Showing papers by "Hebron University published in 2005"

Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer

Abstract: The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation of the EGFR leads to enhanced proliferation and other tumor-promoting activities, which provide a strong rationale to target this receptor family. There are two classes of anti-EGFR agents: monoclonal antibodies (MAbs) directed at the extracellular domain of the receptor and small molecule, adenosine triphosphate-competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR MAbs have shown antitumor activity in advanced colorectal carcinoma, squamous cell carcinomas of the head and neck, non-small-cell lung cancer (NSCLC) and renal cell carcinomas. The tyrosine kinase inhibitors (TKIs) have a partially different activity profile. They are active against NSCLC, and a specific EGFR inhibitor has shown improvement in survival. Recently, mutations and amplifications of the EGFR gene have been identified in NSCLC and predict for enhanced sensitivity to anti-EGFR TKIs. In addition to specific anti-EGFR TKIs, there are broader acting inhibitors such as dual EGFR HER-2 inhibitors and combined anti-pan-ErbB and antivascular endothelial growth factor receptor inhibitors. Current research efforts are directed at selecting the optimal dose and schedule and identifying predictive factors of response and resistance beyond EGFR gene mutations and/or amplifications. Finally, there is a need for improved strategies to integrate anti-EGFR agents with conventional therapies and to explore combinations with other molecular targeted approaches including other antireceptor therapies, receptor-downstream signaling transduction inhibitors, and targeted approaches interfering with other essential drivers of cancer, such as angiogenesis.

Phase II Multicenter Study of the Antiepidermal Growth Factor Receptor Monoclonal Antibody Cetuximab in Combination With Platinum-Based Chemotherapy in Patients With Platinum-Refractory Metastatic and/or Recurrent Squamous Cell Carcinoma of the Head and Neck

Abstract: Purpose To evaluate the efficacy and safety of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods Ninety-six eligible patients received cetuximab (initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2) followed by platinum chemotherapy at the same dose and schedule at which progressive disease was documented before entry onto the study. Results The response rate, based on an independently read assessment, in the intent-to-treat population was 10%, with a disease control rate (complete response, partial response [PR], and stable disease) of 53%. The median time to progression and overall survival were 85 and 183 days, respectively; both were longest in patients achieving a PR (median, 203.5 and 294 days, respectively). Treatment was well tolerated. The most common cetuximab-related adv...

Phase II Study of Efficacy, Safety, and Pharmacokinetics of Trastuzumab Monotherapy Administered on a 3-Weekly Schedule

Abstract: Purpose This phase II study investigated the efficacy, safety, and pharmacokinetics of trastuzumab monotherapy given as first-line treatment once every 3 weeks (3-weekly) in women with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC). Patients and Methods Patients with previously untreated HER2-positive MBC received a loading dose of trastuzumab, 8 mg/kg intravenously (IV) and then 6 mg/kg IV at 3-week intervals until disease progression or patient withdrawal. Results In total, 105 patients received a median of five cycles of therapy (range, 1 to 35+). The overall response rate was 19% (23% in patients with measurable centrally confirmed immunohistochemistry [IHC] 3+ and/or fluorescence in situ hybridization [FISH] -positive disease) and clinical benefit rate (complete and partial responses plus stable disease for at least 6 months) was 33% (36% in patients with measurable centrally confirmed IHC 3+ and/or FISH-positive disease). Median time to progression was 3.4 m...

Phase II and Tumor Pharmacodynamic Study of Gefitinib in Patients with Advanced Breast Cancer

Abstract: Purpose To evaluate the antitumor activity and pharmacodynamic/biologic effect of gefitinib 500 mg/day monotherapy in patients with previously treated, advanced breast cancer. Methods In this phase II multicenter trial, the primary objective was assessment of the tumor response rate with gefitinib; secondary objectives included analysis of the pharmacodynamic and biologic profiles in healthy and tumor tissue. Results Of 31 assessable patients, 12 (38.7%) had stable disease, including 3 (9.7%) with recurrent breast cancer that stabilized for ≥ 6 months. No complete or partial responses were observed. Pretreatment tumor samples were available in all patients. In addition, paired baseline and on-treatment (day 28) assessable skin and tumor biopsies were available in 27 and 16 patients, respectively. Sequential immunohistochemical studies in skin and tumor biopsies demonstrated complete inhibition of epidermal growth factor receptor (EGFR) phosphorylation in both healthy and malignant tissues. The downstream ...

The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies.

