Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to explore the possible interaction of 5-fluorouracil (5-FU) and 7-ethyl-10-hydroxycamptothecin (SN-38) in vitro. Human colon cancer LoVo cells were treated in both a dose- and time-dependent manner using clinically relevant concentrations of and exposure to 5-FU and/or SN-38. The expression of thymidylate synthase (TS), topoisomerase I, and cell cycle kinetics were evaluated by Western blot analysis and flow cytometry, respectively. Cytotoxicity was evaluated by MTT (3-[4,5-dimethylthiazol-2yl]-2,5-diphenyl tetrazolium bromide) assay. The cytotoxic effects of combination treatment were determined by median effect analysis. Topoisomerase I expression was downregulated following 12 hours of exposure to treatment, and topoisomerase I expression recovered 8 hours after SN-38 was removed. The TS expression was decreased following 24 hours of 5-FU and it remained at reduced levels for > 24 hours after removal of 5-FU. SN-38 induced an arrest at S/G2/M phase, reaching its maximum effect at 12 hours. This cell cycle arrest was reversed 24 hours after SN-38 was removed. 5-FU induced an arrest at the S phase, and maximum arrest occurred at 12 hours and lasted for > 48 hours. After 12 hours of sequential SN-38, LoVo cells were arrested in S phase, thereby potentiating the effect of 5-FU. Cytotoxicity studies confirmed the synergistic interaction between 5-FU and irinotecan. These findings suggest that the proper sequencing of 5-FU/irinotecan depends on regulation of topoisomerase I, and cell cycle kinetics
Clin Colorectal Cancer 2002 Nov
PMID:Combination of 5-fluorouracil and irinotecan on modulation of thymidylate synthase and topoisomerase I expression and cell cycle regulation in human colon cancer LoVo cells: clinical relevance. 1248 36

Surgery is the primary modality for cure in patients with localized colorectal cancer. However, despite potential curative surgery, the risk of recurrence is high. In colon cancer, the role of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) is now established in stage III disease. The benefit of adjuvant treatment in stage II disease is likely to be small, and studies performed thus far have been generally underpowered to detect what might be a clinically significant effect on survival. Whereas bolus scheduling of 5-FU and LV is favored in North America, infusion of 5-FU/LV is preferred in Europe. Indeed, infused 5-FU/LV may be a safer partner with new drugs such as oxaliplatin and irinotecan. Oral fluoropyrimidines are attractive agents that might one day replace parenteral 5-FU. In rectal cancer, postoperative combined chemoradiation was recommended as standard practice in stages II and III disease. Despite a lack of randomized data demonstrating clinical benefit, preoperative chemoradiation has been increasingly used in patients with T3 disease in North America. However, preoperative radiation therapy is more frequently used in Europe. There are discrepancies in pathologic reporting of circumferential resection margin involvement and lymph node status between the United States and Europe. Standardized reporting with improved preoperative imaging would allow patients with truly early-stage disease to undergo more conservative management and be spared the morbidity and mortality of unnecessary adjuvant or neoadjuvant treatment.
Clin Colorectal Cancer 2003 May
PMID:Overview of preoperative and postoperative therapy for colorectal cancer: the European and United States perspectives. 1277 89

This study is designed to clarify the benefits and risks of chemotherapy and radiation therapy in elderly patients with colorectal cancer through a systematic review of the literature. Searches of the Medline, Embase, and Cochrane Library databases; PDQ Cancer Information Summaries, American Society of Clinical Oncology Guidelines, Cancer Care Ontario Practice Guideline Initiative, Interprovincial Drug Strategies and Guidelines Group, and OncoLink Web sites; and manual searches of meeting proceedings and bibliographies were performed. Additional studies known to the authors were also identified. Randomized controlled trials, reviews, and guidelines evaluating the impact of age on overall survival and/or toxicity with adjuvant and palliative therapies for colorectal adenocarcinoma were selected. A preset study selection form was applied to all identified studies. All selected studies underwent a preset study appraisal. Analyses of the effect of age on overall survival benefits and/or toxicity of therapy were extracted. A qualitative synthesis and narrative review was undertaken. There is good evidence to support that patients = 80 years of age have similar overall survival benefits with adjuvant 5-fluorouracil (5-FU)-based chemotherapy for colon cancer and with palliative first-line monotherapy for metastatic colorectal cancer, as do younger patients. Data are limited with regard to toxicity of therapy in older patients in these settings. An increase in toxicity with bolus 5-FU chemotherapy regimens is evident. There is a paucity of data regarding adjuvant treatment of older patients with rectal cancer. More elderly patients need to be enrolled in clinical trials in order to fully evaluate the outcomes of colorectal cancer therapy in this population. Further studies are warranted.
Clin Colorectal Cancer 2003 Nov
PMID:Systematic review of management of colorectal cancer in elderly patients. 1470 76

