Twenty-year results of the Naples GUN randomized trial: predictive factors of adjuvant tamoxifen efficacy in early breast cancer.

Purpose: Tamoxifen (TAM) is increasingly administered to new early breast cancer patients. Because it is not devoid of toxic effects, we studied factors potentially predictive of its efficacy.

Experimental Design: From 1978 to 1983, 433 patients were enrolled in the GUN randomized trial: 206 were assigned to TAM versus 227 controls (no-TAM).

Critical role of both p27KIP1 and p21CIP1/WAF1 in the antiproliferative effect of ZD1839 ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, in head and neck squamous carcinoma cells.

High expression of the epidermal growth factor receptor (EGFR) has been implicated in the development of squamous-cell carcinomas of head and neck (SCCHN). ZD1839 ('Iressa') is an orally active, selective EGFR-TKI (EGFR-tyrosine kinase inhibitor) that blocks signal transduction pathways implicated in proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. We have demonstrated that ZD1839 induces growth arrest in SCCHN cell lines by inhibiting EGFR-mediated signaling.

Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa).

Purpose: The epidermal growth factor receptor (EGFR) is expressed in the majority of human epithelial cancers and has been implicated in the development of cancer cell resistance to cyotoxic drugs and to ionizing radiation.

Experimental Design: We used ZD1839, a selective small molecule EGFR tyrosine kinase inhibitor currently in clinical development. We tested the antiproliferative and the proapoptotic activity of ZD1839 in combination with ionizing radiation in human colon (GEO), ovarian (OVCAR-3), non-small cell lung (A549 and Calu-6), and breast (MCF-7 ADR) cancer cell lines.

Theophylline-induced apoptosis is paralleled by protein kinase A-dependent tissue transglutaminase activation in cancer cells.

It has been reported that theophylline induces growth inhibition and apoptosis in tumour cells. We report that theophylline induces growth inhibition and apoptosis of several human epithelial tumour cells with an IC:50 of 2.5 mM after 48 h of exposure.

Cardiac ankyrin repeat protein, a negative regulator of cardiac gene expression, is augmented in human heart failure.

The technique of representational difference analysis of cDNA has been applied to screen for differentially expressed genes in a canine model of pacing-induced heart failure. We identified the canine homolog of the cardiac ankyrin repeat protein (CARP) which has been shown to be involved in the regulation of the transcription of cardiac genes. To confirm the significance for human heart failure, cardiac tissue specimens obtained from non-failing donor hearts and from explanted hearts from patients with end-stage heart failure were investigated.

The effects of ageing on the response to cardiac surgery: protective strategies for the ageing myocardium.

Unlabelled: With ageing of the general population, increasing numbers of elderly patients are presenting for interventional cardiac treatment such as cardiac surgery, angioplasty and thrombolysis. However, the results of these interventions in the elderly are inferior to those in the young. A likely contributing factor is an age-related reduction in cellular energy production in the myocardium during interventions that induce aerobic or ischaemic stress.

Cardiac membrane fatty acid composition modulates myocardial oxygen consumption and postischemic recovery of contractile function.

Background: Regular fish consumption is associated with low cardiovascular disease morbidity and mortality. Fish oils modify cardiac membrane phospholipid fatty acid composition with potent antiarrhythmic effects. We tested the effects of dietary fish oil on ventricular hemodynamics and myocardial oxygen consumption (MVO2).

Preclinical and phase I study of oxaliplatin and topotecan in combination in human cancer.

Background: DNA damage caused by platinum agents is frequently followed by induction of topoisomerase I, providing a rationale for use of platinum-based compounds with topoisomerase I inhibitors.

Materials And Methods: We studied the effect of a sequential schedule of oxaliplatin on day I and topotecan on days 2-5, in human colon and ovarian cancer cells in vitro, in nude mice bearing human cancer xenografts and finally in cancer patients in a phase I trial.

Results: We demonstrated a supra-additive effect of this combination on inhibition of colony formation and induction of apoptosis in vitro.

Coenzyme Q10 protects the aging heart against stress: studies in rats, human tissues, and patients.

With aging of the population, increasing numbers of elderly patients are presenting for cardiac surgery. However, the results in the elderly are inferior to those in the young. A likely contributing factor is an age-related reduction in cellular energy production in the myocardium during surgery, which is known to induce aerobic and ischemic stress.

Similar therapeutic serum levels attained with emulsified and oil-based preparations of coenzyme Q10.

