Predicting 5-FU sensitivity using human colorectal cancer specimens: comparison of tumor dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferase activities with in vitro chemosensitivity to 5-FU

Isshi, Kimio; Sakuyama, Toshikazu; Gen, Tomoyasu; Nakamura, Yasuyuki; Kuroda, Tôru; Katuyama, T; Maekawa, Yoshimi

doi:10.1007/s101470200051

Cited by 61 publications

(50 citation statements)

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“…Previous clinical studies also revealed the positive expression and activity of OPRT to be associated with the responsiveness to 5-FU in a variety of human cancers, including colorectal cancers (Isshi et al, 2002;Fujii et al, 2003;Ichikawa et al, 2003a;Matsuyama et al, 2006) and bladder carcinomas (Mizutani et al, 2004). However, these studies were performed using relatively small number of patients, and then were evaluated by biochemical assays for OPRT enzyme activity or reverse transcriptional PCR (RT -PCR) assays for OPRT gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical studies have reported their sensitivity to be associated with the target molecule TS (Rustum et al, 1997), fluoropyrimidinemetabolising enzymes such as orotate phosphoribosyltransferase (OPRT) (Peters et al, 1986), and the 5-FU-catabolitic enzyme such as dihydropyrimidine dehydrogenase (DPD) (Beck et al, 1994). However, there were only a few clinical studies on the simultaneous evaluations of these biomarkers to evaluate 5-FU sensitivity (Isshi et al, 2002;Fujii et al, 2003;Ichikawa et al, 2003a).…”

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confidence: 99%

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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: 99%

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confidence: 99%

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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“…High OPRT activity was associated with good in vitro sensitivity to 5-FU, measured by Collagen Gel Droplet Embedded Culture Drug Sensitivity test, Fluoresceine Diacetate Assay or Histoculture Drug Response Assay, in human colorectal cancer tissues. 68,69 Furthermore, in 37 patients treated with oral tegafur-uracil for disseminated colorectal cancer, responding tumours had higher expressions of OPRT than nonresponding tumours. 70 In the same study, there was no difference in UP mRNA between responding and nonresponding tumours.…”

Section: -Fluorouracilmentioning

confidence: 99%

“…To find such gene panels, far more studies are needed. Looking at current data, a combination of the expression of DPD, TS, TP and OPRT, all four crucial enzymes in the metabolism of 5-FU, at least appears to be a promising approach in colorectal cancer [68][69][70][184][185][186] (Table 5). …”

Section: Impact Of Current Data On Clinical Practicementioning

confidence: 99%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumourspecific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5 0 -nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

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“…Several 5-FU-related metabolic enzymes are thought to correlate with the sensitivity to 5-FU (4)(5)(6)(7)(8)(9)(10). Two main modes of action have been proposed for 5-FU through its active metabolites, 5-fluoro-2'deoxyuridine-5'-monophosphate (FdUMP) and 5-fluoro-uridine-5'-triphosphate (FUTP) (10).…”

Section: Introductionmentioning

confidence: 99%

Correlation between chemosensitivity and mRNA expression level of 5-fluorouracil-related metabolic enzymes during liver metastasis of colorectal cancer

Okumura

Shiomi²,

Mekata³

et al. 2006

Oncol Rep

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Abstract. The attainment of chemoresistance during tumor metastasis is often experienced. In this study, we evaluated the correlation between sensitivity to 5-fluorouracil (5-FU) and the mRNA expression level of several 5-FU-related metabolic enzymes [thymidylate synthase, dihydropyrimidine dehydrogenase (DPD), thymidylate phosphorylase (TP), orotate phosphoribosyl transferase, and uridine phosphorylase] in primary colorectal cancer and synchronous liver metastases from ten patients to investigate how colorectal cancer acquires 5-FU resistance during liver metastases. A liver metastasis model of xenotransplanted human colon cancer cell line (HCT116) in nude mice and several cell lines from metastatic liver tumors were also established and analyzed. Chemosensitivity and mRNA expression levels were measured by using collagen gel droplet-embedded culture drug sensitivity tests and real-time quantitative reverse transcriptionpolymerase chain reaction. Metastatic liver tumors were significantly more resistant to 5-FU than primary colorectal cancer (T/C, 88.7% versus 69.7%, p<0.05). DPD and TP mRNA levels were significantly higher in metastatic liver tumors (DPD: 10.36±1.81 versus 3.95±0.99, p<0.01; and TP: 18.80±4.96 versus 7.28±1.23, p<0.05) and inversely correlated with 5-FU sensitivity (DPD: R=0.570, p<0.05; TP: R=0.600, p<0.05). In the mouse model, metastatic liver tumors were significantly more resistant to 5-FU than HCT116 (T/C, 92.7%, 96.2% versus 68%, p<0.001). The DPD and TP mRNA levels increased with repeated liver metastases. DPD and TP may affect the acquisition of resistance to 5-FU during liver metastasis of colorectal cancer. This mouse model may be useful for analyzing the mechanisms of how colorectal cancer acquires resistance to 5-FU during liver metastases.

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Predicting 5-FU sensitivity using human colorectal cancer specimens: comparison of tumor dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferase activities with in vitro chemosensitivity to 5-FU

Abstract: DPD and OPRT activities within cancer cells may predict positive sensitivity to 5-FU.

Cited by 61 publications

References 5 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

Genetic factors influencing Pyrimidine-antagonist chemotherapy

Correlation between chemosensitivity and mRNA expression level of 5-fluorouracil-related metabolic enzymes during liver metastasis of colorectal cancer

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