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PubMedDate not supplied

CPT-11 (irinotecan) in the treatment of colorectal cancer.

Colorectal cancer is one of the most common cancers in the Western World. Although 50% of patients are cured by surgery alone, the outcome is poor in high-risk patients (Dukes stages B2 and C) despite adjuvant chemotherapy with 5-fluorouracil (5-FU)-based regimens. CPT-11 (irinotecan) is a promising new agent for the treatment of colorectal cancer with a unique mechanism of action. CPT-11 is a DNA topoisomerase I inhibitor, which has not demonstrated susceptibility to the P-glycoprotein-mediated multidrug-resistant phenotype. Phase II studies with CPT-11 have demonstrated definite activity against colorectal cancer in both chemotherapy-naive and pretreated patients (response rates of 15-32% observed) even with clinical evidence of resistance to 5-FU. The response rate appears to be consistent, reproducible and equivalent to that achieved with 5-FU plus folinic acid in chemotherapy-naive patients.

Antineoplastic Agents, Phytogenic↗

PubMed2000

Novel chemotherapeutic agents in colorectal cancer.

Colorectal cancer remains the second most common cause of cancer death in Europe. A number of new agents, with varying mechanisms of action, have been developed and are being evaluated, both as single agents and in combination. Irinotecan, a topisomerase I inhibitor, and oxaliplatin, a new platinum compound, have proven efficacy in advanced colorectal cancer resistant to 5-fluorouracil. Capecitabine and other oral fluoro-pyrimidines are also emerging as potentially effective drugs. Raltitrexed and other inhibitors of thymidylate synthase (TS) are entering clinical practice although their role has yet to be determined. The new fluoro-pyrimidines and TS inhibitors are important classes of drug which have been designed to take advantage of the knowledge of folate metabolism gained from basic clinical research. Their design features could perhaps reduce the toxicity seen with the first generation cytotoxic agents. This review will focus on these new chemotherapeutic agents in colorectal cancer with respect to their mechanisms of action, current clinical activity and their potential use both in the adjuvant and palliative settings.

Antineoplastic Agents↗

PubMedDate not supplied

[Nutrition and colorectal cancer].

Colorectal cancer is the most common tumor behind lung cancer in men and breast cancer in women. Its prevalence shows a wide geographic variability, which, along with epidemiological and experimental evidence, suggests a considerable participation of environmental factors, mainly dietary in its cause. It is not known which dietary components have an undisputed influence on the risk of colorectal cancer, nor how they condition the different genetic susceptibilities of the individuals. However, we do know of the protective action that consuming vegetables has, and the increased risk associated with saturated fats and red meats, especially when associated with other factors like a hypocaloric diet, obesity, sedentary life, or the use of alcohol. Fiber, however, has not proven the risk reducing properties that were attributed to it by epidemiological studies, possibly because this term encompassed several very different substances. Moreover, it is very difficult to know the effect of an isolated nutrient as these are intimately entwined in the foods. It should be kept in mind that many substances, like plants, as well as the usual nutrients, contain a large number of components with unknown effects and that the manner in which the foods are prepared or eaten, no doubt are of influence. A healthy lifestyle with regard to the risk of colorectal cancer, should no doubt include the consumption of large amounts of vegetables and whole cereals, a limit of the caloric intake with fats not exceeding 30%, to eat fish and chicken rather than red meat, to avoid alcohol, and to regularly partake of physical exercise.

Central Nervous System Depressants↗

PubMed1996

Matrix metalloproteinase-1 is associated with poor prognosis in colorectal cancer.

Colorectal cancer is one of the commonest malignant tumors and has a relatively poor prognosis. The outcome depends on the extent of local and particularly metastatic tumor spread. The matrix metalloproteinases (MMPs) are a family of closely related enzymes that degrade the extracellular matrix and are considered to be important in facilitating tumor invasion and spread (1-3). Using immunohistochemistry we have investigated the occurrence in colorectal cancer of MMP-1 (interstitial collagenase). Our monoclonal antibody was prepared against a synthetic peptide corresponding to an amino acid sequence specific for MMP-1 and was selected to react in formalin-fixed wax-embedded sections, thus allowing use in diagnostic histopathology and also enabling access to archival material. We found that the presence of MMP-1 in colorectal cancer is associated with a poor prognosis (P = 0.006) and has prognostic value independent of Dukes stage. One MMP inhibitor that strongly inhibits MMP-1 has already been shown to inhibit growth of human colon cancer xenografts in nude mice (4). Our results suggest that treatment of those individuals whose colon tumors produce MMP-1 with MMP inhibitors is a therapeutic strategy worth pursuing.

Animals↗

PubMed2005

Screening for colorectal cancer.

