Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The data reviewed here have further established the promise of anti-EGFR-targeted therapies. This statement is supported by the evidence of antitumor activity of the TK inhibitors ZD1839 and OSI-774 against several tumor types and by the ability of the monoclonal antibody IMC-C225 to reverse clinical chemotherapy resistance. These results are further supported by an emerging number of compounds, monoclonal antibodies, and TK inhibitors directed at the EGFR that are in clinical development (see Fig. 2, Table 1). Among the TK inhibitors, these compounds can be further categorized by their receptor specificity and reversibility of binding. In the case of anti-EGFR monoclonal antibodies, compounds in clinical development include chimeric, humanized, and bispecific antibodies. The fundamental observation is that these compounds have shown activity in several tumor types, including NSCL cancer, prostate carcinoma, colorectal carcinoma, ovarian carcinoma, renal cell carcinoma, and head and neck cancers. These findings observed with different agents and in different tumor types validate EGFR as a target for cancer therapy. The results of ongoing studies with these agents in diverse indications and tumor types may establish the role of these promising therapies to our current cancer treatments.
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PMID:Epithelial growth factor receptor interacting agents. 1251 82

In women with CIN at fertile age and those over 50 years of age, EGFR expression is lower in the presence of Chlamydia trachomatis (Cht) infection. In all Cht infected women over 50 years of age expression of Ki 67 is higher; the increase is significant among women with invasive carcinoma. In these groups of women with CIN and invasive carcinoma TGF-alpha expression is insignificantly augmented. Chronic Cht infection is associated with cervical hypertrophy.
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PMID:Chlamydia trachomatis infection in women with CIN and invasive uterine cervix cancer. Significance of hormonal status. 1255 93

For more than a decade, the de facto "standard of care" for palliative mangement of recurrent head/neck squamous carcinoma (HNSCC) has been the combination of cisplatin/5-flourouracil. With the advent of new cytotoxins, such as the taxanes, and of the molecularly targeted agents, eg., the EGFR inhibitors, the number of options for treatment in this setting has increased. However, none of these new approaches has yet been proven to be more effective than cisplatin/5-fluorouracil. Further, despite the pallitive intent of therapy in this setting, the palliative effects have been only infrequently assessed, with many studies relying on response as a surrogate for palliation. This chapter will focus on clinical and translational research efforts in the past decade focusing on the patient with incurable locoregionally recurrent or metastatic HNSCC. Ongoing and planned future trails will also be discussed.
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PMID:Treatment of metastatic head and neck cancer: chemotherapy and novel agents. 1261 47

Hybridization with cDNA arrays was used to obtain expression profiles of 263 protein-tyrosine kinase (PTK), protein-tyrosine phosphatase (PTP), dual-specific phosphatase (DuSP), and other genes for the normal prostate tissue, primary prostate carcinomas (PC) of 84 patients, 7 xenografts, and 5 carcinoma cell lines. Analysis of 96 profiles revealed eight clusters of genes coexpressed in PC (coefficient of correlation r > 0.7). According to the known functions of their genes, the clusters were designated as proliferating-cell (CDC42, TOP2A, FGFR3, MYC, etc.), neoangiogenesis and blood-cell (LCK, VAV1, KDR, VEGF, MMP9, SYK, PTPRS, and FLT4), invasion-1 and invasion-2 (ADAM17, TRPM2, DUSP6, VIM, CAV1, CAV2, JAK1, PTPNS1, FYN, and PDGFB), HER2, and PSA/PSM/HER3. Basing on expression profiles of 66 genes, a molecular classification of PC was constructed and allowed discrimination between PC and cell lines or xenografts at 98.9% probability. The results suggested that, along with PSA, PSM (FOLH1), kallikrein-2, and a-2-macroglobulin, cell signaling genes EGFR, HER2, HER3, TOP2, KRT8, KRT18, VEGF, CD44, VIM, CAV1, and CAV2 may serve as diagnostic and prognostic markers in PC. The HER2, VEGF, and CD44 genes and the MMP and ADAM families were assumed to be promising targets for inhibitors of PC cell proliferation and metastasis.
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PMID:[Gene expression profiles of protein kinases and phosphatases obtained by hybridization with cDNA arrays: molecular portrait of human prostate carcinoma]. 1262 52

