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)

Inhibition of epidermal growth factor receptor (EGFR) signalling contributes to the therapy of colorectal cancer. Gefitinib, an oral EGFR tyrosine kinase inhibitor, shows supra-additive growth inhibition with irinotecan and fluoropyrimidines in xenograft models. We designed a study to determine the tolerability and efficacy of gefitinib in combination with irinotecan, infusional 5-fluorouracil (5-FU) and leucovorin (LV), on a 2-week schedule. Among 13 patients with advanced colorectal cancer, 10 required dose reductions of irinotecan and 5-FU because of dehydration, diarrhoea, and neutropenia, seven of whom required hospitalisation, three with neutropenic fever. One patient achieved partial response and seven had disease stabilisation. The combination of this standard chemotherapy regimen with gefitinib is associated with excessive toxicity, suggesting an interaction at a pharmacokinetic or pharmacodynamic level.
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PMID:A phase II trial of gefitinib with 5-fluorouracil, leucovorin, and irinotecan in patients with colorectal cancer. 1587 Jul 19

The epidermal growth factor receptor (EGFR) is overexpressed in as many as 77% of colorectal cancer (CRC) cases. The EGFR is known to be involved in carcinogenetic processes such as cell proliferation, apoptosis, angiogenesis, cell motility, and metastasis. Preclinical and clinical studies have shown that targeting EGFR is a valid strategy for anticancer therapy. Currently, 2 classes of anti-EGFR agents are in phase II/III clinical development: monoclonal antibodies and tyrosine kinase (TK) inhibitors. The most established monoclonal antibody is cetuximab, the only EGFR inhibitor that is currently approved for use in patients with metastatic CRC. Several clinical studies of cetuximab, as a single agent or in combination with irinotecan, have shown promising efficacy in patients with metastatic CRC. Two other monoclonal antibodies, matuzumab (EMD 72000) and panitumumab (ABG-EGF), also have shown activity against EGFR-expressing CRC but are still in the early stage of clinical development. The activity of the EGFR TK inhibitors erlotinib and gefitinib have already been investigated in clinical phase III trials in patients with non-small-lung cancer, suggesting that sequential rather than concurrent erlotinib/gefitinib-based treatment provides a benefit in clinical outcome. The EGFR-targeting agents are reasonably well tolerated and have limited overlapping toxicities in combination with other cytotoxic drugs. The most common side effect of anti-EGFR treatment is an acneiform skin rash, which is associated with the clinical outcome of treatment with monoclonal antibodies and TK inhibitors. Future clinical studies are needed to establish these EGFR-targeting agents in anticancer treatment to investigate efficacy of therapies combining EGFR-targeted agents with other targeting agents and to describe additional markers determining the clinical outcome of anti-EGFR therapy.
Clin Colorectal Cancer 2005 Apr
PMID:Epidermal growth factor receptor as a target for chemotherapy. 1587 62

We have prepared the map of regional distribution of cervical cancer in Hungary. Serial HPV genotyping of sexual partners provided evidence for the sexually transmitted infections. Molecular epidemiology studies revealed activating c-kit mutation in bilateral testicular cancers. A cost-effective molecular staging method was introduced to the management of breast cancer patients. Genomic profiling identified the gene signature of Herceptin and taxane sensitivity of breast cancer. In colon cancer patients we have determined the mutational spectrum of hMLH1 and hMSH2 genes in Hungary. The prognostic power of SHMT and MTHFR polymorphism was determined in colorectal cancer patients. In head and neck cancer the gene signature of cisplatin sensitivity and the EGFR polymorphism was determined. We have introduced a cost-effective in vitro assay to determine the drug resistance of pediatric leukemias. The prognostic power of N-myc genotyping was determined in neuroblastoma patients. A phase I trial for gene therapy of brain cancer was started by using a GM-CSF adenoviral vector system. Using global genomic approaches the gene signature of malignant melanoma and its metastatic disease was determined. We have found that Ca-channel blockers and EGFR tyrosine kinase inhibitors are effective in preclinical human melanoma models in breaking the apoptosis resistance of this tumor.
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PMID:[Activity of the National Oncology R&D Consortium in 2004]. 1590 26

Colorectal cancers frequently overexpress the epidermal growth factor receptor. Gefitinib (Iressa), an inhibitor of the epidermal growth factor receptor tyrosine kinase, is synergistic with oxaliplatin in preclinical colon cancer models. The authors conducted a phase I/II trial of gefitinib plus oxaliplatin in patients with previously treated metastatic colorectal cancer. In the phase I portion, 14 patients received oxaliplatin 130 mg/m2 intravenously every 21 days and gefitinib orally daily at 1 of 2 dose levels: 250 mg/day (8 patients), and 500 mg/day (6 patients). There were no objective responses. Three patients (38%) in the 250-mg cohort experienced disease stabilization for a median of 12 weeks, and 1 patient in the 500-mg cohort had stable disease for 18 weeks. Nausea/vomiting and rash were dose limiting. The randomized phase II part of the trial, in which patients were to receive oxaliplatin with or without gefitinib, was canceled due to the inactivity of single-agent gefitinib observed in the phase I portion, and emergent phase III data regarding the minimal activity of single-agent oxaliplatin. The authors conclude that the combination of gefitinib plus oxaliplatin is inactive in advanced colorectal cancer.
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PMID:Phase I/II trial of gefitinib and oxaliplatin in patients with advanced colorectal cancer. 1606 74

