Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic metastases occur in about half of patients with colorectal cancer. Since hepatic metastases are often not accessible for surgery, chemotherapy of metastases is important. The most commonly used chemotherapy drugs for hepatic metastases are fluorouracil, irinotecan, and oxaliplatin. Several enzymes are known to be involved in the catabolism and anabolism of these drugs, and the activity of these enzymes varies greatly between individuals. The causes of this variation include genetic polymorphisms, different regulation between normal and cancer tissue, and the influence of chemotherapy on enzyme expression. The varying enzyme activity may have an important effect on the outcome of chemotherapy. Several studies confirm the influence of the activity of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase on the outcome of fluorouracil therapy for colorectal cancer, with higher enzyme activities predicting lower treatment efficacy. Although fewer studies are available regarding therapy of hepatic metastases, the same relationship between thymidylate synthase activity and outcome of fluorouracil therapy observed for primary colorectal cancer was found. For the other two enzymes, only a few studies are available, but the results indicate similarly that higher enzyme activity seems to be disadvantageous. The enzymes responsible for the activation, metabolism and mechanism of action of irinotecan, namely carboxylesterase 2, cytochrome P450 (CYP) 3A4, uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1), and topoisomerase-I, also exhibit variable interindividual activity. Thus, there may be an association between enzyme activity and response to therapy. For instance, in patients with colorectal cancer, higher enzyme activity of topoisomerase-I seems to be predictive of a better response to irinotecan. CYP3A4 and UGT1A1 activity levels might be predictive of irinotecan toxicity rather than efficacy. The degradation of oxaliplatin is independent of potentially varying enzyme activity, but for this drug, the DNA repair enzyme ERCC1 may influence the survival time after chemotherapy. Taken together, the available data indicate the importance of the different enzyme activities on the outcome of chemotherapy of hepatic metastases in colorectal cancer. More information is needed, especially for the newer drugs irinotecan and oxaliplatin. However, the existing data are very promising in respect to the potential to guide dose and drug selection for more efficient and less toxic chemotherapy of hepatic metastases.
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PMID:Pharmacogenomics of fluorouracil, irinotecan, and oxaliplatin in hepatic metastases of colorectal cancer: clinical implications. 1572 86

To clarify the correlation between the expression level of thymidine phosphorylase (TP) and efficacy of doxifluridine (5'-DFUR) and 5-fluorouracil (5-FU), samples from 177 colorectal cancer patients who underwent curative resection were evaluated by immunohistochemical staining using a newly developed monoclonal antibody 1C6-203. Patients were randomly given either oral 5'-DFUR or 5-FU as postoperative adjuvant chemotherapy. In Dukes' C staged colon cancer patients treated with 5'-DFUR, better survival was observed in the high TP patients than the low TP patients (P=0.025 by the log-rank test). The observed 5-year survival rates were 91.2 and 74.8%, respectively. No correlation between TP expression and patient prognosis was detected in the 5-FU group. In Dukes' C stage colon patients with high TP expression, the 5'-DFUR group had slightly better survival than the 5-FU group. These findings suggest that TP may be a chemosensitive marker for 5'-DFUR as postoperative adjuvant chemotherapy for advanced colon cancer patients.
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PMID:Thymidine phosphorylase expression and efficacy of adjuvant doxifluridine in advanced colorectal cancer patients. 1575 33

Thymidylate synthase [TS], thymidine phosphorylase [TP] and dihydropyrimidine dehydrogenase [DPD] play the essential role in the activation and catabolism of the fluoropyrimidines used in cancer therapy. Its expression may influence the antitumor activity or toxicity of these drugs. We studied the expression levels of selected enzymes in colorectal tumors and adjacent normal mucosa. The analysis of TS, TP and DPD gene expression was performed using quantitative Real time PCR technique (Roche) in 15 (TS), 64 (TP) and 12 (DPD) of 64 colorectal cancer patients. The mean gene expression of TS, TP and DPD was found to be 3.29; 3.79 and 8.24 in tumors and 1.88; 3.80 and 19.69 in normal mucosa. The corresponding median gene expression was 1.87; 2.32 and 4.50 for tumors and 2.14; 2.63 and 11.64 for normal tissue. We did not find any significant differences in TS, TP and DPD gene expression between colorectal tumor and surrounding mucosa.
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PMID:Comparative analysis of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase expression in colorectal cancer and surrounding normal tissue. 1587 81