Studies of the therapeutic efficacy of coenzyme Q10 (CoQ10) have been confounded by the variable bioavailability of numerous CoQ10 preparations. The aims of the present study were to determine the early serum levels attained by two different preparations of CoQ10, a soybean oil-based preparation and a complex micelle emulsion and to assess whether these preparations of oral CoQ10 influence plasma lipid profiles. Twelve healthy individuals received 300 mg CoQ10 daily of either preparation for 7 days in a double-blind cross-over design with a 21-day washout period.

Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes.

Stretching of cardiac muscle modulates contraction through the enhancement of the Ca2+ transient, but how this occurs is still not known. We found that stretching of myocytes modulates the elementary Ca2+ release process from ryanodine-receptor Ca2+-release channels (RyRCs), Ca2+ sparks and the electrically stimulated Ca2+ transient. Stretching induces PtdIns-3-OH kinase (PI(3)K)-dependent phosphorylation of both Akt and the endothelial isoform of nitric oxide synthase (NOS), nitric oxide (NO) production, and a proportionate increase in Ca2+-spark frequency that is abolished by inhibiting NOS and PI(3)K.

The old heart: operating on the edge.

Excitation of cardiac cells is accompanied by Ca2+ influx which triggers a transient increase in cytosolic [Ca2+], (Cai), and contraction. While the amplitudes of the Cai transient and contraction increase with the extent of cell Ca2+ loading, excess Ca2+ loading leads to dysregulation of Ca2+ homeostasis, impaired contraction, arrhythmia and cell death. The cell Ca2+ load is determined by membrane structure and permeability characteristics, the intensity of stimuli that modulate Ca2+ influx or efflux via regulatory function of proteins within membranes, and reactive oxygen species (ROS), which affect both membrane structure and function.

Cardioplegic strategies for calcium control: low Ca(2+), high Mg(2+), citrate, or Na(+)/H(+) exchange inhibitor HOE-642.

Background: Ca(2+) overload plays an important role in the pathogenesis of cardioplegic ischemia-reperfusion injury. The standard technique to control Ca(2+) overload has been to reduce Ca(2+) in the cardioplegic solution (CP). Recent reports suggest that Na(+)/H(+) exchange inhibitors can also prevent Ca(2+) overload.

Retinoic acid induces neuronal differentiation of embryonal carcinoma cells by reducing proteasome-dependent proteolysis of the cyclin-dependent inhibitor p27.

Retinoic acid (RA) treatment of embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1) induces growth arrest and terminal differentiation along the neuronal pathway. In the present study, we provide a functional link between RA and p27 function in the control of neuronal differentiation in NT2/D1 cells. We report that RA enhances p27 expression, which results in increased association with cyclin E/cyclin-dependent kinase 2 complexes and suppression of their activity; however, antisense clones, which have greatly reduced RA-dependent p27 inducibility (NT2-p27AS), continue to synthesize DNA and are unable to differentiate properly in response to RA as determined by lack of neurite outgrowth and by the failure to modify surface antigens.

Cardiac synthesis, processing, and coronary release of enkephalin-related peptides.

Although preproenkephalin mRNA is abundant in the heart, the myocardial synthesis and processing of proenkephalin is largely undefined. Isolated working rat hearts were perfused to determine the rate of myocardial proenkephalin synthesis, its processing into enkephalin-containing peptides, their subsequent release into the coronary arteries, and the influence of prior sympathectomy. Enkephalin-containing peptides were separated by gel filtration and quantified with antisera for specific COOH-terminal sequences.

Tolerance to ischemia and hypoxia is reduced in aged human myocardium.

Background: Recovery of cardiac function after cardiac surgery and other interventional cardiac procedures in elderly patients is inferior to that in younger patients, suggesting that the aged myocardium is more sensitive to ischemia and other stresses. Although convincing data from animal studies of senescence now exist, there is a dearth of controlled in vitro studies that examine the specific response of aged human myocardium to the stress of hypoxia or ischemia.

Objective: We sought to determine the effect of age on the capacity of human atrial trabeculae to recover contractile function after in vitro hypoxic or ischemic stress.

Mitochondria in heart ischaemia and aging.