PTK/ZK is a novel, oral angiogenesis inhibitor that specifically targets all 3 vascular endothelial growth factor (VEGF) receptor tyrosine kinases and is currently in phase III clinical trials. In early clinical trials, PTK/ZK demonstrated a dose-dependent reduction in tumor vascular parameters as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and an acute increase in plasma VEGF levels. The reduction in tumor vascularity was significantly correlated with improved clinical outcome in patients with advanced colorectal cancer and liver metastases. To assess the predictive value of a mouse model of tumor metastases, comparisons were performed for the biological activity of PTK/ZK in the mouse model and in patients with liver metastases in the clinical phase I trials. An orthotopic, syngeneic mouse model was used: C57BL/6 mice injected in the ear with murine B16/BL6 melanoma cells which metastases to the cervical lymph-nodes. The primary tumor and spontaneous metastases express VEGF and VEGF receptors and respond to treatment with VEGFR tyrosine kinase inhibitors. PTK/ZK was administered orally, with assessments by DCE-MRI of the metastases and plasma VEGF taken predose and at 3 days posttreatment and efficacy determined at 7 days posttreatment. Dose-ranging studies in naive mice provided preclinical pharmacokinetic data, while two dose-escalation phase I studies provided clinical pharmacokinetic data. An exposure-response relationship was observed both for mouse metastases (measured as % tumor weight treated/control) and for human liver metastases (measured as % regression). In the B16/BL6 model, the active dose of 50 mg/kg PTK/ZK yielded 62.4 (+/- 16.0) h microM plasma exposure, which is comparable to the plasma area under the concentration time curve (AUC) achieved by the 1000 mg dose of PTK/ZK used in clinical trials. At this exposure level in clinical trials, DCE-MRI showed a reduction in the area under the enhancement curve (IAUC) to 47% of baseline. At a similar exposure in the PTK/ZK-treated mice, a reduction in IAUC to 75% of baseline was observed. Furthermore, at doses of 50 mg/kg PTK/ZK and above, an increase in plasma VEGF level 10 h after drug administration was observed in mice which was consistent with findings from the clinical trials. In conclusion, the preclinical pharmacodynamics of PTK/ZK correlate well with clinical activity in phase I trials over comparable exposures to the drug. Thus, data from this preclinical model proved to be consistent with and thus predictive of the biologic effects of PTK/ZK in phase I/II clinical trials.
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PMID:Biomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK): translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases. 1617 7

The epidermal growth factor receptor (EGFR) is expressed in the majority of colorectal cancers (CRCs) and is associated with poor clinical outcome. Ample evidence suggests that inhibition of this pathway by monoclonal antibodies directed against EGFR leads to antitumor activity in CRC. Small-molecule tyrosine kinase inhibitors (TKIs) provide distinct advantages over monoclonal antibodies by virtue of lower production costs, ease of oral administration, and ability to target multiple cellular survival pathways. Despite theoretical advantages, multiple early-phase trials of EGFR TKIs fail to demonstrate single-agent activity in CRC. However, the unusually high response rates observed when gefitinib, an EGFR TKI, is combined with chemotherapy for patients with metastatic CRC suggest a possible synergistic effect. This effect is not seen in non-small-cell lung cancer (NSCLC), for which larger phase III trials have been conducted. The differences between NSCLC and CRC with respect to EGFR expression and mutation status do not completely explain this dichotomy, and further investigation into the pharmacogenomics of EGFR tyrosine kinase inhibition in CRC is under way. Significant effort is directed toward newer strategies targeted at the EGFR in CRC. A new generation of small-molecule TKIs is emerging in which multiple receptor pathways, including ErbB2 and vascular endothelial growth factor receptor, can be simultaneously targeted with EGFR. These agents are still in early-phase clinical trials, and specific data for patients with CRC are forthcoming.
Clin Colorectal Cancer 2005 Nov
PMID:Current status of small-molecule tyrosine kinase inhibitors targeting epidermal growth factor receptor in colorectal cancer. 1633 51

