Molecular determinants of efficacy for 5‐FU‐based treatments in advanced colorectal cancer: mRNA expression for 18 chemotherapy‐related genes

Gustavsson, Bengt; Kaiser, Christopher J.; Carlsson, Göran; Wettergren, Yvonne; Odin, Elisabeth; Lindskog, Elinor Bexe; Niyikiza, Clet; Ma, Doreen

doi:10.1002/ijc.23852

Cited by 33 publications

(24 citation statements)

References 39 publications

(53 reference statements)

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“…Previously, we identified TP gene expression in microdissected tumour samples from colorectal carcinomas as a possible predictor of chemotherapy response and survival in advanced colorectal cancer [12]. This finding was in keeping with the observations of other independent reports [12-15].…”

Section: Introductionsupporting

confidence: 90%

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Thymidine phosphorylase expression is associated with time to progression in patients with metastatic colorectal cancer

et al. 2014

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Background5-Fluorouracil (5-FU) is the cornerstone of chemotherapeutic treatment for patients with colorectal cancer. The enzyme thymidine phosphorylase (TP) catalyzes the conversion of 5-FU to its active metabolite, 5-fluoro-2’-deoxyuridine. TP is expressed in tumour epithelial cells and stromal cells, particularly in tumour-associated macrophages. These macrophages may affect sensitivity to chemotherapy. Previously, we identified TP as a predictive factor in microdissected tumour samples of patients with advanced colorectal cancer. In the present study, we analysed TP expression in tissues and associated stromal cells from patients with advanced colorectal cancer and associated TP levels to tumour response and time-to-event variables during first-line chemotherapy treatment. We also investigated the association between serum TP levels at the time of surgery and gene expression in primary tumour tissues.MethodsThis study included 125 patients with metastatic colorectal cancer treated with first-line 5-FU-based chemotherapy. To quantify TP gene expression levels in tumour tissues, real-time polymerase chain reaction was performed using the 7500 Fast Real-Time PCR system (Applied Biosystems, Foster City, CA, USA). TP protein concentration in matched serum samples was determined using an enzyme-linked immunosorbent assay system (USCN Life Science Inc.).ResultsThe tumour response rate was 31%, and 30% of patients exhibited stable disease. No associations between TP expression level and age or gender were observed. Levels of TP mRNA in mucosa and tumours were positively correlated (r = 0.41, p < 0.01). No correlation between TP expression and tumour response rate was observed. Time to progression was significantly longer in patients with high TP expression (p < 0.01). Serum TP protein levels were not associated with tumour response or time-to-event variables and did not correlate with gene expression in tumour tissues.ConclusionsHigh TP gene expression in non-microdissected tumour tissues of patients with advanced colorectal cancer correlates with longer time to progression, which could be related to treatment. These results are in contrast to previous studies where microdissected tumour cells were analysed and may be due to the presence of adjacent stromal cells. Serum TP protein expression does not correlate to TP gene expression in tissues of patients with advanced colorectal cancer.

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Section: Introductionsupporting

confidence: 90%

“…This finding was in keeping with the observations of other independent reports [12-15]. In the present study, we included tumour-associated stromal cells in our analysis of TP gene expression, because the majority of expression appears to be associated with TAMs.…”

Section: Introductionsupporting

confidence: 87%

Thymidine phosphorylase expression is associated with time to progression in patients with metastatic colorectal cancer

et al. 2014

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“…In addition, elevated intratumoural DPD expression results in an increased fluoropyrimidine catabolism at the expense of anabolism, and may cause fluoropyrimidine resistance, as recently shown by others (Gustavsson et al , 2009) and us at the preclinical (Beck et al , 1994) and clinical levels (Etienne et al , 1999). Two randomized trials of 5FU-based adjuvant therapy vs no treatment have reported that stage II–III patients bearing dMMR tumours do not benefit from 5FU-based therapy (Ribic et al , 2003; Sargent et al , 2010).…”

Section: Discussionmentioning

confidence: 74%

Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study

Mahamat

Chazal³

et al. 2014

Br J Cancer

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Background:To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours.Methods:This prospective multicentric study involved 251 stage I–III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12–13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4–9), CpG island methylation phenotype status, ploidy, S-phase, LOH.Results:The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS-mutated (P=0.005), BRAF wt (P=0.009) and pMMR tumours (P=0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (P<0.001) and show higher DPD expression (median 14.9 vs 7.9, P=0.027) and EGFR content (median 69 vs 38, P=0.037) relative to pMMR.Conclusions:Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy.

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“…TP and TS expressions were found to be independent variables in these tumours, so that low expression levels of both TS and TP in tumours predicted a high response rate to 5-FU/LVas well as a significantly longer survival, whereas none of the patients with high expression of either TP or TS were responders [58]. In another study, Gustavsson et al retrospectively examined the pretreatment expression of TP and other 17 genes in archival tumour samples from patients with advanced CRC to determine if one or more of the selected genes can be used as either a prognostic or predictive marker of 5-FU-based treatment outcomes [59]. One hundred and fortyfour CRC patient samples were analysed via real-time PCR for gene expression.…”

Section: Tp As a Predictive Biomarkermentioning

confidence: 99%

Thymidine Phosphorylase in Cancer; Enemy or Friend?

Elamin

Rafee

Osman

et al. 2015

Cancer Microenvironment

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Thymidine phosphorylase (TP) is a nucleoside metabolism enzyme that plays an important role in the pyrimidine pathway.TP catalyzes the conversion of thymidine to thymine and 2-deoxy-α-D-ribose-1-phosphate (dRib-1-P). Although this reaction is reversible, the main metabolic function of TP is catabolic. TP is identical to the angiogenic factor platelet-derived endothelial-cell growth factor (PD-ECGF). TP is overexpressed in several human cancers in response to cellular stressful conditions like hypoxia, acidosis, chemotherapy and radiotherapy. TP has been shown to promote tumor angiogenesis, invasion, metastasis, evasion of the immuneresponse and resistance to apoptosis. Some of the biological effects of TP are dependent on its enzymatic activity, while others are mediated through cytokines like interleukin 10 (IL-10), basic fibroblast growth factor (bFGF) and tumour necrosis factor α (TNFα). Interestingly, TP also plays a role in cancer treatment through its role in the conversion of the oral fluoropyrimidine capecitabine into its active form 5-FU. TP is a predictive marker for fluoropyrimidine response. Given its various biological functions in cancer progression, TP is a promising target in cancer treatment. Further translational research is required in this area.

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Molecular determinants of efficacy for 5‐FU‐based treatments in advanced colorectal cancer: mRNA expression for 18 chemotherapy‐related genes

Cited by 33 publications

References 39 publications

Thymidine phosphorylase expression is associated with time to progression in patients with metastatic colorectal cancer

Thymidine phosphorylase expression is associated with time to progression in patients with metastatic colorectal cancer

Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study

Thymidine Phosphorylase in Cancer; Enemy or Friend?

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