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)

The presence of epidermal growth factor, estrogen, and progesterone receptors (EGFR, ER, and PR) was investigated by a competitive binding assay in 43 colorectal adenocarcinomas and 32 normal colorectal mucosa specimens. EGFR were expressed in most of the tumor specimens analyzed at levels comparable with normal mucosa. There was no correlation between EGFR and tumor localization, tumor size, tumor stage, and grading. Among tumor specimens, 13.9% and 6.9% expressed very low but detectable ER and PR levels, respectively. No statistically significant difference was found between steroid hormone receptor levels in the tumor and normal mucosa specimens, and neither was there any correlation of ER and PR with the pathological findings. Our results suggest that the EGFR system may play a role in regulating the growth of colorectal tissues. Further studies should demonstrate whether, despite the lack of correlation with histopathological parameters, EGFR expression may have a biological significance in human colorectal cancer.
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PMID:Receptors for epidermal growth factor and steroid hormones in primary colorectal tumors. 194 15

The coexpression of EGFR and c-erbB-2 protein was examined immunohistochemically in a total of 62 freshly frozen specimens of colorectal cancer, and correlations between the coexpression of both receptors and their clinicopathological variables were analyzed. Positive staining of both receptors was found in 21 cases, and it was related to the degree of lymphatic or vascular invasion of cancer cell, the synchronous metastasis to liver or lung, and the most advanced stage (Dukes' D). Moreover, the incidence of the distant metastasis including metachronous metastasis to other organs such as liver, lung or peritoneum were significantly higher in the positive cases of both receptors. These results suggest that the coexpression of EGFR and c-erbB-2 protein may be related to the distant metastasis of colorectal cancer.
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PMID:[Immunohistochemical study of the coexpression of epidermal growth factor receptor (EGFR) and c-erbB-2 protein in colorectal cancer]. 790 10

The class I IgG receptor (Fc gamma RI or CD64 receptor), which is present on key cytotoxic effector cells, has been shown to initiate the destruction of tumor cells in vitro and has been hypothesized to play a role in the destruction of antibody-coated cells such as platelets in idiopathic thrombocytopenia purpura (ITP). This overview summarizes the clinical experience with CD64-directed immunotherapy in cancer patients with the bispecific antibodies MDX-447 [humanized Fab anti-CD64 x humanized Fab anti-(epidermal growth factor receptor, EGFR)] and MDX-H210 (humanized Fab anti-DC64 x Fab anti-HER2/neu), and with the anti-CD64 monoclonal antibody (mAB) MDX-33 (H22) in the modulation of monocyte CD64 in vivo. In an ongoing phase I/II open-label trial with progressive dose escalation (1-15 mg/m2), patients with treatment refractory EGFR-positive cancers (renal cell carcinoma (RCC), head and neck, bladder, ovarian, prostate cancer and skin cancer) are treated weekly with intravenous MDX-447, with and without granulocyte-colony-stimulating factor (G-CSF). MDX-447 has been found to be immunologically active at all doses, binding to circulating monocytes and neutrophils (when given with G-CSF), causing monocytopenia and stimulating increases in circulating plasma cytokines. MDX-447 is well tolerated, the primary toxicities being fever, chills, blood pressure lability, and pain/ myalgias. Of 36 patients evaluable for response, 9 have experienced stable disease of 3-6 month's duration. The optimal dose and the maximal tolerated dose (MTD) have yet to be defined; dose escalation continues to define better the dose, toxicity, and the potential therapeutic role of this bispecific antibody. Three MDX-H210 phase II trials are currently in progress, all using the intravenous dose of 15 mg/m2 given with granulocyte/macrophage (GM-CSF). These consist of one trial each in the treatment of RCC patients, patients with prostate cancer, and colorectal cancer patients, all of whom have failed standard therapy. At the time of writing, 11 patients have been treated in these phase II trials. Four patients have demonstrated antitumor effects. Patients demonstrating responses include 2 with RCC and 2 with prostate cancer. One RCC patient has had a 54% reduction in size of a hepatic metastatic lesion and the other has had a 49% decrease in the size of a lung metastasis with simultaneous clearing of other non-measurable lung lesions. Regarding the two patients with prostate cancer, one has had a 90% reduction in serum prostate-specific antigen (PSA; 118-11 ng/ml), which has persisted for several months; the other patient with prostate has had a 70% reduction of serum PSA (872 ng/ml to 208 ng/ml) within the first month of treatment. Both patients have also demonstrated symptomatic improvement. In a completed phase I and in ongoing phase I/II clinical trials, patients with treatment-refractory HER2/neu positive cancers (breast, ovarian, colorectal, prostate) have been treated with MDX-H210, which has been given alone and in conjunction with G-CSF, GM-CSF, and interferon gamma (IFN gamma). These trials have been open-label, progressive dose-escalation (0.35-135 mg/m2) studies in which single, and more often, multiple weekly doses have been administered. MDX-H210 has been well tolerated, with untoward effects being primarily mild-to-moderate flu-like symptoms. The MTD has not yet been defined. MDX-H210 is immunologically active, binding to circulating monocytes, causing monocytopenia, as well as stimulating increases in plasma cytokine levels. Furthermore, some patients have evidence of active antitumor immunity following treatment with MDX-210. Antitumor effects have been seen in response to MDX-H210 administration; these include 1 partial, 2 minor, and 1 mixed tumor response; 15 protocol-defined stable disease responses have occurred. (ABSTRACT TRUNCATED)
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PMID:Clinical experience with CD64-directed immunotherapy. An overview. 943 76

