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)

Capecitabine is a fluoropyrimidine carbamate that was rationally designed as an oral drug capable of mimicking continuous infusion 5-fluorouracil (5-FU) and delivering 5-FU preferentially to tumour tissue. Following extensive absorption, capecitabine is rapidly converted to 5-FU via a three-step enzymatic pathway. The final step depends on thymidine phosphorylase, an enzyme present at higher concentrations in malignant compared with normal tissue. This results in the delivery of 5-FU preferentially to the tumour site. Capecitabine has demonstrated high activity in preclinical xenograft models for a wide range of human solid tumours, including those resistant to 5-FU. Phase I studies have determined the maximum tolerated dose (MTD) of capecitabine and identified a number of dosage regimens, which were subsequently evaluated in a randomised, phase II study as first-line treatment for metastatic colorectal cancer. This established an intermittent regimen of capecitabine 1250 mg/m2 twice daily for 14 days followed by a 7-day rest period as the most appropriate regimen for further clinical development.
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PMID:Rational development of capecitabine. 1184 29

The oral fluoropyrimidine, capecitabine is attracting great interest in the context of tumour-selective therapy and rationally designed combination regimens. Agents such as taxanes upregulate thymidine phosphorylase (TP), and there is therefore a clear rationale for their combination with capecitabine. Preclinical studies of capecitabine/taxane combination therapy demonstrated synergistic antitumour activity and phase I studies showed encouraging efficacy. Therefore, a randomised, phase III trial (docetaxel versus docetaxel/capecitabine) has been initiated in anthracycline-refractory metastatic breast cancer patients. Recruitment is complete. In colorectal cancer, capecitabine/oxaliplatin combination therapy is promising and a phase I, dose-finding trial has been conducted in patients with refractory metastatic solid tumours. A similar trial has evaluated capecitabine/irinotecan combination treatment. Capecitabine is also being investigated as adjuvant therapy for colorectal and breast cancers. The primary objective of the ongoing X-ACT trial in almost 2000 Dukes' C colon cancer patients is to demonstrate at least equivalent disease-free survival between capecitabine and the Mayo Clinic regimen. In addition, the CALGB is planning a randomised, phase III trial of capecitabine versus doxorubicin/cyclophosphamide or cyclophosphamide/methotrexate/5-fluorouracil (CMF) as adjuvant treatment in high-risk, node-negative breast cancer patients aged >65 years.
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PMID:Future treatment options with capecitabine in solid tumours. 1184 32

The need for dependable prognostic markers in colorectal cancer, both in the advanced as well the as adjuvant setting, is greater than ever. The introduction of new chemotherapeutic agents in the clinic, with different mechanisms of action as well as different side-effect profiles, has made this even more important. Angiogenesis, the formation of new vessels, is essential for tumour growth and metastasis. The adverse impact of tumour angiogenesis in the context of colorectal cancer on relapse and prognosis has been evaluated in numerous retrospective studies. Most of these studies have tended to be relatively small in terms of patient numbers and sometimes have reached conflicting conclusions. A number of different angiogenic factors, including vascular endothelial growth factor (VEGF), thymidine phosphorylase (TP) and intratumoural microvessel density (IMD), have been assessed to varying extents. This article highlights some of the important developments in this rapidly expanding field.
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PMID:Prognostic role of angiogenesis in colorectal cancer. 1190 90

Thymidylate synthase is a target enzyme for chemotherapeutic agents such as 5-fluorouracil and capecitabine, its oral prodrug. The human thymidylate synthase gene promoter is polymorphic, having either double or triple repeats of a 28-bp sequence. It has previously been shown that colorectal cancer patients who are homozygous for the triple tandem repeats (L/L) have significantly higher thymidylate synthase mRNA expression than those homozygous for the double repeat variant (S/S). Capecitabine is converted to 5-fluorouracil by a sequential triple enzyme pathway, with the last step catalyzed by the tumor-associated angiogenic factor thymidine phosphorylase. We have recently shown that individuals with metastatic colorectal cancer treated with 5-fluorouracil have a higher response rate if they are homozygous for the genotype S/S as opposed to S/L or L/L. Our hypothesis is that individuals homozygous for the double repeat variant (S/S) should have a better response to capecitabine than their counterparts with S/L or L/L. In this retrospective pilot study we assessed the thymidylate synthase polymorphic status of 24 patients with metastatic colorectal cancer and determined their response to capecitabine. We found that 75% (3/4) of individuals with the S/S variant responded to capecitabine, compared to 8% (1/12) and 25% (2/8) of those with the S/L and L/L variants, respectively. Our data suggest that genotyping patients for the thymidylate synthase polymorphism would be useful in identifying patients who are more likely to respond to capecitabine treatment for advanced colorectal cancer.
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PMID:Thymidylate synthase gene polymorphism predicts response to capecitabine in advanced colorectal cancer. 1201 54