5-Fluorouracil (5-FU) is still a key drug in the treatment of various kinds of advanced cancer, including breast and gastrointestinal carcinomas. To predict the sensitivity of colorectal cancer to 5-FU, mRNA is extracted from surgically obtained cancer specimens and expression of thymidylate synthetase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), uridine phosphorylase (UP), es-nucleoside transporter (NT), and E2F1 are detected by real-time reverse transcription polymerase chain reaction (RT-PCR) (TaqMan). Previous results have shown that the catabolic rate-limiting enzymes DPD and NT, which are important membranous transporter of nucleosides, may regulate the sensitivity to 5-FU.
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PMID:Real-time RT-PCR (TaqMan) of tumor mRNA to predict sensitivity of specimens to 5-fluorouracil. 1591 84

Thymidine phosphorylase levels are higher in some human cancer tissues than in adjacent normal tissue. However, the ultrastructural localization of thymidine phosphorylase in cancer tissue has been demonstrated only in advanced gastric and colorectal cancer. We investigated the localization of thymidine phosphorylase in breast cancer tissue by immunohistochemistry and its ultrastructural localization by immunoelectron microscopy. Surgically resected specimens from 30 cases of breast cancer were analyzed. Immunohistochemical analysis revealed that cancer cells were positive in 13 cases. However, there were 21 cases that showed thymidine phosphorylase-positive inflammatory cells in cancer tissue. Thymidine phosphorylase-positive staining was detected among both cancer cells and inflammatory cells in 11 cases. Thymidine phosphorylase was diffusely positive in the cytoplasm of cancer cells and specifically positive in mitochondria of neutrophils and specific cytoplasmic granules of macrophages in cancer tissue by immunoelectron microscopy. These findings suggest that thymidine phosphorylase is produced by macrophages and is present in mitochondria of neutrophils and cytoplasmic granules of cancer cells.
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PMID:Localization of thymidine phosphorylase in breast cancer tissue. 1594 18

The significance of tumor tissue thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) levels, as well as the TP/DPD ratio have recently been reported as prognostic factors and for custom-made chemotherapy. However, there have been no distinct studies on actual tumor sampling methods. For 16 patients who had undergone resection of advanced colorectal cancer, we: i) measured TP and DPD levels in different portions of the tumor using enzyme-linked immunosorbent assay (ELISA); ii) categorized the tumor into an edge, center, and base area, and histo-pathologically calculated the ratio of cancer cell/cancer cell + stromal cell; and iii) examined the correlation between cancer and stromal cell TP expression and TP value. Variation within the same tumor was seen in each activity level and TP/DPD ratio. The ratio of cancer cell in the edge area was high, with the ratio of stromal cell in the center and base areas increasing in that order. A correlation was seen between TP expression and TP levels, and TP expression was evident in the stromal cells. It is therefore recommended to sample the edge area for tumor TP levels.
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PMID:The activities of thymidine phosphorylase and dihydropyrimidine dehydrogenase in colorectal cancer depend on where the sample is taken. 1601 11

Protracted venous infusion 5-fluorouracil (5FU) combined with mitomycin C (MMC) has demonstrated significant activity against metastatic colorectal cancer. Owing to potential synergy based upon upregulation of thymidine phosphorylase by MMC, the combination of capecitabine and MMC may improve outcomes in irinotecan-refractory disease. Eligible patients with progressive disease during or within 6 months of second-line chemotherapy were treated with capecitabine (1250 mg m(-2) twice daily) days 1-14 every 3 weeks and MMC (7 mg m(-2) IV bolus) once every 6 weeks. A total of 36 patients were recruited, with a median age of 64 years (range 40-77), and 23 patients (78%) were performance status 0-1. The objective response rate was 15.2%. In all, 48.5% of patients had stable disease. Median failure-free survival was 5.4 months (95% CI 4.6-6.2). Median overall survival was 9.3 months (95% CI: 6.9-11.7). Grade 3 toxicities were palmar-plantar erythema 16.7%, vomiting 8.3%, diarrhoea 2.8%, anaemia 8.3%, and neutropenia 2.8%. No patients developed haemolytic uraemic syndrome. Symptomatic improvement occurred for pain, bowel symptoms, and dyspnoea. Capecitabine in combination with MMC is an effective regimen for metastatic colorectal cancer resistant to 5FU and irinotecan with an acceptable toxicity profile and a convenient administration schedule.
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PMID:Capecitabine and mitomycin C as third-line therapy for patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan. 1649 15

Thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) are predictive markers for tumor response to 5-fluorouracil-based therapies. To determine whether gene expression values measured in primary cancer tissue would be useful for prediction of response of lymph node metastases, the expressions of these genes were quantitatively analyzed in 35 pairs of primary colorectal cancer (CRC) and corresponding lymph node metastases using real-time PCR. DPD and TP mRNA levels were significantly lower in the primary colorectal tumor and lymph node metastases compared with the normal adjacent stroma tissue (p<0.01), whereas TS mRNA levels were significantly higher in the primary tumor and lymph node metastases than in the normal adjacent tissue (p<0.001). Median gene expression levels of TP and TS did not differ significantly between primary colorectal tumor and corresponding lymph node metastasis but median DPD gene expression levels in the lymph node metastases were significantly higher compared to matched primary colorectal tumors (p=0.015). There was a significant correlation for DPD, TP and TS gene expression levels between primary colorectal tumor specimens and the matched lymph node metastasis. These results suggest that biopsies of the tumor of origin may be valid for determining predictive markers for chemotherapy response in patients with metastatic CRC.
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PMID:Molecular factors of 5-fluorouracil metabolism in colorectal cancer: analysis of primary tumor and lymph node metastasis. 1639 9

Gene expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyl transferase (OPRT) have been shown to be associated with response to 5-fluorouracil-based therapies. Analyzing these gene expression levels in liver metastases is important to obtain the best prediction of therapy. Our aim was to determine how TS, DPD, TP and OPRT gene expression levels in primary colorectal cancer (CRC) were related to those in liver metastases. Formalin-fixed, paraffin-embedded tumor specimens from 31 pairs of primary CRC and corresponding liver metastases were dissected by using laser-captured microdissection. RNA was extracted and cDNA was prepared by reverse-transcription. Quantitation of target gene and internal reference gene was performed using real-time PCR. No significant difference was seen between median mRNA expression levels of TS, DPD, TP and OPRT in primary cancer and those in corresponding liver metastases (median value: TS 1.48 vs. 1.43; p=0.92, DPD 0.19 vs.0.12; p=0.10, TP 1.20 vs. 0.98; p=0.39, OPRT 1.17 vs. 0.95; p=0.10). When matched tissue sets were compared on an individual basis, there was a significant correlation for TS mRNA expression between primary cancer and corresponding liver metastases (rs=0.52, p=0.0026). However, no correlation was seen between matched sets for DPD, TP or OPRT. Significant correlation was seen between DPD and TP expression levels in both primary CRC (rs=0.38, p=0.03) and liver metastases (rs=0.72, p<0.0001). A good prediction of TS mRNA levels in liver metastases can be obtained by measuring those of primary CRC, although no correlation was seen for DPD, TP and OPRT.
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PMID:5-fluorouracil-related gene expression levels in primary colorectal cancer and corresponding liver metastasis. 1657 20

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism may influence the chemosensitivity of colorectal cancers to fluorouracil (5-FU) by increasing intracellular 5,10-methylenetetrahydrofolate. The effect of this polymorphism on the expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT) and thymidine phosphorylase (TP) in colorectal cancer was investigated. The MTHFR C677T polymorphism was analysed and TS, DPD, OPRT and TP mRNA expression was measured in tumour and adjacent normal mucosal tissue. In all patients, the genotypes of the tumour and normal tissues were identical. No differences were found in the expression of TS, DPD or TP mRNA by genotype in either tumour or normal tissue. Although the OPRT mRNA level in tumour tissue was not associated with the genotype, normal mucosa with the TT genotype showed a significantly higher OPRT mRNA level than mucosa with other genotypes. The MTHFR C667T polymorphism is not associated with intratumoural expression of TS, DPD, OPRT or TP.
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PMID:Methylenetetrahydrofolate reductase C677T is not associated with expression of pyrimidine metabolic enzyme genes in colorectal cancer. 1686 26


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