The immunohistochemical Cathepsin D (CD) expression of tumour and stromal cells was investigated in a series of 93 human colorectal adenocarcinomas and 22 adenomas with the intention to evaluate its prognostic significance and its contribution in the metastatic potential of colorectal cancer. CD expression was correlated with the expression of extracellular matrix components (collagen type IV, laminin and fibronectin), p53 protein, pRb, bcl-2, c-erbB-2, EGFR, proliferation indices (Ki-67, PCNA) as well as with other conventional clinicopathological features. CD expression (> 10% of positive tumour cells) was observed in 60.2% of carcinomas and in 72.7% of adenomas. Stromal CD expression was detected in all cases. A statistically significant positive correlation between neoplastic cells CD and stromal cells CD (SCCD) was observed in both carcinomas and adenomas. Cancer cells CD (CCCD) was positively correlated with collagen type IV and pRb expression as well as with PCNA score. In carcinomas, SCCD expression was statistically correlated with p53 protein and pRb expression and a trend for correlation with PCNA score was found. These data suggest that Cathepsin D of cancer and stromal cells, especially in combination with other markers, may provide more information about the biological behaviour of colorectal cancer.
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PMID:Immunohistochemical evaluation of cathepsin D expression in colorectal tumours: a correlation with extracellular matrix components, p53, pRb, bcl-2, c-erbB-2, EGFR and proliferation indices. 1047 Jan 63

As an animal model for human inflammatory bowel disease and colorectal cancer, the cotton-top tamarin remains controversial. Demonstration of antigenic similarity to the human would enhance its validity. Using colonic extracts and washings, we compared binding of seven monoclonal antibodies reactive with bowel and cancer antigens in both tamarins and humans with inflammatory bowel disease. Additionally, telomerase activity was tested for. Expression of a mucin antigen specific to human cancer was increased in tamarin colonic washings as well as aminoproteoglycans and EGFR in tamarin extracts, as compared to those of humans with inflammatory bowel disease (P < 0.005). An adenoma-associated antigen and k-ras p21 protein were negative in the tamarin. A trend to greater telomerase activity exists in tamarins. The antigenic similarity validates this model for human inflammatory bowel disease and colorectal cancer. A trend to increased telomerase activity in tamarins is consistent with the greater predisposition to cancer in these animals.
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PMID:Gastrointestinal tract antigenic profile of cotton-top tamarin, Saguinus oedipus, is similar to that of humans with inflammatory bowel disease. 1125 47

