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R Paoletti

Publications and source records attributed to R Paoletti.

At least 19 recordsLinked to original sources
PubMed1992

Simvastatin, an inhibitor of cholesterol biosynthesis, shows a synergistic effect with N,N'-bis(2-chloroethyl)-N-nitrosourea and beta-interferon on human glioma cells.

The effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on human glioma cell growth was investigated. When incubated with simvastatin, cell proliferation decreased in a concentration-dependent fashion, as measured by cell number and [3H]-thymidine incorporation into DNA (concentration producing 50% inhibition, 60 nM). The effect was detectable 12 h after cells were exposed to the drug and persisted for 2 days. Addition of mevalonate to cells exposed effect of simvastatin in combination with beta-interferon and N,N'-bis(2-chloroethyl)-N-nitrosourea, both antitumoral drugs, was also evaluated by cell growth inhibition assay. The concentration producing 50% inhibition for each of these drugs was 650 units/ml and 50 nM, respectively. Subliminal concentrations of beta-interferon or N,N'-bis(2-chloroethyl)-N-nitrosourea were incubated together with 1 nM simvastatin. The data were analyzed with the aid of an isobologram using the concept of an envelope of additivity. Simultaneous cell exposure to simvastatin with either N,N'-bis(2-chloroethyl)-N-nitrosourea or beta-interferon produced a strong synergistic inhibitory effect on cell proliferation. These data provide in vitro support for the possibility that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, utilized as plasma cholesterol-lowering agents, could potentiate the effect of antiblastic drugs on tumor growth.

Anticholesteremic Agents↗
PubMed1992

Classification of calcium channels and calcium antagonists: progress report.

The molecular biology and electrophysiology of calcium channels is proceeding apace, partially driven by the clinical success of the drugs classed as "calcium antagonists." Indeed, there are now more than 70 drugs in development that have been claimed to be "calcium antagonists" of one type or another. In order to ensure that there is a logical nomenclature for the channels and the drugs acting at the channels, an international committee has met over the last 2 years to classify the channels and the drugs. This report consists of an overview of current thinking, which will be finalized in a document submitted to the IUPHAR (International Union of Pharmacologists) nomenclature committee.

Calcium Channel Blockers↗
PubMed1992

Focus on anti-atherosclerotic therapy.

Calcium antagonists (CA) exert an anti-atherosclerotic effect in cholesterol-fed rabbits through reduction of cholesterol accumulation in the arterial wall. Further studies in our Institute indicate that verapamil-like compounds and diltiazem stimulate receptor-mediated LDL uptake by human fibroblasts in culture, while nifedipine-like compounds and flunarizine are inactive. Verapamil and diltiazem stimulated LDL-receptor activity also in cells from a heterozygous FH patient, while they were inactive in a receptor defective homozygous FH patient. A basic group needs to be present on the CA molecule to modulate the LDL receptor expression. Preliminary data in our laboratory suggest that some CA can achieve concentrations in the aortic wall likely to exert effects on LDL receptors. This stimulatory activity may improve lipid metabolism in the arterial wall.

Animals↗
PubMed1992

Cholesterol and mevalonic acid modulation in cell metabolism and multiplication.

Cholesterol in animals is a major structural component of cell membranes. It may therefore play a functional role in the modulation of cell osmolarity, the process of pinocytosis and the activities of membrane-associated proteins such as ionic pumps, immune responses, etc. A major relationship exists between the cell-growth processes and the cholesterol biosynthetic pathway. The cholesterol needed for new membranes may be derived either from endogenous synthesis or from exogenous sources, principally plasma low-density-lipoproteins (LDL) which enter the cells by receptor-mediated endocytosis. Both these pathways are enhanced in rapidly growing cells. Conversely, if synthesis is inhibited and no exogenous cholesterol is available, cell growth is blocked. The 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductase (the rate-limiting reaction in cholesterol biosynthesis) is the enzyme which catalyzes the conversion of HMGCoA to mevalonic acid. It has been suggested that mevalonate may play an important role in cell proliferation. All cells need at least two products synthesized from mevalonate in order to proliferate, and the only one yet identified is cholesterol. Other melavonate-derived potential candidates as cell-cycle and cell-survival products include the dolichols ubiquinone side chains, isopentenyladenosine derivatives, etc. Furthermore, it has recently been shown that membrane association appears to be an important function in mevalonate-derive modifications of several important proteins such as cellular membrane G proteins, those coded for by oncogenes (ras proteins) and lamins (nuclear proteins). In recent years the development of cholesterol-synthesis-inhibiting drugs, for lowering plasma cholesterol levels has mainly been centred on the control of HMGCoA reductase activity (vastatins). However, because mevalonic acid is the precursor of numerous metabolites, any reduction of such activity may potentiate pleiotropic effects. Vastatins are now, therefore, receiving increased attention as potential pharmacological tools for the control of abnormal cell growth in pathological situations, i.e. tumours and vascular smooth muscle cell proliferation under atherogenic conditions. In our laboratories, we have demonstrated that simvastatin can prevent arterial myocyte proliferation both in vivo and in vitro. Simvastatin can also inhibit in vitro the rate of human glioma cell growth, since it shows a strong synergistic inhibitory effect on cell proliferation when used in association with anticancer agents such as Carmustine or beta-interferon. Both simvastatin-induced cell growth inhibition and the synergy observed with these drugs can be completely reversed by incubating cells with mevalonate. This shows that the effect of simvastatin of cell proliferation is due to its specific inhibitory activity on intracellular mevalonate synthesis.

