Prognostic significance of HER3 and HER4 protein expression in colorectal adenocarcinomas

BACKGROUND: Colorectal cancer remains a major cause of cancer mortality in the Western world. A limited number of studies has been conducted in respect of Her-3 and Her-4 expression and their correlation with clinical parameters and prognosis in colorectal carcinomas . In this study we sought to determine the pattern and the prognostic significance of HER-3 and HER-4 in colorectal adenocarcinoma. METHODS: We studied HER-3 and HER-4 protein expression in106 paraffin embedded specimens of primary colorectal tumors using immunohistochemistry. The pattern and protein expression levels of HER-3 and HER-4 were correlated with several clinical and pathological parameters. RESULTS: HER-3 staining displayed membranous and cytoplasmic expression pattern in 18 (17%) and 30 samples (28,3%), respectively. HER-4 membranous and cytoplasmic expression was found in 20 (18,9%) and 32 samples (30,2%), respectively. Specimens regarded as positive for HER-3 cytoplasmic expression were associated with moderate tumor grade (p = 0,032) and older median age (p = 0,010). Specimens regarded as positive for HER-4 membranous protein expression were associated with involved lymphnodes (p = 0,0003). Similar results were obtained when considering Her-3 and Her-4 protein expression irrespective of their cellular localization. There was no correlation between the expression of HER-3 and HER-4 and patients outcome. CONCLUSION: HER-4 membranous protein expression was found to predict for lymph nodes positivity in this cohort of patients with colorectal cancer.HER-4 expression status may identify tumors with aggressive biological behavior and increased metastatic potential

Cetuximab potentiates oxaliplatin cytotoxic effect through a defect in NER and DNA replication initiation

Preclinical studies have demonstrated that the chemotherapeutic action of oxaliplatin, a third generation platinum derivative, is improved when combined with cetuximab, a monoclonal antibody inhibitor of epidermal growth factor receptors. To explore the mechanism of this synergistic benefit, we used HCT-8 and HCT-116, two human colon cancer cell lines, respectively, responsive and non-responsive to the oxaliplatin/cetuximab combination. We examined the effect of drug exposure on glutathione-S-transferase-mediated oxaliplatin detoxification, DNA–platinum adducts formation, cell cycle distribution, apoptosis, and the expression of multiple targets involved in DNA replication, recombination, and repair. The major changes we found in HCT-8 were a stimulation of oxaliplatin–DNA adduct formation associated with reduced expression of the key enzyme (excision repair cross complementation group1: ERCC1) in the key repair process of oxaliplatin–DNA platinum adduct, the nucleotide excision repair (NER), both at the mRNA and protein levels. We also observed a reduced expression of factors involved in DNA replication initiation, which correlates with an enrichment of cells in the G1 phase of the cell cycle as well as an acceleration of apoptosis. None of these changes occurred in the non-responsive HCT-116 cell that we used as a negative control. These findings support the fact that cetuximab potentiates the oxaliplatin-mediated cytotoxic effect as the result of inhibition of NER and also DNA replication initiation

Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer

Erlotinib (Tarceva™, OSI-774), a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR), was evaluated in a phase II study to assess its activity in patients with metastatic colorectal cancer. In all, 38 patients with metastatic colorectal cancer were treated with erlotinib at a continuous daily oral dose of 150 mg. Radiological evaluation was carried out every 8 weeks and tumour biopsies were performed before treatment and on day 8. Of 31 evaluable patients, 19 (61%) had progressive disease and 12 (39%) had stable disease (s.d.). The median time to progression for those patients having s.d. was 123 days (range 108–329 days). The most common adverse events were rash in 34 patients and diarrhoea in 23 patients. Correlative studies were conducted to investigate the effect of erlotinib on downstream signalling. Tumour tissue correlations were based on usable tissue from eight match paired tumour samples pre- and on therapy, and showed a statistically significant decrease in the median intensity of both pEGFR (P=0.008) and phospho-extracellular signal-regulated kinase (ERK) (P=0.008) a week after commencement of treatment. No other statistically significant change in tumour markers was observed. Erlotinib was well tolerated with the most common toxicities being rash and diarrhoea. More than one-third of evaluable patients had s.d. for a minimum of 8 weeks. Correlative studies showed a reduction in phosphorylated EGFR and ERK in tumour tissue post-treatment

Targeting EGFR and HER-2 with cetuximab- and trastuzumab-mediated immunotherapy in oesophageal squamous cell carcinoma

