed an immunohistochemical study on the clinical significance of TS, OPRT, and DPD expression using 151 resected non-small-cell lung cancer (NSCLC) patients postoperatively treated with a combination of tegafur and uracil (UFT). Eightytwo carcinomas were TS-positive, 105 carcinomas were OPRT-positive, 68 carcinomas were DPD-positive. No correlation was observed in the HSCORE between the TS and OPRT expression (r ¼ 0.203), between the TS and DPD expression (r ¼ 0.098), or between the OPRT and DPD expression (r ¼ 0.074). Regarding the survival of NSCLC patients treated with UFT, the 5-year survival rate of patients with TS-negative tumours was significantly higher than that with TS-positive tumours (P ¼ 0.0133). The 5-year survival rate of patients with OPRT-positive stage II to III tumours was significantly higher than that with OPRT-negative stage II to III tumours (P ¼ 0.0145). In addition, the 5-year survival rate of patients with DPD-negative tumours was also significantly higher than that with DPD-positive tumours (P ¼ 0.0004). A Cox multivariate regression analysis revealed the TS status (hazard ratio 2.663; P ¼ 0.0003), OPRT status (hazard ratio 2.543; P ¼ 0.0005), and DPD status (hazard ratio 2.840; Po0.0001) to all be significant prognostic factors for the survival of resected NSCLC patients postoperatively treated with UFT.

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Section: Discussionmentioning

confidence: 98%

Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT

et al. 2006

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“…As to the methodology of 5-FU metabolic pathway enzymes, protein activity, immunohistochemistry, enzymelinked immunosorbent assay (ELISA) and mRNA levels have been reported (13)(14)(15). Concerning the routine measurement of these enzymes, protein activity measurements are not technically feasible because of the complexity in the use of radioisotopes.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that a high-expression level of TS and low-expression levels of DPD were correlated with poor prognosis (13,14). In contrast, it has been reported that OPRT, though not TS and DPD have a prognostic value in patients treated with 5-FU-based adjuvant chemo-therapy (15). It was thought that one of the reasons for these confused results is the purity of tumor samples.…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of 5-fluorouracil metabolic enzyme genes in Dukes' stage B and C colorectal cancer patients treated with oral 5-fluorouracil-based adjuvant chemotherapy

Yamada

Iinuma²,

Watanabe³

2008

Oncol Rep

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Abstract. 5-Fluorouracil (5-FU) is the most commonly used anticancer drug for colorectal cancer (CRC). In this study, we aimed to clarify the prognostic value of the expression of the 5-FU metabolic enzyme genes, including orptate phosphoribosyl transferase (OPRT), dihydropyrimidine dehydrogenase (DPD), thymidylate synthetase (TS) and thymidylate phosphorylate (TP) genes in CRC patients treated with oral 5-FU-based adjuvant chemotherapy. We examined 103 CRC patients with Dukes' stage B and C who underwent oral 5-FU-based adjuvant chemotherapy. Formalin-fixed, paraffin-embedded tumor specimens from primary CRC tissues were dissected by laser-captured microdissection and quantification of mRNA levels of OPRT, DPD, TS and TP were measured by real-time reverse transcription (RT) PCR. The relationship between these 5-FU metabolic enzyme gene levels and disease-free and overall survival rates were examined. The disease-free and overall survival curves of the OPRT mRNA high-expression group were significantly longer than that of the OPRT mRNA low-expression group. The disease-free and overall survival curves of the DPD mRNA high-expression group were significantly shorter than that of the DPD mRNA low-expression group. In contrast, there were no significant differences between the TS or TP mRNA highexpression and low-expression groups in the disease-free and overall survival curves. In a multivariate Cox regression analysis, it was demonstrated that the OPRT mRNA level is an independent prognostic variable for disease-free and overall survival. These results suggest that the OPRT mRNA is a useful indicator in the prediction of disease-free and overall survival in Dukes' B and C stage CRC patients treated with oral 5-FU-based adjuvant chemotherapy.

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“…This result may support Grothey's report in dual responders. Several studies have investigated individualization in 5-FU-based chemotherapy based on the 5-FU metabolism-associated enzymatic and genetic characteristics of the individual patient (22)(23)(24)(25)(26)(27)(28)(29). In addition, the individualization of 5-FU-based chemotherapy based on the serum 5-FU concentration has been reported lately (30)(31)(32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Impact of the individualization of the first‑line chemotherapy for advanced colorectal cancer based on collagen gel droplet‑embedded drug sensitivity test

Ochiai¹,

Nishimura²,

Watanabe³

et al. 2017

Oncol Lett

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Abstract. Leucovorin (FOL) and fluorouracil (5-FU) plus oxaliplatin (l-OHP; FOLFOX) or FOL and 5-FU plus irinotecan FOLFIRI) are widely used as first-line chemotherapy regimens in the treatment of advanced colorectal cancer (CRC). However, second-line chemotherapy must be abandoned in certain cases due to disease progression, adverse effects or high medical cost. Therefore, the most effective regimen should be selected as first-line chemotherapy. We reported that individualization of first-line treatment (FOLFOX/FOLFIRI/Dual/Poor responder) was possible using the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) and that individualized first-line chemotherapy with CD-DST may improve the prognosis of patients with unresectable CRC. The aim of the present prospective cohort study was to evaluate the individualization of first-line chemotherapy using CD-DST, with a focus on prognosis. Between March 2008 and December 2015, tumor specimens were obtained from 120 patients with CRC who had not received preoperative chemotherapy. CD-DST was performed and the growth inhibition rate (IR) was determined by exposure for 24 h with 5-FU and l-OHP (6.0 and 3.0 µg/ml, respectively) and 5-FU and SN-38 (6.0 and 0.2 µg/ml, respectively). The cumulative distribution of IR values under each condition was evaluated on the basis that the clinical response to FOLFOX and FOLFIRI is equivalent (~50%). The prognosis of dual responder was improved compared with that of poor responders, however this difference was identified to be significant. There was no different prognosis between patients treated with an appropriate first-line regimen and patients treated with an inappropriate first-line regimen in dual responders. However, in poor responders, there were significant differences of prognosis between patients treated with an appropriate first-line regimen and patients treated with an inappropriate first-line regimen (P= 0.036). In conclusion, the results from the present study suggest that administration of the recommended first-line regimen using CD-DST for patients with unresectable CRC is important for the improvement of prognosis, particularly in poor responders.

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Prognostic impact of orotate phosphoribosyl transferase among 5‐fluorouracil metabolic enzymes in resectable colorectal cancers treated by oral 5‐fluorouracil‐based adjuvant chemotherapy

Cited by 29 publications

References 21 publications

Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT

Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT

Prognostic value of 5-fluorouracil metabolic enzyme genes in Dukes' stage B and C colorectal cancer patients treated with oral 5-fluorouracil-based adjuvant chemotherapy

Impact of the individualization of the first‑line chemotherapy for advanced colorectal cancer based on collagen gel droplet‑embedded drug sensitivity test

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