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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Colorectal cancer is one of the most frequent human malignancies. Therapeutic options are mainly limited to chemotherapy with 5-fluorouracil in various schedules or in combination with irinotecan and oxaliplatin; however, novel approaches are also in development. These new agents specifically attack molecular targets involved in tumor biology. One such target is the epidermal growth factor receptor (EGFR), which is highly expressed in many tumors and is associated with a poor prognosis. The EGFR plays a key role in cell proliferation and has been implicated in several processes that mediate cancer progression. ZD1839 is an orally active, selective EGFR tyrosine kinase inhibitor that has shown extensive preclinical activity and favorable tolerability in advanced clinical trials in a variety of tumors. In colorectal cancer cells, ZD1839 has shown both in vitro and in vivo antitumor activity as monotherapy or in combination with cytotoxic agents such as paclitaxel and irinotecan. Preclinical data have also shown that ZD1839 reverses resistance to irinotecan and enhances its efficacy by improving oral bioavailability. These studies indicate that EGFR inhibition by ZD1839 may have a valuable role in the treatment of colorectal cancer, and clinical studies in patients with colorectal cancer are ongoing.
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PMID:Development of ZD1839 in colorectal cancer. 1280 91

Despite surgical, radiotherapeutic, and chemotherapeutic advances, a large proportion of gastrointestinal (GI) cancers remain incurable. An improved understanding of the molecular pathogenesis of cancer has promulgated the development of novel agents designed to target critical pathways involved in cancer development and progression. The crucial role of the epidermal growth factor receptor (EGFR) in tumor proliferation and the overexpression of EGFR in several GI cancers provides the rationale for targeting and interrupting this key signaling network. EGFR blockade through monoclonal antibodies (C225 and ABX-EGF) and tyrosine kinase inhibitors (ZD1839 and OSI-774) has translated into promising evidence of clinical benefit. Ras-mediated signal transduction has been targeted using inhibitors of farnesyl transferase (R115777 and SCH66336) to block the post-translation modification of Ras. Inhibitors of vascular growth factor receptor (bevacizumab and PTK787) and matrix metalloproteinase target the effects of the host environment. Cyclooxygenase-2 inhibitors in colorectal cancer and STI571 in GI stromal tumors represent novel therapies of interest for these specific GI cancers. Evidence suggests that novel agents can be administered alone or in combination with standard therapies with little additional toxicity. The results of ongoing and future research efforts will clarify the optimal use and survival benefit of targeted therapies for patients with GI malignancies.
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PMID:New targeted therapies in gastrointestinal cancers. 1294 Nov 99

Oxaliplatin is a new third-generation platinum analogue with unique activity in colorectal cancer. This agent has changed the approach to chemotherapy for this disease. Novel biologic or molecular targeting agents are now under study in phase I to III clinical trials. Many of these agents are quite promising in colorectal cancer therapy. Most advanced among these include anti-vascular endothelial growth factor antibodies, antibodies directed against the epidermal growth factor receptor (HER-1), small-molecule tyrosine kinase inhibitors of epidermal growth factor receptor, and the proteasome inhibitor PS-341 (bortezomib). The rationale for combinations with oxaliplatin and early clinical trial results are discussed.
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PMID:Opportunities for newer agents in combination with oxaliplatin. 1452 97

Epidermal growth factor receptor [EGFR (HER1, erbB1)] is a receptor with associated tyrosine kinase activity, and is expressed in colorectal cancers and many other solid tumors. We examined the effect of the selective EGFR tyrosine kinase inhibitor (EGFR-TKI) gefitinib ("Iressa") in combination with the DNA topoisomerase I inhibitor CPT-11 (irinotecan) on human colorectal cancer cells. EGFR mRNA and protein expression were detected by RT-PCR and immunoblotting in all 7 colorectal cancer cell lines studied. Gefitinib inhibited the cell growth of the cancer cell lines in vitro with an IC(50) range of 1.2-160 microM by 3,(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Lovo cells exhibited the highest level of protein and autophosphorylation of EGFR and were the most sensitive to gefitinib. The combination of gefitinib and CPT-11 induced supra-additive inhibitory effects in COLO320DM, WiDR and Lovo cells, assessed by an in vitro MTT assay. Administration of gefitinib and CPT-11 had a supra-additive inhibitory effect on WiDR cells and tumor shrinkage was observed in Lovo cell xenografts established in nude mice, whereas no additive effect of combination therapy was observed in COLO320DM cells. To elucidate the mechanisms of synergistic effects, the effect of CPT-11-exposure on phosphorylation of EGFR was examined by immunoprecipitation. CPT-11 increased phosphorylation of EGFR in Lovo and WiDR cells in time- and dose-dependent manners. This EGFR activation was completely inhibited by 5 microM gefitinib and gefitinib-induced apoptosis was enhanced by combination with CPT-11, measured by PARP activation although no PARP activation was induced by 5 microM CPT-11 alone. These results suggested that these modification of EGFR by CPT-11, in Lovo cells, is a possible mechanism for the synergistic effect of CPT-11 and gefitinib. These findings imply that the EGFR-TKI gefitinib and CPT-11 will be effective against colorectal tumor cells that express high levels of EGFR, and support clinical evaluation of gefitinib in combination with CPT-11, in the treatment of colorectal cancers.
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PMID:Synergistic interaction between the EGFR tyrosine kinase inhibitor gefitinib ("Iressa") and the DNA topoisomerase I inhibitor CPT-11 (irinotecan) in human colorectal cancer cells. 1464 15