Abstract: The use of epidermal growth factor receptor (EGFR) inhibitors for the treatment of solid tumours is increasing. However, the tolerability profile for EGFR-inhibitors, such as the monoclonal antibody cetuximab and the tyrosine kinase inhibitor erlotinib, is characterised by a unique group of skin reactions dominated by an acneiform eruption, xerosis, eczema and changes in the hair and nails. The possibility that this skin toxicity correlates with anti-tumour activity offers the potential to titrate dosing on a case-by-case basis. These skin effects may constitute a significant obstacle to treatment compliance. Accordingly, there is a need for consistent, multi-disciplinary management strategies that will allow patients to receive the recommended dosages of such targeted therapies. The eruption responds well to some acne therapies and xerosis can be controlled by standard emollients. Here we present an overview of the treatment options for skin reactions that are available today, and evaluate some of the ways in which the treatment of such EGFR-inhibitor-related skin reactions may be improved in the future. Evidence-based studies are needed to determine the best way to manage these effects.

Ectodomain shedding of the hypoxia-induced carbonic anhydrase IX is a metalloprotease-dependent process regulated by TACE/ADAM17.

Abstract: Carbonic anhydrase IX (CA IX) is a transmembrane protein whose expression is strongly induced by hypoxia in a broad spectrum of human tumours. It is a highly active enzyme functionally involved in both pH control and cell adhesion. Its presence in tumours usually indicates poor prognosis. Ectodomain of CA IX is detectable in the culture medium and body fluids of cancer patients, but the mechanism of its shedding has not been thoroughly investigated. Here, we analysed several cell lines with natural and ectopic expression of CA IX to show that its ectodomain release is sensitive to metalloprotease inhibitor batimastat (BB-94) and that hypoxia maintains the normal rate of basal shedding, thus leading to concomitant increase in cell-associated and extracellular CA IX levels. Using CHO-M2 cells defective in shedding, we demonstrated that the basal CA IX ectodomain release does not require a functional TNFα-converting enzyme (TACE/ADAM17), whereas the activation of CA IX shedding by both phorbol-12-myristate-13-acetate and pervanadate is TACE-dependent. Our results suggest that the cleavage of CA IX ectodomain is a regulated process that responds to physiological factors and signal transduction stimuli and may therefore contribute to adaptive changes in the protein composition of tumour cells and their microenvironment.

Interferon-beta 1b in the treatment of multiple sclerosis.

Abstract: Ever since IFN-β1b was first approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) in the US and Europe, other disease-modifying drugs have become available. Phase III clinical trials have shown the efficacy of IFN-β1b in the treatment of RRMS and secondary progressive MS in that it can reduce the annual relapse rate as well as magnetic resonance imaging parameters of activity and progression. There is mounting evidence that the best time to initiate treatment is early in the course of the disease, and available data suggest that efficacy is sustained for at least 5 years. IFN-β1b is safe and well tolerated, although there are adverse events such as the flu-like complex and skin reactions. In the face of a proportion of RRMS patients experiencing a poor response to the drug, other therapeutic approaches need to be considered.

Basic Mechanisms in Intracranial Large-Artery Atherosclerosis: Advances and Challenges

Abstract: Intracranial large-artery atherosclerosis is a major cause of ischemic stroke worldwide. Patients affected by this disease are at a high risk of suffering recurrent ischemic events despite antithrombo

Survey of traumatic brain injury management in European Brain-IT centres year 2001.

Abstract: Background The aim of this study was to obtain basic knowledge about the current local conditions and neurointensive care of traumatic brain injury (TBI) in the new multi-centre collaborative BrainIT group

Matrix metalloproteases and tumor invasion.

Abstract: A new study shows that a matrix metalloprotease cleaves the protease-activated receptor 1, thereby stimulating the migration and invasion of cancer cells.

N-terminal cleavage of proTGFα occurs at the cell surface by a TACE-independent activity

Abstract: ProTGFα (transforming growth factor α precursor) maturation and conversion into soluble TGFα is a complex process that involves three proteolytic steps One, that occurs co-translationally, eliminates the signal sequence Another, occurring at the juxtamembrane domain, solubilizes TGFα A third cleavage removes the N-terminal extension of proTGFα This latter step has been poorly studied, mainly because of the rapid kinetics of this cleavage In the present study, we have designed a strategy to analyse several aspects regarding this N-terminal cleavage In vivo treatment with the hydroxamate-based metalloprotease inhibitors BB3103 or TAPI-2 (tumour necrosis factor-α protease inhibitor 2) reversibly induced accumulation of forms of proTGFα that included the N-terminal extension N-terminal shedding was rapid, and occurred at the cell surface However, the machinery responsible for the N-terminal cleavage was inactive in other cellular sites, such as the endoplasmic reticulum Experiments of proTGFα expression and maturation in cells deficient in TACE (tumour-necrosis-factor-α-converting enzyme) activity indicated that this protease was dispensable for N-terminal processing of proTGFα in vivo, but was required for regulated cleavage at the C-terminus These findings indicate that TACE is not involved in N-terminal processing of proTGFα, and suggest differences in the machineries that control the cleavage at both ends of TGFα within its precursor

Usefulness of prostate-specific antigen nadir as predictor of androgen-independent progression of metastatic prostate cancer.

