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

Caveolin is a major component of caveolae which is a plasma membrane microdomain. The emerging role of caveolin in tumorigenesis was based mainly on in vitro experiments with cancer cell lines. We performed semi-quantitative RT-PCR for caveolin, Akt and EGFR to understand the role of caveolins in colorectal tumor biology. Cancer tissue samples and the neighboring normal colon mucosa were obtained from 95 colorectal cancer patients who underwent operations at Ewha Womans University Mokdong Hospital. With these fresh tissues, semi-quantitative RT-PCR was performed by coamplification of the gene for caveolin-1, EGFR and Akt-1 with beta-actin. The average age was 60.21+/-13.33 years old, and sex ratio was 1.44:1. Caveolin-1 is more expressed in tumors than normal mucosa (P=0.025). The expression of caveolin-1 and Akt-1 had a definitive positive relationship (P=0.002). But, the expression of caveolin-1 and EGFR was not significantly related. We could not find correlations between caveolin-1 expression and clinical factors. In conclusion, caveolin-1 is more expressed in cancer tissues than normal colon and related with Akt-1, not with EGFR expression in colorectal cancer tissues, which suggests that signaling for caveolin-1 affects Akt-1 activation, but this reaction is not initiated by EGFR stimulation in colon cancer.
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PMID:Expression of caveolin-1 is correlated with Akt-1 in colorectal cancer tissues. 1620 96

Strategies for the treatment of metastatic colorectal cancer must take into account the contribution of monoclonal antibodies. A group of new efficient tools in oncology, these drugs target tumor antigens. Bevacizumab recognizes VEGF. Vascular endothelial growth factor (VEGF) is a key mediator in angiogenesis. This antibody combined with chemotherapy increases the survival of patients treated for metastatic colorectal cancer. Median survival of patients treated with antibodies and chemotherapy is 20 months, compared with only 15 months for patients treated with chemotherapy alone. Cetuximab is a monoclonal antibody that binds competitively and with high affinity to the EGF receptor. Cetuximab is currently approved for use in patients with pretreated colorectal cancer. EGF is a major cell growth factor. The side effects of these new biotherapies are different from chemotherapy: bevacizumab affects vascular elements and the most common side effect of anti-EGFR treatment is acneiform skin rash.
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PMID:[Biotherapy in colorectal cancer]. 1629 7

The prognostic value of EGFR expression in colorectal cancer, usually evaluated by immunohistochemistry, is actually based on heterogeneous data, considering tumour stage or survival rates. Results are variable due to differences in evaluation criteria between studies. The development of standardized scoring systems and the evaluation of expression variability in tumour led to reconsider this question. It seems to be important to evaluate precisely EGFR reactivity in the deepest region of the tumour. The finding of a profile linked to worse prognosis could allow pointing out tumours where EGFR overexpression is associated to disease progression and therefore could help to define EGFR- inhibitors' indications in colorectal cancer.
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PMID:[Prognostic value of EGFR in colorectal cancer]. 1638 64

Several monoclonal antibodies directed against EGFR are currently in clinical evaluation and include notably the agent cetuximab (C225). Tyrosine kinase inhibitors have chemical structures close to that of ATP and are thus ATP competitors on the tyrosine kinase site (ATP pocket) which is located in the intracellular domain of EGFR (gefitinib and erlotinib, respectively Tarceva and Iressa being the most advanced in clinical development). Well-conducted experimental studies open the way to new clinical applications with the most rewarding currently being the association between cetuximab and irinotecan. The two approaches of EGFR targeting have the same target and similar intracellular molecular impacts but they may differ under several aspects. For instance for the mechanism of action where, for monoclonal antibodies, there is a potential complement of cytotoxic activity brought by the ADCC phenomenon (antibody-directed cell cytotoxicity). One of the main current questions about the clinical use of anti-EGFR drugs is to dispose of faithful predictors for identifying tumors sensitive to this targeted treatment. The agents targeting VEGF are conceptually the same to those applied to EGFR. A major therapeutic advance brought by antiangiogenic drugs in colorectal cancer is attributable to bevacizumab. Bevacizumab is a monoclonal antibody impacting VEGF itself. A controlled clinical trial recently conducted on more than 800 advanced colorectal cancer patients concluded to a significant improvement in both response rate and global survival. This trial was comparing the combination 5FU-leucovorin-bevacizumab to 5FU-leucovorin and the advantage was in favor of the triple combination.
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PMID:[Pharmacological skills for targeting EGFR and VEGF]. 1638 65