Initial studies with angiogenesis inhibitors showed little clinical benefit. However, recently reported clinical studies in colorectal cancer have shown that bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with cytotoxic therapy has positive effects on patient survival. Furthermore, the VEGF receptor kinase (VEGF-R) tyrosine kinase inhibitor, vatalanib, has also shown encouraging results in colorectal cancer, with molecular resonance imaging providing evidence that the anti-tumor efficacy was indeed the result of anti-angiogenic activity. Both of these agents are progressing in phase III trials. This proof of concept has stimulated the desire for second-generation VEGF-R inhibitors having an improved profile. Structural biology insight regarding the binding mode of protein kinase inhibitors is valuable for the design of molecules possessing superior selectivity, efficacy and tolerability. Towards this goal, we have developed a new series of VEGF-R2 kinase inhibitors, based upon an anthranilic acid amide scaffold. An X-ray crystal structure of a representative compound, AAL993 (ZK260253), in complex with the catalytic domain of diphosphorylated VEGF-R2 has revealed that this molecule binds to an inactive conformation of the protein. This binding mode, similar to that observed for the anti-leukemia drug, imatinib in complex with c-Abl kinase, may be responsible for the high selectivity of AAL993 and provides valuable insight for the design of further compounds.
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PMID:Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis. 1502 47

Inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) activity have shown promise as novel anticancer agents in a variety of common solid tumors. In preclinical studies and phase I trials, tumor responses to EGFR-TK inhibitors (EGFR-TKIs), such as gefitinib (Iressa, AstraZeneca Pharmaceuticals LP, Wilmington, DE) and erlotinib (Tarceva, OSI Pharmaceuticals, Melville, NY, and Genentech, Inc., South San Francisco, CA) were observed in heavily pretreated patients with advanced non-small cell lung cancer (NSCLC), head and neck cancer, breast cancer, colorectal cancer, and other solid tumors. Subsequent phase II studies resulted in tumor responses, disease stabilization, symptom improvement, and improved quality of life in patients with advanced NSCLC who had received prior platinum-based chemotherapy or platinum and docetaxel chemotherapies. Side effects related to treatment with EGFR-TKIs were generally mild, reversible, and noncumulative. Severity and frequency of drug-related adverse events were related directly to dose. The potential role of EGFR-TKIs in treating other solid tumors currently is being studied. Furthermore, research is being conducted to explore the potential use of EGFR-TKIs in novel combinations with chemotherapy, radiation therapy, endocrine therapy, and other molecular targeted therapies.
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PMID:Epidermal growth factor receptor tyrosine kinase inhibitors: evolving role in the treatment of solid tumors. 1510 18