The epidermal growth factor receptor (EGFR) provides survival signals and is overexpressed in the majority of colorectal cancers. As more is learned about the molecular details of EGFR signaling, antibodies can be designed to interfere with specific domains of the EGFR molecule. In this review, we analyze preclinical and current clinical data on EGFR-targeting molecules and their potential role in the treatment of colorectal cancer. Cetuximab binds to domain III of EGFR and hinders ligand binding. It is now approved by the US Food and Drug Administration for metastatic colorectal cancer treatment. Panitumumab is another widely studied anti-EGFR antibody with similar properties. Bispecific antibodies are modified immunoglobulin molecules containing 2 different binding specificities. These antibodies can redirect the immune response against tumor cells by tethering effector cells such as CD3e-expressing T cells or CD16-expressing natural killer cells and granulocytes to the surface of cancer cells. Tyrosine kinase inhibitors are quinazoline-derived, low molecular weight synthetic molecules that can block the intracellular tyrosine kinase domain of several receptors, including EGFR, Erb2, and vascular endothelial growth factor receptor, and thereby inhibit ligand-induced receptor phosphorylation and abrogate the biologic effect of EGFR signaling. The presence of skin rash and EGFR gene amplification have been advanced as possible predictors of clinical effectiveness of targeted anti-EGFR therapies.
Clin Colorectal Cancer 2005 Nov
PMID:Overview of monoclonal antibodies and small molecules targeting the epidermal growth factor receptor pathway in colorectal cancer. 1633 52

Targeted therapies that are approved for metastatic colorectal cancer are divided into two groups: those affecting vascular endothelial growth factor (VEGF) known to interrupt tumor growth and metastasis (also called neo-angiogenesis), and agents that affect the tumor directly by interrupting the epidermal growth factor (EGF) and its receptor. Anti-angiogenic VEGF therapies are divided into two categories: one affecting the VEGF ligand, such as bevacizumab, and those that inhibit the VEGF receptor, such as PTK/ZK. Epidermal growth factor receptor (EGFR) therapies are divided into monoclonal antibodies that affect EGFR, such as cetuximab, and EGFR tyrosine kinase inhibitors, such as gefitinib. Both VEGF and EGFR areas of treatment have shown promising efficacy in first-line, combination therapy settings. Future targeted therapeutic strategies include gene profiling, combinations of capecitabine and oxaliplatin, with bevacizumab and/or cetuximab therapies.
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PMID:Molecular mechanisms and targeting of colorectal cancer. 1636 5

During neuronal development, netrin and its receptors UNC5 and DCC (deleted in colorectal cancer) guide axonal growth cones in navigating to their targets. Netrin also plays important roles in the regulation of cell migration, tissue morphogenesis and tumor growth. Here, we show that netrin induces UNC5 tyrosine phosphorylation and that this effect of netrin is dependent on its co-receptor DCC. UNC5 tyrosine phosphorylation is known to be important for netrin to induce cell migration and axonal repulsion. Src tyrosine kinase activity is required for netrin to stimulate UNC5 tyrosine phosphorylation in neurons and transfected cells. The SH2 domain of Src kinase directly interacts with the cytosolic domain of UNC5 in a tyrosine-phosphorylation-dependent manner. Furthermore, the tyrosine kinase focal adhesion kinase (FAK) is also involved in netrin-induced UNC5 tyrosine phosphorylation. Both Src and FAK can phosphorylate UNC5. Our data suggest a model in which netrin stimulates UNC5 tyrosine phosphorylation and signaling in a manner dependent on the co-receptor DCC, through the recruitment of Src and FAK kinases.
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PMID:FAK and Src kinases are required for netrin-induced tyrosine phosphorylation of UNC5. 3078 81

The scientific rationale to block angiogenesis as a treatment strategy for human cancer has been developed over the last 30 years, but is only now entering the clinical arena. Preclinical studies have demonstrated the importance of the vascular endothelial growth factor (VEGF) pathways in both physiologic and pathologic angiogenesis, and have led to the development of approaches to block its role in tumor angiogenesis. Bevacizumab is an antibody to VEGF and has been shown to prolong survival when given with chemotherapy in the treatment of metastatic colorectal cancer (CRC). Although this is the first anti-angiogenic treatment to be approved for the treatment of human epithelial malignancy, a number of other approaches currently are in development. Soluble chimeric receptors to sequester serum VEGF and monoclonal antibodies against VEGF receptors have both shown considerable promise in the laboratory and are being brought into clinical investigation. A number of small-molecule tyrosine kinase inhibitors that have activity against VEGF receptors also are in clinical trials. Although these novel treatments are being pioneered in CRC, anti-angiogenic approaches also are being tested in the treatment of other gastrointestinal malignancies. Anti-VEGF therapy has shown promise in such traditionally resistant tumors as pancreatic cancer and hepatocellular carcinoma. This review will examine the preclinical foundation and then focus on the clinical studies of anti-VEGF therapy in gastrointestinal cancers.
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PMID:Anti-angiogenic treatment of gastrointestinal malignancies. 1637 90


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