Increased expression of COX-2 appears to play an important role in the development of colorectal cancer. The level of COX-2 expression is regulated by various factors including activation of members of the EGFR family of RTKs. We previously reported that in HT29 human colon cancer cells EGCG, the major biologically active component of green tea, inhibits activation of two members of this family, EGFR and HER2, and multiple downstream signaling pathways. In this study we examined the effects of EGCG on the HER3 RTK and on COX-2 expression in the SW837 human colon cancer cell line that expresses a high level and constitutive activation of HER3 and also expresses a high level of COX-2. Treatment of these cells with 20 microg/ml of EGCG (the IC50 concentration for growth inhibition) caused, within 6 hours, a decrease in the phosphorylated (i.e. activated) forms of not only EGFR and HER2, but also HER3. At 6 to 12 hours there was a decrease in the phosphorylated forms of the downstream signaling proteins ERK and Akt. Within 6 to 12 hours there was a decrease in cellular levels of both COX-2 protein and mRNA, and within 48 hours the cells displayed apoptosis. Reporter assays indicated that EGCG inhibited the transcriptional activities of the COX-2, AP-1, and NF-kappaB promoters. EGCG also caused a decrease in production of PGE2, a major product of COX-2. With a longer incubation time, 96 hours, a very low dose (1.0 microg/ml) of EGCG also caused inhibition of cell growth, inhibition of activation of EGFR, HER2, and HER3, a decrease in the levels of COX-2 and Bcl-xL proteins, and apoptosis. These results provide the first evidence that a low concentration of EGCG can inhibit activation of, at least, three members of the EGFR family of RTKs, and also inhibit COX-2 expression in colon cancer cells. These findings extend our previous evidence that EGCG may be useful in the chemoprevention and/or treatment of colorectal cancer.
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PMID:EGCG inhibits activation of HER3 and expression of cyclooxygenase-2 in human colon cancer cells. 1641 3

For many years, the treatment of metastatic colorectal cancer was restricted to 5FU and its biomodulation. Oxaliplatin and irinotecan, combined with continuous infusion of 5FU significantly improved response rate, progression-free survival and overall survival. Folfox4 (oxaliplatin and LV5FU2) is more active than LV5FU2 alone, and has shown also a superiority over IFL (irinotecan, 5FU bolus, leucovorin). Combining a 2-line strategy (Folfox then Folfiri or the reverse sequence), a median overall survival over 20 months has been reached. In the Optimox1 trial, comparing Folfox4 until progression and Folfox7 followed by a maintenance of simplified LV5FU2 and reintroduction of Folfox7, a similar response rate, progression-free survival and overall survival is observed. The next trial, Optimox2, is testing a "stop and go" strategy, in order to reduce the number of cycles and the cumulative toxicity. Combinations of capecitabine and oxaliplatine are also promising. The next step will come from the two new targeted therapies in metastatic colorectal cancer, directed against EGFR and VEGF.
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PMID:[Reflexion on a good strategy of use of oxaliplatine with 5-fluorouracil and its derivatives in patients with advanced colorectal cancer]. 1648 41

The anti-epidermal growth factor receptor (anti-EGFR) cetuximab has been proven to be efficient in metastatic colorectal cancer. The molecular mechanisms underlying the clinical response to this drug remain unknown. Genetic alterations of the intracellular effectors involved in EGFR-related signaling pathways may have an effect on response to this targeted therapy. In this study, tumors from 30 metastatic colorectal cancer patients treated by cetuximab were screened for KRAS, BRAF, and PIK3CA mutation by direct sequencing and for EGFR copy number by chromogenic in situ hybridization. Eleven of the 30 patients (37%) responded to cetuximab. A KRAS mutation was found in 13 tumors (43%) and was significantly associated with the absence of response to cetuximab (KRAS mutation in 0% of the 11 responder patients versus 68.4% of the 19 nonresponder patients; P = 0.0003). The overall survival of patients without KRAS mutation in their tumor was significantly higher compared with those patients with a mutated tumor (P = 0.016; median, 16.3 versus 6.9 months). An increased EGFR copy number was found in 3 patients (10%) and was significantly associated with an objective tumor response to cetuximab (P = 0.04). In conclusion, in this study, KRAS mutations are a predictor of resistance to cetuximab therapy and are associated with a worse prognosis. The EGFR amplification, which is not as frequent as initially reported, is also associated with response to this treatment.
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PMID:KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. 2748 Sep 59

EGFR Inhibitors are used to treat Non-Small-Cell Lung Cancer (NSCLC) and colorectal cancer (CRC). A common side effect of EGFR Inhibitors is a follicular/pustular skin eruption. We report a case of gefitinib (Iressa) associated skin eruption. The treatment regimen consisted of triamcinolone 0.1% cream twice daily, clindamycin 1% lotion twice daily and sodium sulfacetamide lotion twice daily. The clinical presentation, etiology, and management options of EGFR Inhibitor associated skin eruptions are discussed.
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PMID:Epidermal growth factor receptor (EGFR) inhibitor associated skin eruption. 1667 7