Colorectal cancer (CRC) is the most common cancer in the Nordic countries after breast and prostate cancer. About 15,000 new cancers are diagnosed and more than 7000 patients will die from CRC in 2005. CRC fulfils most of the criteria for applying screening; the natural history is well known compared with many other cancers. CRC may be cured by detection at an early stage and even prevented by removal of possible precursors like adenomas. Faecal occult blood test is the only CRC screening modality that has been subjected to adequately sized randomised controlled trials (RCT) with long-term follow-up results, using Hemoccult-II. Sensitivity for strictly asymptomatic CRC is less than 30% for a single screening round, but programme sensitivity has been estimated to be more. Biennial screening with un-rehydrated Hemoccult-II slides has shown a CRC mortality reduction of 15-18% after approximately 10 years of follow-up in those targeted for screening. For those attending, the mortality reduction has been estimated at 23%. Denmark has decided to do feasibility studies to try to evaluate whether a population-based screening run by the community will have the same effect as has been demonstrated in the randomised trials. In Norway the government has accepted no formal population-based screening. In Finland, the Ministry of Social Affairs and Health made a recommendation in 2003 to the municipalities to run a randomised feasibility study with FOBT screening for colorectal cancer as a public health policy that is repeated every second year. In 2004 the first municipalities started. It has been claimed that today Sweden cannot afford CRC screening despite the potential mortality benefit. There is sufficient evidence for the efficacy of screening for colorectal cancer with fecal occult blood test every second year. There is, however, only little evidence on the effectiveness of screening when run as a public health service and there is insufficient knowledge of harmful effects and costs, even in RCTs.

Colorectal Neoplasms↗

PubMed2005

Genomic rearrangements in MSH2 and MLH1 are rare mutational events in Spanish patients with hereditary nonpolyposis colorectal cancer.

Colorectal cancer (CRC) is one of the most common neoplasms and a leading cause of death related to cancer worldwide. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent autosomal dominant predisposition to the development of CRC, accounting for approximately 2.5% of the total CRC burden in Spain. Genomic rearrangements in the MSH2 and MLH1 genes have been reported to account for an important proportion of the mutation spectrum in HNPCC, and DNA dosage techniques have been developed facilitating molecular screening of such deletions/duplications. We screened for MSH2 and MLH1 genomic rearrangements by multiplex ligation-dependent probe amplification (MLPA) in 142 Spanish patients at risk for HNPCC prior to the exon-by-exon mutation scanning and found a deletion encompassing exons 9-16 of MSH2 and a duplication encompassing exons 11-16 of MSH2, both only in one case. These results showed that MSH2/MLH1 rearrangements in Spanish patients at risk for HNPCC seem to be a less frequent mutational event than in other populations.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Frequency of hereditary non-polyposis colorectal cancer and other colorectal cancer familial forms in Spain: a multicentre, prospective, nationwide study.

BACKGROUND: Colorectal cancer is the third leading cause of cancer mortality in Western countries. Hereditary nonpolyposis colorectal cancer is the most common type of hereditary colorectal cancer, but its incidence remains controversial, ranging from 1 to 5%. OBJECTIVE: This present prospective, multicentre, nationwide study was aimed at compiling prominent epidemiological and clinical data with respect to hereditary non-polyposis colorectal cancer and other familial colorectal cancer forms in Spain, where information is lacking. METHODS: All patients with a de-novo diagnosis of colorectal cancer and who attended between November 2000 and October 2001 in 25 hospitals all over Spain were registered. Demographic, clinical and tumour-related characteristics of probands, and detailed family history, were obtained. RESULTS: A total of 1872 colorectal cancer patients were included. Clinical diagnosis of hereditary non-polyposis colorectal cancer was established in 46 (2.5%) patients according to the Amsterdam II criteria. Comparison between patients fulfilling either the Amsterdam I or the Amsterdam II criteria revealed no differences with respect to demographic, clinical and tumour-related characteristics. A total of 504 (27.0%) patients had a family history of hereditary non-polyposis colorectal cancer-related neoplasm not fulfilling the Amsterdam criteria (familial colorectal cancer), while 360 (19.2%) patients fulfilled at least one of the Bethesda's criteria. CONCLUSION: These clinicoepidemiological data provide a more accurate characterization of hereditary non-polyposis colorectal cancer and other familial colorectal cancer forms in Spain, with potential implications in preventive strategies.

Adenoma↗

PubMedDate not supplied

Adjuvant treatment of colorectal cancer.

Colorectal cancer is one of the most frequent causes of cancer deaths. Survival for locoregional colorectal cancer is about 70% overall and 30-60% in stage III patients. Several randomized trials have shown that adjuvant chemotherapy can increase this survival rate. 5-Fluorouracil-based chemotherapy is strongly recommended in this context. There are still some questions about the setting in which patients should be treated as well as the optimal treatment. New data for different schedules and combinations are now available. Physicians have to choose between the different options now available to offer the best treatment to their patients. This Review analyses the current options for adjuvant therapy in colon and rectal cancer.