We previously reported that oesophageal squamous cell carcinoma (SCC) had a relatively high incidence of EGFR and HER-2 overexpression. Thus, anti-HER family targeting may become a promising approach to treat oesophageal SCC. In the present study, we investigated (a) the distribution of EGFR and HER-2 expression in oesophageal SCC (n=66) detected by immunohistochemistry and (b) cetuximab- and/or trastuzumab-mediated biological activity (antiproliferative effect by the MTT assay, apoptosis-inducing activity by the annexin V/propidium iodide assay, and antibody-dependent cellular cytotoxicity (ADCC) by the 51Cr-release assay) against oesophageal SCC cell lines with various levels of EGFR and HER-2. Twelve of the 66 patients (18%) showed both EGFR- and HER-2 expression. Out of both EGFR- and HER-2-positive cases, nine cases (75%) showed EGFR and HER-2 expression in individually distinct regions. Furthermore, the combination of cetuximab and trastuzumab could induce synergistic antiproliferative effects and additional ADCC activities against not all, but several oesophageal SCC cell lines with EGFR and HER-2 expression. The combination of cetuximab and trastuzumab may be useful in the treatment of oesophageal SCC with EGFR and HER-2 expression

From proteomic analysis to potential therapeutic targets: functional profile of two lung cancer cell lines, A549 and SW900, widely studied in pre-clinical research

Lung cancer is a serious health problem and the leading cause of cancer death worldwide. The standard use of cell lines as in vitro pre-clinical models to study the molecular mechanisms that drive tumorigenesis and access drug sensitivity/effectiveness is of undisputable importance. Label-free mass spectrometry and bioinformatics were employed to study the proteomic profiles of two representative lung cancer cell lines and to unravel the specific biological processes. Adenocarcinoma A549 cells were enriched in proteins related to cellular respiration, ubiquitination, apoptosis and response to drug/hypoxia/oxidative stress. In turn, squamous carcinoma SW900 cells were enriched in proteins related to translation, apoptosis, response to inorganic/organic substances and cytoskeleton organization. Several proteins with differential expression were related to cancer transformation, tumor resistance, proliferation, migration, invasion and metastasis. Combined analysis of proteome and interactome data highlighted key proteins and suggested that adenocarcinoma might be more prone to PI3K/Akt/mTOR and topoisomerase IIα inhibitors, and squamous carcinoma to Ck2 inhibitors. Moreover, ILF3 overexpression in adenocarcinoma, and PCNA and NEDD8 in squamous carcinoma shows them as promising candidates for therapeutic purposes. This study highlights the functional proteomic differences of two main subtypes of lung cancer models and hints several targeted therapies that might assist in this type of cancer.publishe

Process for coating fine particles with conductive polymers

A process is disclosed for coating fine particles, in which the feed mixture contains: at least one monomer and/or at least one oligomer selected from monomers and/or oligomers of aromatic compounds and/or unsaturated hydrocarbon compounds suitable for forming an electroconductive oligomer, polymer, copolymer, block copolymer or graft copolymer; at least one type of anions which (1) are and/or can be incorporated as doping ions into the structure of the conductive polymer; (2) can be discharged from said structure in the event of a potential fall of the conductive polymer (reduction); and (3) can have an anti-corrosive effect in the presence of a metallic surface; at least one type of particles; if necessary, at least one oxidising agent and water and/or at least another solvent. A coating is formed from the feed mixture on the particle surface, the feed mixture being converted by oxidation into a conductive polymer in the presence of at least one type of mobile anti-corrosive anions. Alternatively, the fine particles are coated with a product mixture that contains a conductive polymer

Process for coating metallic surfaces with an anti-corrosive coating

A process is disclosed for coating fine particles, in which the feed mixture contains: at least one monomer and/or at least one oligomer selected from monomers and/or oligomers of aromatic compounds and/or unsaturated hydrocarbon compounds suitable for forming an electroconductive oligomer, polymer, copolymer, block copolymer or graft copolymer; at least one type of anions which (1) are and/or can be incorporated as doping ions into the structure of the conductive polymer; (2) can be discharged from said structure in the event of a potential fall of the conductive polymer (reduction); and (3) can have an anti-corrosive effect in the presence of a metallic surface; at least one type of particles; if necessary, at least one oxidising agent and water and/or at least another solvent. A coating is formed from the feed mixture on the particle surface, the feed mixture being converted by oxidation into a conductive polymer in the presence of at least one type of mobile anti-corrosive anions. Alternatively, the fine particles are coated with a product mixture that contains a conductive polymer