We studied 89 colorectal cancer patients conducting immunohistological staining of thymidine phosphorylase (TP) and investigated correlation between the enzyme activity levels, clinicopathologic factors and patient prognosis. Based on TP expression level, we also assessed p53, an anti-oncogene related to hematogenesis and nucleic acid metabolism. TP staining results were classified into: i) strongly stained group (8 patients) in which 20% or more tumor cell nuclei were stained and ii) weakly stained group (39 patients) in which less than 20% of the nuclei were stained. These 2 groups were defined as TP positive group and those without TP staining (42 patients) were defined as TP negative group. TP positive group showed: a significantly higher incidence of vascular infiltration (p=0.0065) than TP negative group, and slightly higher incidence of lymphatic permeation and tumor progress. Strongly stained group showed significantly higher incidences of vascular infiltration and lymphatic permeation (p=0.0001, p=0.0271). As for 5-year survival rate, TP positive group showed a significantly lower rate (29%) than TP negative group (52%) (p=0.05) indicating that TP expression level was an important prognostic factor in colorectal cancer patients. No differences were found in pathologic factors and patient prognosis between groups with or without point mutation. As for relationship between TP staining and p53, there were significantly more patients with strongly positive TP staining in the p53 negative group. These findings suggest that TP is an important prognostic factor for colorectal cancer patients, and p53, in conjunction with other factors, is also a prognostic indicator.
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PMID:Correlation between malignancy grade and p53 gene in relation to thymidine phosphorylase activity in colorectal cancer patients. 1237 32

Attempts at improving the efficacy of 5-fluorouracil (5-FU) by protracted continuous infusion and/or biochemical modulation have been hindered by the need for indwelling central venous catheters and their associated toxicity. Capecitabine, an oral fluoropyrimidine carbamate, has been rationally synthesized as an inactive precursor that is absorbed intact through the intestinal mucosa and is sequentially converted by an enzymatic cascade involving 3 distinct enzymes to 5'-deoxy-5-fluorocytidine, to 5'-deoxy-5-fluorouridine (5'-DFUR), and finally to 5-FU. Preclinical studies provided evidence of preferential intratumoral conversion of inactive 5'-DFUR to active 5-FU due to the relative overexpression of the final anabolizing enzyme, thymidine phosphorylase, in tumor tissues, with a resultant decrease of 5-FU exposure in normal tissues. The safety of capecitabine and optimal dosing schedules have been explored in phase I/II studies, resulting in the evaluation of the intermittent schedule (1250 mg/m2 twice daily for 14 days, every 3 weeks) in most subsequent clinical trials. Two large randomized phase III studies in patients with metastatic colon cancer established at least equivalent efficacy and improved tolerability with capecitabine compared to the Mayo Clinic bolus 5-FU/leucovorin regimen. The most common treatment-related adverse events are palmar-plantar erythrodysesthesia, diarrhea, and stomatitis, with grade 3/4 events occurring in 17%, 15%, and 2%-8% of patients, respectively. Myelosuppression was minimal. Overall toxicity was easily managed, with a significant reduction in the frequency of hospitalizations and medical resource use. The spectrum of clinical efficacy of capecitabine is expected to encompass other tumor types and administration in the adjuvant setting. As a home-based outpatient regimen, capecitabine represents a safe and effective advance in modern drug development.
Clin Colorectal Cancer 2002 May
PMID:Capecitabine (Xeloda): from the laboratory to the patient's home. 1245 32

The prognosis of patients with colorectal cancer is impacted by various factors at the time of diagnosis, including location of the tumor, gender, age and overall performance status of the patient. Optimal postoperative management of patients who have undergone successful tumor resection involves the utilization of reliable determninants of prognosis to help select patients who would benefit from adjuvant treatment, while sparing others from drug-related adverse effects. Tailoring chemotherapy for patients with disseminated cancer, or for patients who receive adjuvant chemotherapy, is also critical. Interpatient differences in tumor response and drug toxicity are common during chemotherapy. Genomic variability of key metabolic enzyme complexes, drug targets, and drug transport molecules is an important contributing factor. The identification of genetic markers of response and prognosis will aid in the development of more individualized chemotherapuetic strategies for cancer patients. Potential prognostic indicators in colorectal cancer include oncogenes, tumor suppressor genes, genes involved in angiogenic and apoptotic pathways and cell proliferation, and those encoding targets of chemotherapy. Specifically, molecular markers such as deletion of 18q (DCC), p27 and microsatellite instability are promising as indicators of good or poor prognosis. Molecular determinants of efficacy and host toxicity of the most commonly used drugs in colorectal cancer, fluoracil, irinotecan and oxaliplatin, are being investigated. Alterations in gene expression, protein expression and polymorphic variants in genes encoding thymidylate synthase, dihydropyrimidine dehydrogenase, dUTP nucleotidehydrolase and thymidine phosphorylase (for fluoropyrimidine-based chemotherapy), uridine diphosphate glucosyltransferase (UGT) 1A1 and carboxylesterase (for irinotecan therapy), and excision repair cross-complementing genes (ERCC1 and ERCC2) and glutathione-S-transferase P1 (for oxalilplatin-based regimens) may be useful as markers for clinical drug response, survival and host toxicity.
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PMID:Implications of genetic testing in the management of colorectal cancer. 1274 25

