Impact of 5-fluorouracil metabolizing enzymes on chemotherapy in patients with resectable colorectal cancer

Ochiai, Takumi; Umeki, Masahiko; Miyake, Hiroshi; Iida, Takuya; Okumura, Minoru; Ohno, Kazuhide; Sakamoto, Masashi; Miyoshi, Nobukazu; Takahashi, Masahīko; Tsumura, Hidenori; Tokunaga, Yukihiko; Naitou, H; Fukui, Takuji

doi:10.3892/or.2014.3299

Cited by 17 publications

(7 citation statements)

References 33 publications

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“…[ 55 ] In this regard, literature data showed that 5-FU sensitivity is associated with OPRT gene polymorphisms and OPRT/DPD activity ratio. [ 56 – 58 ] This finding leads to the hypothesis that UM show better PFS and higher rate of severe toxicities, due to the increased amount of 5-FU active metabolites. ( Fig 4 )…”

Section: Discussionmentioning

confidence: 99%

Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?

et al. 2016

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Background5-FU based chemotherapy is the most common first line regimen used for metastatic colorectal cancer (mCRC). Identification of predictive markers of response to chemotherapy is a challenging approach for drug selection. The present study analyzes the predictive role of 5-FU degradation rate (5-FUDR) and genetic polymorphisms (MTHFR, TSER, DPYD) on survival.Materials and MethodsGenetic polymorphisms of MTHFR, TSER and DPYD, and the 5-FUDR of homogenous patients with mCRC were retrospectively studied. Genetic markers and the 5-FUDR were correlated with clinical outcome.Results133 patients affected by mCRC, treated with fluoropyrimidine-based chemotherapy from 2009 to 2014, were evaluated. Patients were classified into three metabolic classes, according to normal distribution of 5-FUDR in more than 1000 patients, as previously published: poor-metabolizer (PM) with 5-FU-DR ≤ 0,85 ng/ml/106 cells/min (8 pts); normal metabolizer with 0,85 < 5-FU-DR < 2,2 ng/ml/106 cells/min (119 pts); ultra-rapid metabolizer (UM) with 5-FU-DR ≥ 2,2 ng/ml/106 cells/min (6 pts). PM and UM groups showed a longer PFS respect to normal metabolizer group (14.5 and 11 months respectively vs 8 months; p = 0.029). A higher G3-4 toxicity rate was observed in PM and UM, respect to normal metabolizer (50% in both PM and UM vs 18%; p = 0.019). No significant associations between genes polymorphisms and outcomes or toxicities were observed.Conclusion5-FUDR seems to be significantly involved in predicting survival of patients who underwent 5-FU based CHT for mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?

et al. 2016

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“…The alterations in orotate are therefore intriguing; elevated orotate levels have been reported in selected cell lines after treatment with the anti-cancer drug 5-fluorouracil (5-FU) [53]. This drug is metabolized by orotate phosphoribosyltransferase (OPRT), the enzyme which also converts orotate to orotidine monophosphate in vivo [54,55]. OPRT converts 5-FU to its active metabolite fluorouridine monophosphate.…”

Section: Discussionmentioning

confidence: 99%

Identification of Circulating Genomic and Metabolic Biomarkers in Intrahepatic Cholangiocarcinoma

Winter

Kaisaki

Harvey

et al. 2019

Cancers

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Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer arising from the bile ducts with a need for earlier diagnosis and a greater range of treatment options. KRAS/NRAS mutations are common in ICC tumours and 6–32% of patients also have isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations associated with metabolic changes. This feasibility study investigated sequencing circulating tumour DNA (ctDNA) combined with metabolite profiling of plasma as a method for biomarker discovery in ICC patients. Plasma was collected from four ICC patients receiving radio-embolisation and healthy controls at multiple time points. ctDNA was sequenced using Ampliseq cancer hotspot panel-v2 on Ion Torrent PGM for single nucleotide variants (SNV) detection and with Illumina whole genome sequencing for copy number variants (CNV) and further targeted examination for SNVs. Untargeted analysis of metabolites from patient and control plasma was performed using liquid chromatography coupled with high-resolution tandem mass spectrometry (LC-MS/MS). Metabolite identification was performed using multi-parameter comparisons with analysis of authentic standards, and univariate statistical analysis was performed to identify differences in metabolite abundance between patient and control samples. Recurrent somatic SNVs and CNVs were identified in ctDNA from three out of four patients that included both NRAS and IDH1 mutations linked to ICC. Plasma metabolite analysis revealed biomarker metabolites associated with ICC and in particular 2-hydroxyglutarate (2-HG) levels were elevated in both samples from the only patient showing a variant allele in IDH1. A reduction in the number of CNVs was observed with treatment. This study demonstrates that ctDNA and metabolite levels can be identified and correlated in ICC patient blood samples and differentiated from healthy controls. We conclude that combining genomic and metabolic analysis of plasma offers an effective approach to biomarker identification with potential for disease stratification and early detection studies.

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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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Impact of 5-fluorouracil metabolizing enzymes on chemotherapy in patients with resectable colorectal cancer

Cited by 17 publications

References 33 publications

Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?

Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?

Identification of Circulating Genomic and Metabolic Biomarkers in Intrahepatic Cholangiocarcinoma

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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