We have examined the effect of dietary polyunsaturated fatty acids (PUFAs) upon mitochondrial Ca2+ content and dehydrogenase activation in the rat heart. Diets were either a conventional low-fat chow (Ref) or were rich in n-3 PUFAs from fish oils (n-3) or n-6 PUFAs from animal fat (n-6). We found that the n-3 diet minimized the rise in mitochondrial Ca2+ seen in response to positive inotropic intervention with noradrenaline, and also minimized the activation of pyruvate dehydrogenase, which is Ca2+ dependent.

Mitochondrial function in ischaemia and reperfusion of the ageing heart.

1. In addition to Ca2+-dependent mediation of excitation-contraction coupling during cardiac work and ATP hydrolysis, Ca2+ also stimulates the Krebs' cycle and mitochondrial matrix dehydrogenases to maintain the nicotinamide adenine dinucleotide redox potential and ATP synthesis. Thus, the balance between energy demand and supply is maintained during increases in cardiac work by elevated cytosolic Ca2+ that is transmitted to the mitochondrial matrix via regulation of uniporter and antiporter pathways across the inner mitochondrial membrane.

Nuclear DNA content-derived parameters correlated with heterogeneous expression of p53 and bcl-2 proteins in clear cell renal carcinomas.

Background: p53 and bcl-2 are two key genes involved in cell cycle and cell death regulation. Altered expression or mutation of these genes has been found in human cancers and also has been identified in clear cell renal carcinoma (RCC). Their role in RCC progression, however, is still unclear.

[The clinical usefulness of cyclosporine therapeutic monitoring].

Purpose: To review the cyclosporine therapy indications and evaluate determine the incidence of cyclosporine blood levels outside the therapeutic range in patients under treatment, to evaluate the practical utility of the drug monitoring.

Patients And Methods: The blood concentration of monoclonal cyclosporine was monitored in 225 patients by FPIA method, using the trough concentration.

Results: 58% of patients had a drug blood level within the therapeutic range, 26% and 16% of them had respectively, a value below and down this range.

Key role of the cyclin-dependent kinase inhibitor p27kip1 for embryonal carcinoma cell survival and differentiation.

Hexamethylen-bisacetamide (HMBA) represents the prototype of a group of hybrid polar compounds, which induce differentiation in a variety of transformed cells including human embryonal carcinoma cells. Therefore, HMBA has been used in the differentiation therapy of cancer for patients with both hematological and solid malignancies. Upon HMBA treatment, the embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1) accumulates in G1 and undergoes terminal differentiation.

Antisense DNA-targeting protein kinase A-RIA subunit: a novel approach to cancer treatment.

Enhanced expression of the RIa subunit of cAMP-dependent protein kinase type I (PKA-I) has been shown during carcinogenesis, in human cancer cell lines and in primary tumors. We demonstrate that the sequence-specific inhibition of RIa gene expression by antisense oligonucleotides results in the differentiation of leukemia cells and growth arrest of cancer cells of epithelial origin and tumors in mice. The loss of RI by the antisense results in rapid increase in the half-life of the competitor molecule, RII protein, via its stabilization in a holoenzyme complex (PKA-II) that insures depletion of PKA-I and sustained inhibition of tumor growth.

Measurement of neovascularization is an independent prognosticator of survival in node-negative breast cancer patients with long-term follow-up.

We measured neovascularization, epidermal growth factor receptor, and c-erbB-2 expression in a consecutive series of 233 surgically resected axillary lymph node-negative breast cancer patients with a long-term follow-up to define the usefulness of these parameters as independent prognostic indicators of overall survival (OAS). Microvessel count (MVC), as a measure of neovascularization, was determined using a monoclonal antibody against human factor VIII-related antigen. The median MVC of 20 (range, 4-76) was used as a cutoff value for discriminating between low and high vascularized tumors.

Interferon-alpha induces apoptosis in human KB cells through a stress-dependent mitogen activated protein kinase pathway that is antagonized by epidermal growth factor.

We have demonstrated that interferon-alpha2-recombinant (IFNalpha) at growth inhibitory concentrations enhances the expression and signalling activity of the epidermal growth factor receptor (EGF-R) in human epidermoid carcinoma KB cells. Here we report that KB cells exposed to IFNalpha underwent apoptotic cell death and this effect was antagonized by EGF. We have also found that IFNalpha enhanced the expression of heat shock proteins (HSP) HSP-70, HSP-90 and HSP-27 and activated the NH2-terminal Jun kinase-1 (JNK-1) and p38 mitogen activated protein kinase, the target enzymes of a stress-dependent intracellular transduction pathway.