Clinical Trials as Topic↗

PubMed2005

Prospects for cancer control: colorectal cancer.

AIMS: The study assessed the contribution to the control of colorectal cancer achievable from primary prevention, screening, early diagnosis, and treatment in New Zealand. METHODS: Available estimates of the attributable risk or protection offered by significantly increasing consumption of fruit and vegetables were used to predict the number of cases of (and deaths from) colorectal cancer prevented if these activities were effective in 1999. The potential effect of screening was also estimated from published results. Estimates of the potential effect of improvements in early diagnosis and treatment available from cancer-control plans of other countries were used to estimate the likely impact of such improvements in New Zealand. RESULTS: Primary prevention could potentially prevent 81 deaths in men and 77 deaths in women from colorectal cancer each year. The potential impact of screening differed between screening methods, with the prevention of 44 deaths in men and 35 deaths in women from colorectal cancer by screening using faecal occult blood testing or 73 deaths in men and 53 deaths in women annually from colorectal cancer by screening using flexible sigmoidoscopy. Improvements in surgical practice and reorganisation of surgical services together with improved use of radiotherapy and chemotherapy could prevent about 82 deaths in men and 78 deaths in women from colorectal cancer each year. CONCLUSIONS: The most immediate control of colorectal cancer appeared to be achievable by improvements in surgical services and the introduction of screening while increased consumption of fruit and vegetables provided potential longer-term reductions in colorectal cancer incidence and mortality.

Adult↗

PubMed2005

Dynamics of colorectal cancer.

Colorectal cancer results from an accumulation of mutations in tumor suppressor genes and oncogenes. An additional defining characteristic of colorectal cancer is its genetic instability. Two main types of genetic instability have been identified. Microsatellite instability leads to an increased point mutation rate, whereas chromosomal instability refers to an enhanced rate of accumulating gross chromosomal aberrations. All colon cancer cell lines are genetically unstable. An interesting question is whether genetic instability arises early in tumorigenesis. An early emergence of genetic instability could drive most of the somatic evolution of cancer. Here, we review mathematical models of colorectal tumorigenesis and discuss the role of genetic instability.

Colorectal Neoplasms↗

PubMed2001

Advances in the treatment of metastatic colorectal cancer.

Colorectal cancer represents the third leading cause of cancer mortality in the United States. During the past four decades, 5-fluorouracil (5-FU) has served as the cornerstone of therapy for individuals with advanced colorectal cancer (ACRC). Despite numerous attempts at maximizing efficacy of 5-FU through biochemical modulation, a significant benefit in terms of survival has never been realized. The recent emergence of novel chemotherapeutic drugs employing different mechanisms of action than 5-FU has led to the incorporation of irinotecan (CPT-11) with 5-FU/leucovorin as the new standard first-line regimen for future trials. This review outlines emerging data utilizing oral fluoropyrimidines and other new agents including oxaliplatin, raltitrexed, and eniluracil. Randomized clinical trials are currently underway in an effort to define optimal combination chemotherapy regimens, scheduling of agents, duration of therapy, and choice of therapy using a variety of prognostic molecular markers.

Administration, Oral↗

PubMed2006

Tissue microarray analysis of EGFR gene amplification and gain in Bulgarian patients with colorectal cancer.

Colorectal cancer is one of the most common neoplastic diseases and a leading cause of cancer-related deaths. Overexpression of epidermal growth factor receptor (EGFR) is commonly associated with this cancer. The aim of our study was to determine the frequency of epidermal growth factor receptor gene amplification and gain in a large number of colorectal carcinomas, arranged in a tissue microarray, in order to assess their role in colorectal cancer development. A tissue microarray of 498 patients with colorectal tumors was constructed, and 239 samples for EGFR copy number changes were successfully analyzed by fluorescence in situ hybridization. No amplification of EGFR was detected in our cohort of patients with colorectal tumors, and the EGFR gene was upregulated in only 2 tumors (0.84%). Therefore, the development of colon cancer in patients cannot be explained by copy number changes of the EGFR gene.

Bulgaria↗

PubMed2004

Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation.