Abstract: The objective of this study was to analyze the value of the nadir level of prostate-specific antigen (PSA) to predict androgen-independent progression (AIP) in metastatic prostate cancer patients after androgen deprivation therapy. In a group of 185 metastatic prostate cancer patients who received androgen deprivation therapy serum PSA was determined every three months until AIP occurred. Multiple regression analysis was performed to define independent clinical and PSA-related predictors of AIP. AIP was assumed to be present after two consecutive increases in serum PSA after the PSA nadir. Independent predictors of the duration of AIP-free survival (less than 12 months versus more than 12 months) were the extent of bone involvement (six or fewer hot spots versus more than six) with an odds ratio (O.R.) of 3.95, Gleason score (7 or less versus more than 7) with an O.R. of 3.47, and PSA nadir (2 microg/L or less versus more than 2 microg/L) with an O.R. of 14.63. AIP was independently predicted by the extent of bone involvement with an O.R. of 1.72, Gleason score with an O.R. of 1.74, PSA nadir with an O.R. of 3.22, and time to reach the PSA nadir (9 months or less versus more than 9 months) with an O.R. of 2.84. When patients were stratified according to these predictors, those with three good prognostic factors had a median AIP-free survival of 58 months while those with two, one or no good prognostic factors had a median AIP-free survival of 19 months, 12 months and 7 months, respectively. We conclude that the PSA nadir seems to be a good predictor of AIP in patients with metastatic prostate cancer after androgen deprivation therapy. Time to PSA nadir, extent of bone involvement and Gleason score are also independent predictors. The combination of these prognostic factors allows to stratify metastatic prostate cancer patients for the prediction of AIP.

Does epidermal growth factor receptor status predict activity of cetuximab in colorectal cancer patients

Abstract: Does epidermal growth factor receptor status predict activity of cetuximab in colorectal cancer patients?

Irreversible pan-ErbB tyrosine kinase inhibitor CI-1033 induces caspase-independent apoptosis in colorectal cancer DiFi cell line.

Abstract: The epidermal growth factor receptor (EGFR) is overexpressed in the majority of colorectal carcinomas and represents a target for therapeutic interventions with signal transduction inhibitors. We investigated the ability of CI-1033 to induce apoptosis and inhibition of proliferation in the colorectal cancer cell lines DiFi and Caco-2, which both express high levels of EGFR. While in Caco-2 cells CI-1033 treatment at a concentration 0.1 μ M for 72 hours demonstrated only antiproliferative (53.7 ± 4.3%) but no pro-apoptotic effects, treatment of DiFi cells resulted in a reduced proliferation rate (31.4 ± 3.1%) and in apoptosis (44.2 ± 8.9%). In order to define proteins involved in the regulation of apoptosis, we aimed to determine differences in the proteome profile of both cell lines before and after treatment with CI-1033. Cellular proteins were analyzed by 2-D gel electrophoresis followed by computational image analysis and mass spectrometry. Our data show that DiFi cells differ from Caco-2 cells in nine significantly upregulated proteins, and their potential role in apoptosis is described. We demonstrate that induction of apoptosis was triggered via caspase-independent pathways. Overexpression of leukocyte elastase inhibitor (LEI) and translocation of cathepsin D to the cytosol accompanied by upregulation of other defined proteins resulted in Bax-independent AIF translocation from mitochondria into the nucleus and apoptosis. Definition of these proteins can pave the way for functional studies and contribute to a better understanding of the effects of CI-1033 and the pathways of caspase-independent cell death.

182 Improving Results with Percutaneous Fetal Endoscopic Tracheal Occlusion (FETO) for Severe Left Congenital Diaphragmatic Hernia.

Abstract: 182 Improving Results with Percutaneous Fetal Endoscopic Tracheal Occlusion (FETO) for Severe Left Congenital Diaphragmatic Hernia.

Angiotensin I converting enzyme polymorphism effects in patients with normal pressure hydrocephalus syndrome before and after surgery.