This work examined the importance of radiation-induced and ligand-induced EGFR-ERK signaling for the regulation of DNA repair proteins XRCC1 and ERCC1 in prostate carcinoma cells, DU145 (TP53(mut)), displaying EGFR-TGFA-dependent autocrine growth and high MAPK (ERK1/2) activity, and LNCaP (TP53(wt)) cells expressing low constitutive levels of ERK1/2 activity. Using quantitative RT-PCR and Western analyses, we determined that ionizing radiation activated the DNA repair genes XRCC1 and ERCC1 in an ERK1/2-dependent fashion for each cell line. After irradiation, a rapid increase followed by a decrease in ERK1/2 activity preceded the increase in XRCC1/ERCC1 expression in DU145 cells, while only the rapid decrease in ERK1/2 preceded the increase in XRCC1/ERCC1 expression in LNCaP cells. Administration of EGF, however, markedly increased the up-regulation of phospho-ERK, ERCC1 and XRCC1 in both cell lines. Although the EGFR inhibitor tyrphostin (AG-1478) and the MEK inhibitor PD90859 both attenuated EGF-induced levels of the ERCC1 and XRCC1 protein, PD98059 blocked the induction of ERCC1 and XRCC1 by radiation more effectively in both cell lines. Inhibition of ERK at a level that reduced the up-regulation of DNA repair led to the persistence of apurinic/apyrimidinic (AP) sites of DNA damage and increased cell killing. Taken together, these data imply a complex control of DNA repair activation that may be more generally dependent on MAPK (ERK1/2) signaling than was previously noted. These data provide novel insights into the capacity of the EGFR-ERK signaling to modulate DNA repair in cancer cells and into the functional significance of this signaling.
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PMID:Epidermal growth factor and ionizing radiation up-regulate the DNA repair genes XRCC1 and ERCC1 in DU145 and LNCaP prostate carcinoma through MAPK signaling. 1264 88

ZD1839 (Iressa; AstraZeneca Pharmaceuticals LP, Wilmington, DE) is an orally active, selective inhibitor of epidermal growth factor receptor-tyrosine kinase (EGFR-TK) that blocks signaling pathways responsible for driving proliferation, invasion, and survival of cancer cells. In preclinical studies of cell lines and human tumor xenografts, ZD1839 as single-agent therapy produced growth inhibition in a wide variety of common solid tumor types including lung, prostate, breast, colon, and ovarian cancers. In these models, ZD1839 inhibited growth of tumor xenografts with high, moderate, and low expression of EGFR. The A431 vulvar carcinoma model, which expresses abnormally high levels of EGFR, was particularly sensitive to ZD1839 treatment, leading to tumor regression. When ZD1839 was coadministered with cytotoxic chemotherapy agents or radiotherapy, additive or even synergistic antitumor activity was achieved. The inhibition observed with ZD1839 treatment was not restricted to advanced metastatic tumors, but also extended to early lesions such as breast xenografts of human ductal carcinoma in situ. Inhibition of EGFR-TK has also been shown to delay the onset of tumor development in a transgenic animal model. The diverse and profound antitumor activities attained with ZD1839 treatment in tumor cells and in xenograft tumor models provided the rationale for clinical development of ZD1839. Ongoing preclinical studies continue to support the importance of EGFR-TK activity in the biology of solid tumors.
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PMID:Studies with ZD1839 in preclinical models. 1264 80

A case control study of pregnancy/lactation associated breast carcinoma (PAC) was conducted on 24 test cases with two controls per case, matching age, tumor grade, tumor size and axillary lymph nodes status. During seven years of this study, 6% of all patients with breast cancer had PAC. In this study, 67% of the test cases showed positive axillary lymph nodes compared to 49% in our series of 315 cases of non-pregnancy/non-lactating women with breast carcinoma (p < 0.05). The expression of nine prognostic markers, i.e. ER, PR, p53, C-erbB-2, EGFR, Cathepsin-D, PCNA, DNA ploidy and S-phase fraction, were studied by immunohistochemistry and flow cytometry. Hormone receptor status showed a statistically significant difference between the two groups, i.e. 29% immunoreactivity in test cases compared to 58% in controls with a p value of 0.007. Among p53, C-erbB-2, EGFR and Cathepsin-D in the test group, only EGFR showed a significant correlation, i.e. 33% immunoreactivity in test cases and 19% immunoreactivity in controls (p < 0.05). Higher PCNA positivity was seen in the test group compared to controls, i.e. 35% in test patients and 28% in controls (p < 0.05). Metastasis to bone and liver was a common feature of test patients as compared to controls (p < 0.05). After a median follow-up of 72 months, there was no significant difference in the overall survival (OS) of test cases and controls as 54% deaths were recorded in test patients and 44% in controls at the end of this study (p > 0.05). In summary, in spite of some significant differences in the expression of few prognostic markers, i.e. ER/PR, EGFR, PCNA and metastatic potential, there was no significant difference in the OS of PAC vs. control group if compared stage for stage.
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PMID:Case control study of novel prognostic markers and disease outcome in pregnancy/lactation-associated breast carcinoma. 1265 May 13