As a result of substantial advances in recent cancer biology, cell cycle regulation in the G1 phase has attracted a great deal of attention as a promising target for the research and treatment of cancer. Many of the important genes associated with G1 regulation have been shown to play a key role in proliferation, differentiation and oncogenic transformation and programmed cell death (apoptosis). Currently, a variety of "cytostatic" agents that affects G1 progression and/or G1/S transition are being evaluated in clinical trials. Flavopiridol is a potent inhibitor of cyclin-dependent kinases (CDKs). UCN-01 was originally found to be a PKC-selective protein kinase antagonist. More recent studies have revealed that this agent can also inhibit several CDKs and the checkpoint kinase CHK1. FR901228, MS-27-275 and SAHA are histone deacetylase inhibitors that induce changes in the transcription of specific genes via the hyperacetylation of histones. The proteasome inhibitor PS-341 disrupts the degradation process of intracellular proteins, including cell cycle regulatory proteins such as cyclins. R115777, SCH66336 and BMS-214662 are non-peptidic farnesyl transferase inhibitors that prevent p21 ras oncogene activation. Rapamycin derivative CCI-779 downregulates signals through S6 kinase and FRAP (FKBP-rapamycin associating protein), affecting the expression levels of mRNAs important for progression from G1 to S phase. 17-Allylaminogeldanamycin targets the Hsp-90 (heat shock protein-90) family of cellular chaperones regulating the function of signaling proteins. TNP-470 (AGM-1470), a fumagillin derivative shows antiangiogenic action through binding to MetAP-2 (methionine aminopeptidase-2). The antitumor sulfonamide E7070, causing a cellular accumulation in the G1 phase, has been shown to suppress the activation of CDK2 and cyclin E expression in HCT116 colorectal cancer cell line highly sensitive to the drug. With respect to several growth factor receptors such as EGFR, PDGFR, bFGFR and VEGFR, potent and specific inhibitors of receptor tyrosine kinases have been also examined as hopeful drug candidates. In this report, we review the current status of extensive efforts directed towards the discovery and development of new chemotherapeutic anticancer agents targeting cell cycle regulation in the G1 phase, with particular focus on the compounds undergoing clinical investigations.
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PMID:Cell cycle regulation in the G1 phase: a promising target for the development of new chemotherapeutic anticancer agents. 1156 78

We analyzed H-ras protein expression in 38 human colon cancers and the paired normal tissues. H-ras levels were significantly higher in the malignant tumor (average 0.19+/-0.27) than in its normal adjacent tissues (average 0.06+/-0.15) (p<0.05). The H-ras protein expressed in colon carcinomas contained activated form of H-ras without mutation, based on the findings obtained by RBD-binding (ras binding domain of Raf protein) assay and PCR-SSCP analysis. In addition, we found that H-ras expression was higher in female patients than male, and in cancers with distant metastasis compared to those with non-distant metastasis. Good correlation between H-ras expression levels and those of the upstream and downstream signaling proteins of EGFR, MEK and ERK was found, suggesting that H-ras may play a significant role in carcinogenesis of colorectal cancer.
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PMID:Upregulation of non-mutated H-ras and its upstream and downstream signaling proteins in colorectal cancer. 1160 75

In the last 50 years, 5-fluorouracil-based therapy has been the mainstay of adjuvant and palliative treatment for colorectal cancer but response rates and median survival have been dismal despite the introduction of thymidylate synthase modulators such as leucovorin. Recently, new therapeutic approaches have been introduced. These include oral 5-fluorouracil analogues, pure thymidylate synthase inhibitors, dihydropyrimidine dehydrogenase inhibitors, and agents with mechanism of action unrelated to thymidylate synthase such as irinotecan, a topoisomerase I inhibitor, and oxaliplatin, the only platinum derivative with significant activity in colorectal cancer. Current treatment strategies involve combination therapies because this approach is the most effective. For instance, responses observed with oxaliplatin and 5-fluorouracil indicate synergy between the two agents and the combination of capecitabine plus oxaliplatin or irinotecan has shown high activity both in chemotherapy-naive and in pretreated patients with advanced colorectal cancer. Additionally, it is likely that future therapeutic management of advanced colorectal cancer may include combination therapy of one of the new oral 5-fluorouracil analogues, because of the convenient oral regimens. The identification of colorectal cancer-specific prognostic factors will undoubtedly influence treatment decisions. For instance, patients overexpressing epidermal growth factor receptor and p53 with thymidylate synthase have a worse prognosis. To target these biomarkers, antibodies such as cetuximab, an anti-EGFR antibody, and angiogenesis inhibitors and tyrosine kinase inhibitors have been introduced and are undergoing clinical evaluation. Over the last 5 years the armamentarium to fight colorectal cancer has increased significantly, giving more hope for effective disease management.
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PMID:The role of oxaliplatin in the treatment of advanced metastatic colorectal cancer: prospects and future directions. 1242 6

