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Biomedical subjects

H R Arnstein

Publications and source records attributed to H R Arnstein.

At least 19 recordsLinked to original sources
PubMed1992

Droloxifene (3-hydroxytamoxifen) has membrane antioxidant ability: potential relevance to its mechanism of therapeutic action in breast cancer.

Droloxifene (3-hydroxytamoxifen), is a triphenylethylene derivative recently developed for the treatment of breast cancer. Droloxifene was found to exhibit a membrane antioxidant ability in that it inhibited Fe(III)-ascorbate dependent lipid peroxidation in rat liver microsomes and ox-brain phospholipid liposomes. It also inhibited microsomal lipid peroxidation induced by Fe(III)-ADP/NADPH. Droloxifene was a better inhibitor of lipid peroxidation than tamoxifen, but was less effective than 17 beta-oestradiol in the two microsomal systems and in the preformed liposomal system. When introduced into ox-brain phospholipid liposomes, droloxifene inhibited Fe(III)-ascorbate induced lipid peroxidation to approximately the same extent as similarly introduced cholesterol and tamoxifen, although to a lesser extent than 17 beta-oestradiol. This inhibition of lipid peroxidation by droloxifene may result from a membrane stabilization that could be associated in cancer cells with decreased plasma membrane fluidity. This mechanism may be related to the clinically important antiproliferative action of droloxifene on cancer cells.

Animals↗
PubMed1992

The structural mimicry of membrane sterols by tamoxifen: evidence from cholesterol coefficients and molecular-modelling for its action as a membrane anti-oxidant and an anti-cancer agent.

The anti-cancer drug tamoxifen is a potent inhibitor of lipid peroxidation induced by Fe(III)-ascorbate in ox-brain phospholipid liposomes. Similar anti-oxidant effects, but with varying potencies, are also shown by 4-hydroxy-tamoxifen, cholesterol, ergosterol and 17-beta-oestradiol. We now describe a computer-graphic fitting technique that demonstrates a structural similarity between the five compounds. In addition, we have quantified the differences (relative to cholesterol) between the anti-oxidant activities of the compounds in terms of a novel expression referred to here as the cholesterol coefficient (Cc) Finally, we discuss how the inhibitory effect of tamoxifen on lipid peroxidation may result from a membrane stabilization that is associated with a decrease in membrane fluidity. This action may be related to the anti-proliferative effect exerted by tamoxifen on cancer and fungal cells.

Antifungal Agents↗
PubMed1991

The antioxidant action of ketoconazole and related azoles: comparison with tamoxifen and cholesterol.

The azole antifungal drug ketoconazole was found to inhibit Fe(III)-ascorbate dependent lipid peroxidation using either rat liver microsomes or ox-brain phospholipid liposomes as the substrate. It also inhibited microsomal peroxidation induced by the Fe(III)-ADP/NADPH system. The related azoles, miconazole and clotrimazole, were much weaker inhibitors than ketoconazole. Ketoconazole was approximately equipotent with the triphenylethylene anticancer drug tamoxifen in the microsomal system and was almost as effective as 4-hydroxytamoxifen in the liposomal system. Ketoconazole introduced into phospholipid liposomes during their preparation inhibited Fe(III)-ascorbate induced lipid peroxidation to a greater extent than similarly introduced cholesterol, ergosterol or tamoxifen. Miconazole and clotrimazole were again poor inhibitors of lipid peroxidation in this system. These antioxidant effects of ketoconazole may be due to membrane stabilization in the systems used. The implications of our findings for the clinical applications of these drugs are discussed.

Animals↗
PubMed1990

Mechanism of inhibition of lipid peroxidation by tamoxifen and 4-hydroxytamoxifen introduced into liposomes. Similarity to cholesterol and ergosterol.

The anticancer drug tamoxifen when introduced into phospholipid liposomes during their preparation inhibited Fe(III)-ascorbate induced lipid peroxidation to a greater extent than similarly introduced cholesterol. Ergosterol was equipotent with tamoxifen, but much less effective than 4-hydroxytamoxifen. Possible mechanisms underlying these effects are discussed in relation to structural mimicry of the sterols by these triphenylethylene drugs as membrane stabilizers against lipid peroxidation.

Cholesterol↗
PubMed1990

Protein phosphorylation in erythroid cell development.

Changes in the phosphorylation of proteins during erythroid cell development have been investigated by assaying the activity of three protein kinases in circulating reticulocytes, and dividing and non-dividing erythroblasts obtained from the bone marrow of anaemic rabbits. Kinase activities decreased during erythroid cell development, but protein phosphorylation was generally limited by substrate availability rather than enzyme activity. Using permeabilized cells some changes in the patterns of proteins phosphorylated by [gamma-32P]ATP were observed during erythroid cell development.