Human lung carcinogenesis is accompanied by complex chromosomal changes that may be detected in interphase cells by fluorescence in situ hybridization (FISH) assay using recently developed multitarget DNA probes. Touch preparations of 20 non-small cell lung carcinomas, sputum specimens from 3 patients with lung cancer and from 11 ex-smokers without lung cancer, and cultured benign bronchial epithelium of 42 high-risk smokers, 9 of whom had concurrent invasive carcinoma, were tested using a four-color FISH probe (LAVysion) targeting centromere 6, 5p15.2, 7p12 (EGFR), and 8q24 (MYC). Significantly high frequencies of abnormal cells were found in each of the 20 NSCLC (100%) and in the 3 sputum specimens from lung cancer patients. None of the cytologically normal sputa contained FISH abnormalities. Cultured bronchial epithelial cells from 11 of 42 patients (26%) were abnormal for at least one probe. Abnormal FISH patterns had no association with gender, presence of tumor or histology. Multicolor FISH can readily detect chromosomal abnormalities in imprints and sputa from lung carcinomas. Chromosomal aneusomy is also frequent in bronchial epithelial cells from long-term smokers. The prognostic significance of the multicolor LAVysion FISH probe set should be validated in a controlled clinical trial.
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PMID:Chromosomal abnormalities in non-small cell lung carcinomas and in bronchial epithelia of high-risk smokers detected by multi-target interphase fluorescence in situ hybridization. 1270 75

The constitutively active, truncated epidermal growth factor receptor EGFRvIII lacks the ability of EGF binding due to a deletion of the NH(2)-terminal domain. EGFRvIII confers increased tumorigenicity, is coexpressed with EGFR wild type (wt) in human carcinoma and malignant glioma cells when grown as xenografts, but is not expressed in vitro. The effects of EGFRvIII expression on cellular radiation responses were studied in Chinese hamster ovary (CHO) cells transfected with plasmids expressing EGFRvIII (CHO.EGFRvIII) or EGFRwt (CHO.EGFRwt). CHO cells expressing similar levels of either receptor were employed to define their roles in response to EGF and ionizing radiation. EGF activated EGFRwt with no effect on EGFRvIII. In contrast, a single radiation exposure of 2 Gy resulted in a 2.8- and 4.3-fold increase in Tyr phosphorylation of EGFRwt and EGFRvIII, respectively. Downstream consequences of this radiation-induced activation were examined by inhibiting EGFRwt and EGFRvIII with AG1478 (kinase inhibitor). The radiation-induced 8.5-fold activation of the pro-proliferative mitogen-activated protein kinase and the 3.2-fold stimulation of the antiapoptotic AKT/phosphatidylinositol-3-kinase pathways by EGFRvIII far exceeded that in CHO.EGFR wt cells. Thus, based on colony formation and apoptosis assays, EGFRvIII expression conferred a stronger cytoprotective response to radiation than EGFRwt, resulting in relative radioresistance. Therefore, disabling EGFRvIII in addition to EGFRwt needs to be considered in any therapeutic approach aimed at targeting EGFR for tumor cell radiosensitization.
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PMID:EGFRvIII-mediated radioresistance through a strong cytoprotective response. 1294 1

Different cellular signal transduction cascades are affected by environmental stressors (UV-radiation, gamma-irradiation, hyperosmotic conditions, oxidants). In this study, we examined oxidative stress-evoked signal transduction pathways leading to activation of STATs in A431 carcinoma cells. Oxidative stress, initiated by addition of H2O2 (1-2 mM) to A431 cells, activates STAT3 and, to a lesser extent, STAT1 in dose- and time-dependent manner. Maximum phosphorylation levels were observed after a 2 minutes stimulation at 1-2 mM H2O2. Phosphorylation was blocked by AG1478, a pharmacological inhibitor of the epidermal growth factor receptor tyrosine kinase, implicating intrinsic EGF receptor tyrosine kinase in this process. Consistent with this observation, H2O2-stimulated EGFR tyrosine phosphorylation was abolished by specific Src kinase family inhibitor CGP77675, implicating Src in H2O2-induced EGFR activation. An essential role for Src and JAK2 in STATs activation was suggested by three findings. 1. Src kinase family inhibitor CGP77675 blocked STAT3 and STAT1 activation by H2O2 in a concentration-dependent manner. 2. In Src-/-fibroblasts, activation of both STAT3 and STAT1 by H2O2 was significantly attenuated. 3. Inhibiting JAK2 activity with the specific inhibitor AG490 reduced the level of H2O2-induced STAT3 phosphorylation, but not STAT1 in A431 cells. These data show essential roles for Src and JAK2 inactivation of STAT3. In contrast, H2O2-mediated activation of STAT1 requires only Src kinase activity. Herein, we postulate also that H2O2-induced STAT activation in carcinoma cells involves Src-dependent EGFR transactivation.
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PMID:[STAT1 and STAT3 activation by oxidative stress in A431 cells involves Src-dependent EGF receptor transactivation]. 1452 Oct 54


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