The epidermal growth factor (EGF) receptor and its various ligands (EGF, TGF-alpha, amphiregulin, heparin-binding (HB)-EGF, heregulin, betacellulin) seem to be involved in the growth regulation of intestinal mucosa and might be related to the development and progression of gastrointestinal tumors. However, few quantitative data investigating the impact of tumor-EGF receptor levels in gastrointestinal carcinomas on tumor stage and prognosis are available. Therefore, EGF receptors were quantitatively determined in colorectal carcinomas in comparison to adjacent normal mucosa by 125I[EGF]-binding studies. EGFR capacity was increased in advanced invasive colorectal carcinomas (T1/2 vs. T3/4 tumors, p<0.001) and advanced UICC stages (UICC I vs. UICC II/III, p<0.001). These findings were confirmed with quantitative 125[I]EGF autoradiography performed on frozen tissue slides and analyzed by laser densitometry (p=0.020). EGF receptor analysis with immunohistochemistry with EGFR antibodies directed against the extracellular domain of the receptor was not correlated with tumor invasion or prognosis. mRNA-expression of EGFR ligands was investigated using semiquantitative RT-PCR amplification using specific primers. RT-PCR transcripts of EGFR ligands (EGF, TGF-alpha, HB-EGF, and amphiregulin) were detected in both carcinomas and normal mucosa, indicating that autocrine growth stimulation of colorectal carcinomas is mediated by coexpression of EGF receptor ligands and upregulation of EGF receptors. Survival of colorectal cancer patients with increased tumor EGF receptor levels was significantly reduced in comparison to patients with low/unchanged tumor EGF receptor levels (mean survival+/-SD, 36.2+/-4.0 vs. 46.8+/-4.3 months; p=0.017). Further studies investigating EGF receptor levels in gastric cancer patients have shown that increased tumor EGF receptor levels were associated with poor prognosis in gastric cancer patients with tumors localized distal from the cardia. Several specific EGF receptor tyrosine kinase inhibitors have recently entered clinical phase I-III studies, with promising antitumor effects in several tumors, including gastrointestinal cancer. Therefore, patients with invasive gastric or colorectal carcinomas might benefit from therapies specifically blocking EGFR-mediated signal transduction.
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PMID:Clinical implications of the EGF receptor/ligand system for tumor progression and survival in gastrointestinal carcinomas: evidence for new therapeutic options. 1279 Mar 26

Over-expression of cyclooxygenase-2 (COX-2) has been demonstrated to be tumorigenic in transgenic mice. Chronic treatment with NSAIDs is chemoprotective for colorectal cancer. Gastrin is a growth factor for gastric mucosa and has been shown to promote proliferation of colorectal cells. Recent studies suggest that COX-2 expression levels could mediate the growth effects of gastrin. Here, we report that gastrin increased PGE2 secretion in Swiss 3T3 cells expressing the CCK2 receptor. Gastrin dose dependently induced COX-2 protein levels in a time dependent manner. COX-2 mRNA levels were rapidly induced by a dose dependent increase in gastrin. Prior treatment of the cells with the CCK2 receptor specific antagonist, L365,260, inhibited gastrin-induced COX-2 protein and mRNA expression. Pretreatment with L364,714, the CCK1 receptor specific antagonist did not block COX-2 induction by gastrin. Inhibition of de novo protein synthesis by cycloheximide did not block COX-2 mRNA induction by gastrin. Also, gastrin-dependent COX-2 expression did not require PKC activity, activation of ERK, or transactivation of EGFR. However, co-stimulation with EGF and gastrin synergistically induced COX-2 protein and mRNA expression and PGE2 secretion. Measurements of COX-2 mRNA stability and COX-2 gene transcription reveal that EGF significantly increased the half-life of COX-2 mRNA with only a slight increase in the COX-2 transcription rate. Conversely, gastrin significantly increased COX-2 gene transcription rates but did not enhance COX-2 mRNA stability.
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PMID:Gastrin and EGF synergistically induce cyclooxygenase-2 expression in Swiss 3T3 fibroblasts that express the CCK2 receptor. 1289 2


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