Abstract: Previous reports have suggested an association between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE), cardiovascular disease, and cognitive performance. Normal pressure hydrocephalus (NPH) is considered to be an example of reversible dementia although the clinical improvement after shunting varies from subject to subject. An association has been suggested between vascular risk factors and the development of NPH. The ACE plays a major role in vascular pathology and physiology. In the present study we investigated the distribution of an ACE gene insertion/deletion polymorphism in 112 patients diagnosed with NPH and in 124 controls. We also evaluated the role of this genetic polymorphism in cognitive functioning before and following surgery in a subgroup of 72 patients. No differences in genetic or allele distributions were found between patients and healthy subjects, but among patients, carriers of D/D or D/I genotypes obtained less cognitive benefit following shunt surgery, especially on measures of memory and frontal function. Our data support previous findings in other conditions indicating that possession of at least one D allele is associated with poorer cognitive performance.

Endogenous Mechanisms of Neuroprotection and Neuroregeneration

Abstract: Neurological diseases, both chronic inflammatory and degenerative disorders, such as multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD) have not a definitive cure yet. The functional deficits in these disorders results from dysfunction and death of neurons, and their phenotypes depend on the neuronal population affected and/or the pattern of cell loss . In many neurodegerative diseases, molecular pathogenesis of neuronal death might be a underlying similarity at the cellular level, independently of cell death causes (hereditary compoment, single genetic mutation, immunological-mediated). A historical dogma was that neurons lost in the central nervous system (CNS) are not replaced, contrasting with that occurrs in other adults tissues in which cell loss is balanced by proliferation and differentiation of stem cells . However, accumulated evidences over time suggest otherwise. Probably, a failure of endogenous neuronal stem cells to respond appropiately and replace neurons lost might be a further common mechanism that contributes to functional compromise in neurodegenerative diseases. Although most neurodegenerative diseases are heterogeneous in both their clinical and pathological features, inflammation and neurodegeneration coexist in many of them. MS is a chronic inflammatory demyelinating disease in which inflammatory (myelin and axon destruction) and degenerative (neuronal loss) damage occur , making it a good model of neurodegenerative disease to study endogenous neuroprotective and/or neuroregenerative strategies to promote repair after a harmful insult in the CNS. Neuroprotective inflammation

Targeting of the EGFR As a Modulator of Cancer Chemotherapy

Abstract: The epidermal growth factor (EGF) receptor (EGFR) is a tyrosine kinase receptor of the ErbB family that is abnormally activated in many epithelial tumors. In human tumors, receptor overexpression correlates with a more aggressive clinical course. These observations suggest that the EGFR is a promising target for cancer therapy, and monoclonal antibodies directed at the ligand-binding extracellular domain and low molecular weight (MW) inhibitors of the receptor’s tyrosine kinase inhibitors (TKI) are currently in advanced stages of clinical development. These agents prevent ligand-induced receptor activation and downstream signaling, which results in cell-cycle arrest, promotion of apoptosis, and inhibition of angiogenesis. In preclinical models, these agents markedly enhance the antitumor effects of chemotherapy and radiation therapy. In patients, anti-EGFR agents can be given safely at doses that fully inhibit receptor signaling, and single-agent activity has been observed against a variety of tumor types, including colon carcinoma, non-small-cell lung cancer (NSCLC), head and neck cancer, ovarian carcinoma, and renal-cell carcinoma. However, their antitumor activity is significant but modest, and to improve their efficacy, ongoing research efforts are being directed at the selection of patients with EGFR-dependent tumors, identification of the differences among the various classes of agents, and new clinical development strategies. One such strategy, derived from the preclinical models, is to combine these agents with chemotherapy. Clinical trials of anti-EGFR agents in combination with chemotherapy have been conducted or are underway in a variety of tumor types and in different clinical settings. In NSCLC, a series of well-supported multinational phase III clinical trials have shown that the combined therapy with chemotherapy and anti-EGFR TKI is not superior to chemotherapy alone. On the other hand, in advanced colorectal cancer, the combined treatment with anti-EGFR monoclonal antibodies and conventional chemotherapy was found to be statistically superior in terms of disease-free survival when compared with chemotherapy alone. In addition, in smaller trials, the addition of anti-EGFR monoclonal antibodies to chemotherapy does result in a higher antitumor response rate than with chemotherapy alone. Taken together, anti-EGFR agents are active antitumor agents, and the optimal way to combine these agents with conventional chemotherapy is still to determined and likely to be agent and tumor-type dependent. Intensive clinical research on how best to integrate these agents into treatment is warranted.

183 Lung-To-Head Ratio and Liver Position to Predict Outcome in Early Diagnosed Isolated Left Sided Diaphragmatic Hernia Fetuses: A Multicenter Study.

Abstract: Objective: In utero diagnosed congenital diaphragmatic hernia (CDH) is associated to high antenatal and neonatal loss rates. Accurate prediction of outcome is crucial in counselling parents about management options. We evaluated Lung-to-Head Ratio (LHR) and liver position in prediction of outcome of isolated Left CDH.