Animals↗
PubMed1988

Independent activation of adenylate cyclase by erythropoietin and isoprenaline.

The possibility that catecholamines modulate the erythropoietin-induced increase in production of cyclic AMP was investigated by examining the effect of erythropoietin and/or L-isoprenaline on the activity of the plasma membrane adenylate cyclase of anaemic rabbit bone marrow erythroblasts. Membranes isolated from cells cultured in the presence of both hormones exhibited both the transient stimulation of basal activity characteristic of erythropoietin action and the loss of the in vitro response to L-isoprenaline, concomitant with the loss of beta-adrenergic receptors, characteristic of L-isoprenaline stimulation. The presence of erythropoietin during cell culture with L-isoprenaline had no effect on the desensitization or number of beta-adrenergic receptors. The stimulation of adenylate cyclase by erythropoietin was observed also in the presence of the beta-antagonist propranolol, when both were added either to whole cells or to isolated membranes. We conclude that these two hormones activate adenylate cyclase independently of each other, via different receptors, with little evidence of cross-modulation.

Adenylyl Cyclases↗
PubMed1987

The role of cAMP and calcium in the stimulation of proliferation of immature erythroblasts by erythropoietin.

The hypothesis that cAMP or calcium are the second messengers of erythropoietin (Epo) was tested on fractionated, Epo-responsive immature erythroblasts from anemic rabbit bone marrow by examining whether the proliferative effects of the hormone could be mimicked by agents that increase the intracellular concentration of cAMP or Ca2+. None of the compounds tested (including 10(-6)-10(-4) M db-cAMP, forskolin, isoprenaline or 10(-7)-10(-6) M of the calcium ionophore A23187) alone or in combination could either initiate or potentiate the mitogenic action of the hormone. Furthermore, addition of 0.2 U/ml erythropoietin produced no permanent or transient increase in the uptake of 45Ca2+ by erythroblasts at 37 degrees C. However, cells cultured with imidazole or cordycepin (which reduce the level of intracellular cAMP), or with the calcium chelator EGTA, or the drugs verapamil or TMB-8 (which interfere with the utilization of extracellular or intracellular calcium) showed a decreased stimulation of DNA synthesis by Epo. Finally, the tumour promoter phorbol ester TPA could partially mimic the action of Epo when added to cultures containing more immature progenitor cells. We conclude then that an artificial increase in the cytoplasmic concentration of either cAMP or Ca2+ is not sufficient to elicit the proliferation of Epo-responsive cells.

Animals↗
PubMed1986

Classification of beta-adrenergic subtypes in immature rabbit bone marrow erythroblasts.

The beta-adrenergic receptors of immature rabbit bone marrow erythroid cells (proerythroblasts and basophilic erythroblasts) were identified. [125I]iodocyanopindolol bound to membrane preparations derived from these erythroblasts in a rapid, reversible and saturable manner. Scatchard analysis of binding data revealed a single class of binding sites (Hill coefficient of 0.954) with an apparent equilibrium dissociation constant (Kd) of 8 pM, and a density of binding sites (Bmax) of 1.53 pM/10(6) cells, corresponding to 920 receptors per cell. The binding of [125I]iodocyanopindolol was inhibited stereospecifically by concentrations of (-)-propranolol 2 orders of magnitude lower than by the (+)-isomer. Only L-isoprenaline and L-adrenaline activated the adenylate cyclase of immature rabbit erythroblasts, while L-noradrenaline, a beta 1-adrenergic agonist, was inactive. The order of potency of different agonists for displacement of bound [125I]iodocyanopindolol was: isoprenaline greater than adrenaline greater than noradrenaline with respective EC50 (concentration required for half maximal inhibition of binding) of 7.9 X 10(-7) M, 1.5 X 10(-5) M and 7.9 X 10(-5) M. This agonist potency series did not change with differentiation of rabbit bone marrow erythroblasts. The inhibition of specific [125I]iodocyanopindolol binding to immature cells by beta 1- and beta 2-selective drugs (noradrenaline, practolol, procaterol and butoxamine) resulted in linear Hofstee plots. The inhibition curves obtained with procaterol and butoxamine, with apparent Kd values of 3.1 X 10(-9) M and 4.9 X 10(-9) M, further evidence that the high-affinity binding sites correspond to a homogeneous beta 2-receptor subtype.

Adenylyl Cyclases↗