Patients with ulcerative colitis and Crohn's disease are at increased risk for developing colorectal cancer. To date, no known genetic basis has been identified to explain colorectal cancer predisposition in these inflammatory bowel diseases. Instead, it is assumed that chronic inflammation is what causes cancer. This is supported by the fact that colon cancer risk increases with longer duration of colitis, greater anatomic extent of colitis, the concomitant presence of other inflammatory manifestations such as primary sclerosing cholangitis, and the fact that certain drugs used to treat inflammation, such as 5-aminosalicylates and steroids, may prevent the development of colorectal cancer. The major carcinogenic pathways that lead to sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also occur in colitis-associated colorectal cancers. Unlike normal colonic mucosa, however, inflamed colonic mucosa demonstrates abnormalities in these molecular pathways even before any histological evidence of dysplasia or cancer. Whereas the reasons for this are unknown, oxidative stress likely plays a role. Reactive oxygen and nitrogen species produced by inflammatory cells can interact with key genes involved in carcinogenic pathways such as p53, DNA mismatch repair genes, and even DNA base excision-repair genes. Other factors such as NF-kappaB and cyclooxygenases may also contribute. Administering agents that cause colitis in healthy rodents or genetically engineered cancer-prone mice accelerates the development of colorectal cancer. Mice genetically prone to inflammatory bowel disease also develop colorectal cancer especially in the presence of bacterial colonization. These observations offer compelling support for the role of inflammation in colon carcinogenesis.

Animals↗

PubMed2005

Effects of HIV-1 Nef, a cytotoxic viral protein, on the growth of primary colorectal cancer.

Colorectal cancer is the third leading cause of cancer deaths in American men and women. We describe the cytotoxic use of HIV-1 Nef protein and a cytotoxic peptide identified within the HIV-1 Nef structure in targeting human cancer cells in vitro and in vivo in a human xenograft model. A human colorectal tumor was implanted and propagated in the subcutaneous tissue of SCID mice. The mice were injected biweekly with the Nef apoptotic peptide. The tumor treated with Nef peptide underwent significant growth inhibition by as much as 300 percent when compared to the control (untreated) tumors. The Nef peptides were found to have an apoptotic effect on the human colon tumor similar to the effect seen on CD4 cells when the viral protein is secreted by the HIV-1 virus infected cells. The evidence from the xenograft mouse model suggests that the Nef peptides can be used to inhibit human colorectal cancer growth.

Animals↗

PubMed1998

Promising new agents for treatment of patients with colorectal cancer.

Colorectal cancer continues to be a major problem. There are a number of new agents with promising clinical activity, including the multitargeted antifolate LY 231514 and the thymidylate synthesis inhibitor capecitabine. In addition, other agents have shown promising preclinical activity against the disease: 6-hydroxymethylacylfulvene (HMAF; MGI 114), LY 295501, bizelesin (U-7779; NSC615291), and ONYX-015. Finally, several agents may prevent colorectal cancer through prevention of the formation of colorectal polyps (eg, cyclooxygenase inhibitors).

Adenoviridae↗

PubMedDate not supplied

Epidemiology and molecular genetics of colorectal cancer.

Colorectal cancer is among the most common cancers affecting the western world. By the age of 70 yr, at least 50% of the Western population will develop some form of colorectal tumor, spanning the spectrum from an early benign polyp to an invasive adenocarcinoma. It is estimated that approximately 10% of the benign polypoid lesions will progress to invasive carcinoma. The concept that serial genetic changes are responsible for the transition from benign to neoplastic disease is not new. The description of hereditary cancers and the demonstration of carcinogenic substances inducing DNA damage have provided the foundation for the field of molecular oncology. During the past three decades, our understanding of how genetic alterations culminate in cancer has progressed rapidly, though the complete process has not been fully defined. The research to date has spanned many oncologic diseases, but has been especially well defined in colorectal cancer. The knowledge of the genetic alterations that result in colorectal cancer has important ramifications for future prevention, detection, and treatment of this disease.

Adenomatous Polyposis Coli↗

PubMed2006

Predicting the outcome of chemotherapy for colorectal cancer.

Colorectal cancer is the second leading cause of cancer-related deaths in the Western world. Recently, improvements have been made in treating patients with advanced colorectal cancer; however, response rates still remain low at only 40-50% following combination therapy. The major limitation in treating these patients is the development of drug resistance. Therefore, there is a need to identify which patients will respond to a given chemotherapy regime so that they will be spared the unnecessary time and toxicity of being placed on a regime from which they will derive no benefit. It is also widely accepted that exposure to these chemotherapies themselves can induced acute resistance. Recent developments have been made in predicting response to chemotherapy using global approaches, with the ultimate aim of individualising patient treatment and improving overall survival rates.

Antibodies, Monoclonal↗

PubMed2005

Pharmacogenetics of colorectal cancer.

Colorectal cancer is one of the most common types of cancer in both men and women. Multiple chemotherapy combinations exist; however, there is currently no strategy for individualised therapy selection prior to treatment. Genetic polymorphisms in genes involved in the metabolism, transport or targets for the commonly used chemotherapy drugs (5-fluorouracil, irinotecan and oxaliplatin) have been described. Many require validation in large prospective trials before they can be used as markers for outcome and/or toxicity. This review describes the data available on polymorphisms in key genes that are associated with chemotherapy toxicity and response in colorectal cancer.

Animals↗