This article summarizes the progress of adjuvant systemic chemotherapy of colon cancer. The study by Moertel et al that showed that the combination of 5-fluorouracil (5-FU) and levamisole in the adjuvant setting reduced mortality by 33% in stage III colon cancer; 5-FU/leucovorin (LV) became the standard of care in the adjuvant treatment of colon cancer after it showed superiority to 5-FU/levamisole. However, no standard schedule of 5-FU/LV has been established. The fortnightly regimen of bolus 5-FU/LV and continuous infusion 5-FU (LV5FU2) has the same efficacy as and is less toxic than the monthly regimen of bolus 5-FU/LV. Oxaliplatin combined with 5-FU and LV (FOLFOX4) is the first combination to demonstrate significant superiority in 3-year disease-free survival as compared with 5-FU/LV in the adjuvant treatment of colon cancer. Three-year disease-free survival is an excellent predictor of 5-year overall survival and, in future studies, can serve as a reliable endpoint that is associated with reproducible 5-year overall survival. Results of studies testing irinotecan combined with 5-FU and LV are not yet available. Adjuvant chemotherapy for patients with stage II colon cancer is a controversial subject. Because the available data suggest that stage II patients benefit from adjuvant chemotherapy, although to a lesser extent than patients with stage III disease, all patients with stage III and high-risk stage II disease should be offered adjuvant treatment with the new standard of care, FOLFOX4. Future studies in adjuvant therapy for colon cancer will explore oxaliplatin and 5-FU with or without antiangiogenesis or anti-epidermal growth factor agents.
Clin Colorectal Cancer 2004 Jun
PMID:An overview of adjuvant systemic chemotherapy for colon cancer. 1521 2

Heterogeneity in advanced colon cancer leads to different results from adjuvant chemotherapy. To identify groups of patients who may need adjuvant treatment, molecular staging and correlation with clinical data may be helpful in classifying histologically similar tumors. Colon cancer develops through a multistep process with an accumulation of multiple genetic alterations that are often the cause of a form of genomic instability. The 2 best known mechanisms of genomic instability are chromosomal instability (CIN) and microsatellite instability (MSI). The CIN phenotype is found in approximately 85% of sporadic colon cancers and is characterized by aneuploidy, multiple chromosomal rearrangements, and an accumulation of somatic mutations in oncogenes such as K-ras and tumor suppressor genes such as TP53 and APC. The MSI phenotype is associated with small insertions and deletions mainly in repetitive sequences (microsatellites) and is found in approximately 15% of cases. This instability, often referred to as high-frequency MSI (MSI-H), is caused by defects of the mismatch repair system, which is involved in repairing DNA errors that arise during DNA replication. Clear-cut correlations between the somatic genetic alterations in tumors and the clinical behavior of the tumor are rare. Only a few markers, such as MSI-H and TP53, seem to have a prognostic value. Mutations in the TP53 gene are associated with an aggressive tumor growth and subsequent reduced survival, whereas MSI-H seems to be correlated with a favorable outcome. In general, predicting biologic behavior of in particular stage III colon cancers is difficult and remains a great clinical problem.
Clin Colorectal Cancer 2004 Nov
PMID:Genetic alterations in locally advanced stage II/III colon cancer: a search for prognostic markers. 1555 8

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary colon cancer syndrome and is responsible for as many as 10% of all colorectal cancers. Hereditary nonpolyposis colorectal cancer is autosomally dominant with a prevalence of 1 in 200-2000 and exhibits incomplete penetrance. Affected individuals have an approximately 70% lifetime risk of colon cancer with a mean age of onset of 44 years and an approximately 40% lifetime risk of endometrial cancer. At least 5 mismatch repair genes (MLH1, MSH2, MSH6, PMS1, PMS2) have been implicated in HNPCC; however, no predominant mutations were found in these genes. Mutation detection by direct sequencing has proven to be the most sensitive method. We have developed high-throughput full-length sequencing assays of the MLH1, MSH2, and MSH6 genes. These 3 genes account for approximately 90% of all germline mutations found in HNPCC. In our assays, 19 exons of MLH1, 16 exons of MSH2, 10 exons of MSH6, and the adjacent splice sites were amplified using polymerase chain reaction and loaded onto a capillary sequencing machine. Results were analyzed using sequence analysis software and stored in a relational database. Our assay method was validated using 15 affected patients and normal controls. It is anticipated that our high-throughput assay technique will provide accurate diagnoses for patients at risk for HNPCC and thereby facilitate early curative intervention.
Clin Colorectal Cancer 2004 Nov
PMID:High-throughput gene sequencing assay development for hereditary nonpolyposis colon cancer. 1555 11