Animals↗
PubMed1991

Influence of trapidil and derivatives on cholesterol synthesis and esterification in cultured cells.

The effect of trapidil (Rocornal) and its derivatives AR 12456 and AR 12463 on endogenous cholesterol synthesis and on cholesterol esterification rate was studied in human skin fibroblasts (HSF), in human hepatoma cell line Hep G2 and in primary culture of peritoneal macrophages from mouse (PMM). The cholesterol esterification rate was not influenced by the drugs in the tested cell lines. The incorporation of [14C]acetate into cholesterol in HSF was inhibited by AR 12463 and AR 12456, but not by trapidil. The inhibitory potency of AR 12456 in HSF was enhanced after preincubation of the drug with Hep G2 and removal of the medium to HSF, suggesting that the formed metabolite(s) are more potent inhibitors than the parent substance. The metabolite(s) formed seem(s) to influence the first steps in the endogenous formation of cholesterol, because the incorporation of [14C]mevalonate into cholesterol was not significantly inhibited. These findings suggest that the demonstrated inhibition of the endogenous cholesterol synthesis by AR 12456, especially after transformation into a probably more active substance(s), together with the recently described enhanced expression of LDL receptors in Hep G2 cells may partially explain the hypocholesterolaemic activity of AR 12456.

Acetates↗
PubMed1991

Simvastatin but not pravastatin inhibits the proliferation of rat aorta myocytes.

The in vitro effect of simvastatin and pravastatin, two competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, on the proliferation of rat aortic smooth muscle cells was investigated. Simvastatin, but not pravastatin, inhibited the replication of arterial myocytes in concentrations ranging between 0.01 microM and 10 microM. The inhibition, evaluated as cell number and nuclear incorporation of [3H]thymidine, was dose-dependent and completely prevented by addition of mevalonate (100 microM), confirming the role of mevalonate or its products in regulating cell division and growth. The present results provide evidence that simvastatin, in addition to its effect on cholesterol biosynthesis, interferes in vitro with other processes involved in atherogenesis.

Animals↗
PubMed1991

[Cholesterolemia and ischemic cardiopathy: a causal relationship].

A consistent pool of data obtained in epidemiological and in intervention studies suggests that increased levels of plasma cholesterol are associated to an increased incidence of coronary events. Studies in which a reduction of cholesterol plasma levels was obtained with different approaches (using drugs, diets, surgical procedures) indicate that this reduction, whatever the technique adopted to obtain it, favorably affects the natural history of the atherosclerotic disease in human patients. This information, together with the biochemical evidences linking plasma lipids and lipoproteins with the process of atherogenesis, strongly supports the view that hypercholesterolemia is a causal factor in the development of coronary heart disease in man.

Cholesterol↗
PubMed1990

A new generation of calcium antagonists and their role in atherosclerosis.

A new generation of calcium antagonists is being developed in an attempt to improve the already widespread therapeutic applications of this class of drugs. In this report the effect of these new calcium antagonists on those processes involved in atherogenesis that occur in the cellular component of the arterial wall is reviewed. The new generation of calcium antagonists appears to possess many of the antiatherosclerotic properties demonstrated by their prototypes. Moreover, these new compounds may have unique mechanisms of action and may be more potent than their first-generation counterparts.

Arteriosclerosis↗
PubMed1990

Calcium antagonists and intimal cell proliferation in atherogenesis.

Smooth muscle cell (SMC) migration and intimal proliferation are major events in the formation of the atherosclerotic lesions. Among other processes, calcium may participate in atherogenesis by affecting SMC proliferation. Calcium antagonists, which possess antiatherosclerotic properties in animal models, are effective in inhibiting SMC proliferation. This effect has been demonstrated both in vitro in cell culture and in vivo in balloon-catheterised rats and rabbits. Such an effect, indicates a possible mechanism involved in the antiatherosclerotic activity elicited by this category of drugs.

Animals↗