Epidemiological studies show a strong link between postmenopausal hormone replacement therapy and decreased incidence of colorectal cancer. The colon cancer cell line, COLO 205, develops sensitivity to 17beta-oestradiol (E(2)) in apoptosis assays with increasing passage number (>40), and we hypothesised that genes selectively regulated in multiply passaged cells were likely to be important in E(2)-related apoptosis. Gene array analysis was used to compare the patterns of genes up- or down-regulated in E(2)-sensitive and -insensitive cells. For some genes, changes in mRNA expression were confirmed by protein expression analyses. Changes found in response to E(2) in multiply passaged cells, but not minimally passaged cells, included induction of growth arrest and DNA damage-inducible protein 153 (GADD153), and repression of Kirsten-Ras 2B (K-Ras-2B), metastasis inhibition factor NM23 and vascular endothelial growth factor. A second group of genes was regulated with E(2) exposure in both cell types, and is unlikely to be critically involved in E(2)-associated apoptosis. These included up-regulation of butyrate response factor 1 (BRF1) and down-regulation of c-jun and the breast cancer associated ring domain gene known as BARD1. By comparing control arrays from the two cell populations, cAMP-response element-binding protein (CBP), which is associated with steroid receptor-dependent target gene transcription and the oncoprotein, tyrosine kinase-T3 (TRK-T3), were up-regulated whereas retinoic acid receptor alpha (RARalpha) was down-regulated in multiply passaged cells. This study provides evidence for selective regulation of genes in colon cancer cells by E(2), indicates which of those regulated are likely to be involved in induced apoptosis, and suggests genes likely to be responsible for facilitation.
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PMID:Targets of 17beta-oestradiol-induced apoptosis in colon cancer cells: a mechanism for the protective effects of hormone replacement therapy? 1512 81

Angiogenesis is an obligatory event for the growth of tumours beyond 2 mm in diameter, above which simple oxygen diffusion can no longer support the rapid proliferation of malignant cells. Angiogenesis is a fine balance between inhibitory and stimulatory factors, the knowledge of which offers novel targets for the treatment of gastrointestinal neoplasia. A literature search of Pubmed and Medline databases was undertaken, using the keywords colorectal cancer, pancreatic cancer, gastrointestinal cancer, angiogenesis and anti-angiogenesis therapy. It was found that angiogenesis in primary tumours is a sequential and highly complex cascade of molecular events resulting in the rapid exponential growth of the tumour. Hepatic metastases of primary tumours may be less reliant on traditional angiogenic pathways, by co-opting pre-existing hepatic vasculature. Research into angiogenesis has revealed many different sites that can be targeted by agents such as tyrosine kinase inhibitors. Many anti-angiogenic agents are undergoing preclinical evaluation, with only a few entering phase I and phase III clinical trials. However, early results suggest that anti-angiogenic therapy could be an important adjunct to conventional chemotherapy treatment of gastrointestinal neoplasia.
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PMID:Angiogenesis of gastrointestinal tumours and their metastases--a target for intervention? 1517 88

Colorectal carcinoma is the third most common malignancy worldwide. The use of currently available therapies results in only a modest impact on overall survival of patients with advanced-stage disease. New approaches for the treatment of colorectal cancer are urgently needed. The epidermal growth factor receptor (EGFR) is frequently dysregulated in colorectal carcinoma, and overexpression of the receptor confers a poor prognosis. Targeting the EGFR has become a rational approach for the treatment of colorectal carcinoma. Several strategies to inhibit the EGFR and its downstream signaling pathways are currently being investigated in preclinical and clinical studies, including monoclonal antibodies directed against the extracellular domain of the receptor and small-molecule inhibitors of its tyrosine kinase activity. Some of these drugs have already been tested in colorectal cancer and have shown preliminary evidence of antitumor efficacy. Important issues to elucidate in the future include the definition of the biologic context in which these drugs are more likely to be effective and the integration of the different agents in current therapeutic strategies for colorectal cancer. This article will provide a comprehensive review of the current available preclinical and clinical data on EGFR-targeted therapies in colorectal cancer.
Clin Colorectal Cancer 2004 May
PMID:Epidermal growth factor receptor as a therapeutic target for the treatment of colorectal cancer. 1520 21

The cation [Cr(3)O(propionate)(6)(H(2)O)(3)](+) has recently been found by oral or intravenous administration to increase insulin sensitivity and improve serum lipids in healthy and type 2 diabetic model rats. Serum insulin concentrations and, hence, insulin sensitivity are in part responsible for the relationship between diet and the incidence of colorectal cancer. This strongly suggested that the synthetic cation, which in vitro is able to stimulate insulin receptor tyrosine kinase activity in a fashion similar to the oligopeptide chromodulin, could influence the incidence of colorectal cancer. Consequently, the effects of the cation on the inhibition of colon tumorigenesis induced by 1,2-dimethylhydrazine in male Sprague Dawley rats were examined. Gavage administration of aqueous solutions of the complex (1000 microg Cr/kg body mass daily for 6 months) resulted in significantly decreased colon tumor incidence (P<0.003).
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PMID:Chromium-containing biomimetic cation triaqua-mu3-oxo-mu-hexapropionatotrichromium(III) inhibits colorectal tumor formation in rats. 1527 5


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