Colorectal cancer remains a significant public health concern despite the fact that effective screening procedures exist and that the disease is treatable when detected at early stages. Numerous risk factors for colon cancer have been identified, but none are very predictive alone. We sought to determine whether there are certain combinations of risk factors that distinguish well between cases and controls, and that could be used to identify subjects at particularly high or low risk of the disease to target screening. Using data from the Seattle site of the Colorectal Cancer Family Registry, we fit logic regression models to combine risk factor information. Logic regression is a methodology that identifies subsets of the population, described by Boolean combinations of binary coded risk factors. This method is well suited to situations in which interactions between many variables result in differences in disease risk. We found that neither the logic regression models nor stepwise logistic regression models fit for comparison resulted in criteria that could be used to direct subjects to screening. However, we believe that our novel statistical approach could be useful in settings where risk factors do discriminate between cases and controls, and illustrate this with a simulated data set.
 ...
PMID:Identifying target populations for screening or not screening using logic regression. 1556 85

Accurate staging of colon cancer is prognostically and therapeutically important. By identifying those patients who would most benefit from adjuvant chemotherapy, accurate staging should decrease recurrence rates and improve overall survival. Lymphatic mapping and sentinel node analysis allow for a focused review of the lymph nodes, which are most likely to harbor a metastasis and may make ultrastaging techniques, such as immunohistochemistry and reverse-transcriptase polymerase chain reaction, more practical. The prognostic significance of micrometastatic disease detected via ultrastaging techniques remains controversial.
Clin Colorectal Cancer 2005 Jan
PMID:Lymphatic mapping and sentinel node analysis in colon cancer. 1566 35

Adjuvant chemotherapy for colon cancer and combined chemotherapy and radiation therapy (RT) for rectal cancer increases the proportion of patients cured of their disease. Adjuvant chemotherapy is indicated for stage III colon cancer, and although controversial for stage II disease, there is evidence to suggest that these patients may benefit as well. Adjuvant chemotherapy and RT is recommended for patients with stage II/III rectal cancer. Studies incorporating oral fluoropyrimidines as well as combination chemotherapy have been completed, with results demonstrating the value of these approaches. A new generation of studies will evaluate the biologic agents bevacizumab and cetuximab in the adjuvant therapy of colorectal cancer. For rectal cancer, optimal outcomes are dependent not only on the systemic therapy, but also on the expertise of the surgeon and the timing of RT, with improved local control and toxicity seen with preoperative therapy.
Clin Colorectal Cancer 2005 Apr
PMID:An overview of approaches to adjuvant therapy for colorectal cancer in the United States. 1587 61

Irinotecan is a cornerstone drug in the management of metastatic colorectal cancer, as demonstrated by several randomized studies proving a survival benefit for the first time. In the adjuvant setting, FOLFOX (infusional 5-fluorouracil [5-FU]/leucovorin [LV] in combination with oxaliplatin) has improved 3-year disease-free survival in stage II/III colorectal cancer in the MOSAIC trial. Because 5-FU/LV-based combination therapy with oxaliplatin or irinotecan has similar efficacy in metastatic disease in the first-line setting, the impact of irinotecan in the adjuvant setting deserves further randomized clinical trials. Six such trials are ongoing or have already been closed to accrual, the results of which will be reported shortly. Five of these trials presently accruing patients or already closed combine irinotecan with an infusional regimen of 5-FU, based on a better tolerance and efficacy profile established in the metastatic setting according to clinical trials conducted principally in Europe. The results of 2 main randomized trials in the adjuvant therapy of stage III colon cancer will be presented at the 41st Annual Meeting of the American Society of Clinical Oncology in 2005 and are eagerly awaited. These results should provide important new insights as to how to manage stage II/III colon cancer.
Clin Colorectal Cancer 2005 Apr
PMID:Irinotecan-based regimens in the adjuvant therapy of colorectal cancer. 1587 64


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>