Anti-EGFR (epidermal growth factor receptor) therapies, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, demonstrate activity in a variety of tumor types. While both inhibit the EGFR pathway, they act via different mechanisms. Monoclonal antibodies bind to the extracellular domain of EGFR, preventing ligand binding and interrupting the signaling cascade. Tyrosine kinase inhibitors bind to the intracellular domain of EGFR and inhibit the downstream effects of EGFR ligand binding. Both categories of agents have been evaluated in a variety of clinical settings and tumor types, including colorectal cancer, non-small-cell lung cancer (NSCLC), and squamous cell carcinoma of the head and neck (SCCHN). Phase II/III trials in patients with previously treated or untreated metastatic colorectal cancer, including those with documented refractory disease, demonstrate activity of the monoclonal antibody cetuximab (Erbitux) as a single agent or in combination with both irinotecan (Camptosar)- and oxaliplatin (Eloxatin)-based chemotherapy. Activity of cetuximab added to chemotherapy in patients who previously progressed on the same regimen suggests an ability to overcome chemotherapy resistance in some patients. In NSCLC, phase II trials of the TKI gefitinib (Iressa) plus combination chemotherapy showed impressive activity with considerable toxicity. Large, randomized, phase II trials (IDEAL 1 and 2) reported modest activity of gefitinib in NSCLC; however, phase III trials (INTACT 1 and 2)failed to demonstrate a benefit to adding gefitinib to chemotherapy. A similar trend was noted in trials of erlotinib (Tarceva) (TALENT and TRIBUTE). Phase II/III trials have shown promising activity of cetuximab in SCCHN, generating significantly improved survival in combination with radiotherapy over radiotherapy alone in locally advanced disease and significantly improved response rates in combination with chemotherapy over chemotherapy alone in recurrent/metastatic disease, with little enhancement of toxicity profiles. Limited clinical experience with TKIs in SCCHN suggests similar degrees of single-agent activity and dermatologic toxicities. Levels of EGFR expression and the presence of EGFR mutations correlate with responsiveness to TKI therapy, while it remains unclear whether a relationship exists between level of EGFR expression and cetuximab efficacy in colorectal cancer. Anti-EGFR therapies are good candidates for combination with other treatment modalities, including chemotherapy and radiotherapy, due to their tolerable safety profile and nonoverlapping toxicities. In addition, these agents represent important treatment options in patients ineligible for chemotherapy due to refractory or resistant disease. Ongoing trials continue to investigate both the monoclonal antibodies and TKIs in various treatment settings.
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PMID:Anti-EGFR therapies: clinical experience in colorectal, lung, and head and neck cancers. 1673 79

Bevacizumab, a recombinant, humanised monoclonal antibody against vascular endothelial growth factor, when used in combination with intravenous 5-fluorouracil (5-FU)-based chemotherapy as first-line treatment of metastatic colorectal cancer (CRC) improves survival. In a randomised, placebo-controlled Phase III study, the addition of bevacizumab to irinotecan/5-FU/leucovorin (IFL) resulted in significant improvement in survival compared with IFL alone, which led to its approval for first-line use in CRC. Bevacizumab also demonstrates improved efficacy in combination with 5-FU/LV over chemotherapy alone when data were pooled from two randomised Phase II studies utilising bevacizumab with 5-FU/leucovorin, and also in a third treatment arm of bevacizumab/5-FU/LV of a randomised Phase III study. More recently, in the second-line setting, bevacizumab in combination with FOLFOX improved survival from 10.8 to 12.9 months in the ECOG 3200 trial. Clinical activity with the addition of bevacizumab to oxaliplatin and either 5-FU or capecitabine-based regimens has also been shown in TREE-2, and activity with the combination of bevacizumab and the EGFR inhibitor cetuximab has been documented in BOND-2. In this study, bevacizumab was generally well-tolerated with no unexpected toxicities when combined with cetuximab. A few toxicities were uniformly encountered in all of the above studies, in particular grade 3 medically-manageable hypertension (3 - 16%). In addition, other toxicities were haemorrhage (2 - 9.3%), gastrointestinal perforation (1.5%), arterial thromboembolism (3.8%), wound healing (1 - 2%) and proteinuria (1 - 2%). As bevacizumab is becoming widely used in general oncology practice, it is important to understand the toxicities which can arise and to develop practice guidelines for their management. This review addresses the toxicities noted in trials using bevacizumab for the treatment of CRC and provides recommendations for toxicity management.
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PMID:Incidence and management of bevacizumab-related toxicities in colorectal cancer. 1677 93


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