Postoperative adjuvant chemotherapy reportedly improves advanced colorectal cancer patients' survival, however, it is necessary to assess what regimens are useful. Doxifluridine (5'-DFUR) is an intermediate of capecitabine approved in Europe and USA to treat metastatic colorectal cancer. 5'-DFUR is metabolized to 5-fluorouracil (5-FU) by thymidine phosphorylase existing in tumor at high concentrations, suggesting high 5-FU levels in tumor tissues and lesser complications. Present study compared usefulness of 5'-DFUR to that of oral 5-FU. Patients were enrolled at 38 centers from April 1993 to September 1996. They had diagnosed colorectal cancer of TNM stages II and III, and underwent macroscopic curative resection. Patients were prestratified into colon or rectum cancer and allocated into either 5'-DFUR (5'-DFUR 460 mg/m(2)/day + PSK 3 g/day) or 5-FU (5-FU 115 mg/m(2)/day + PSK 3 g/day) group by dynamic randomization (stratification factors such as depth of tumor, degree of lymph node metastasis, and location of tumor). Drugs were orally administered daily from postoperative week 2 to 54, with 6 mg/m(2) mitomycin C at operation and following days. Subjects for analysis were 277 in 5'-DFUR and 281 in 5-FU groups. Median follow-up was 6.5 years. Although no differences in overall survival curves were detected, multivariate analysis showed that 5'-DFUR + PSK regimen was a significantly better prognostic factor in patients with Dukes B or C (risk ratio, 1.451; p=0.048); with tumor depth of pT3 or pT4 (risk ratio, 1.568; p=0.020). For patients with advanced colorectal cancer, 5'-DFUR + PSK therapy may possibly be more useful than 5-FU + PSK, but further study is required.
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PMID:A randomized controlled trial of postoperative adjuvant immunochemotherapy for colorectal cancer with oral medicines. 1279 90

Since its synthesis over 40 years ago, several studies including patients with colorectal cancer have shown that prolonged exposure to 5-fluorouracil (5-FU) is associated with better antitumor activity and decreased toxicity. However, the use of continuous-infusion 5-FU is costly and is associated with the need for a catheter and infusion pump. The use of an oral formulation of 5-FU allows protracted exposure without the inconvenience and cost of intravenous continuous-infusion regimens. Capecitabine is a rationally designed fluoropyrimidine that can be given orally and uses the high concentration of thymidine phosphorylase within cancer cells to concentrate heavily within the tumor. Two large randomized studies that included patients with metastatic colorectal cancer have shown superior response rates for capecitabine compared with bolus regimens of 5-FU with equal times to progression, overall survival, and duration of response. Because of its favorable toxicity profile and the efficacy shown in early trials, capecitabine is currently being investigated in the adjuvant setting and in combination with radiotherapy and with other chemotherapy agents.
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PMID:Practical considerations in the use of oral fluoropyrimidines. 1280 99

To predict the sensitivity of colorectal cancer to 5-fluorouracil (5-FU), we compared the gene expression of surgically obtained colorectal cancer specimens with chemosensitivity to 5-FU as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay. Eighty-eight patients with advanced and/or metastatic colorectal cancer provided written informed consent and entered the trial from September 2000 to October 2001. Fresh surgical specimens were used for the MTT assay, and sensitivity to 5-FU was evaluated at a cutoff concentration of 50 microg/ml and 48-h incubation time. Frozen samples were stored at - 80 degrees C until mRNA analysis of thymidylate synthetase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), es-nucleoside transporter (NT), and E2F1 by real-time RT-PCR. The correlations between the variables were analyzed, and the predictive value of these mRNAs was assessed statistically using a receiver operating characteristic (ROC) curve. NT and DPD, TP and DPD, and TP and NT mRNA expression levels correlated significantly, while TS and E2F1 showed no correlations. High NT expression was associated with low sensitivity to 5-FU (P < 0.013), as were high DPD and E2F1 expression (P < 0.022 for both). High TP mRNA expression correlated with low sensitivity to 5-FU (P < 0.034), although high TS mRNA expression did not. ROC curves indicated that DPD and NT mRNAs were possible predictors of sensitivity to 5-FU, with cutoff values of 0.6 and 0.4, respectively. The sensitivity of colorectal cancer to 5-FU may be regulated by DPD, the rate-limiting enzyme of catabolism, and NT, an important transmembrane transporter of nucleosides.
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PMID:Gene expression in colorectal cancer and in vitro chemosensitivity to 5-fluorouracil: a study of 88 surgical specimens. 1284 74


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