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Biomedical subjects

H Wiseman

Publications and source records attributed to H Wiseman.

At least 55 records · Page 3Linked to original sources
PubMed1995

Tamoxifen as an antioxidant and cardioprotectant.

Tamoxifen is widely used in the treatment of breast cancer and has been proposed as a prophylactic agent in this disease. Tamoxifen is an effective antioxidant and protects membranes and low-density lipoprotein (LDL) particles against oxidative damage. This antioxidant action is shared by endogenous and synthetic oestrogens. The ability of tamoxifen to protect LDL particles against the oxidative damage implicated in atherosclerosis may be an important factor in the reported cardioprotective action of tamoxifen in women being treated for breast cancer. In addition, tamoxifen has been found to act in a similar manner to oestrogens to lower plasma cholesterol levels. The cardioprotective action of tamoxifen may be a key factor in predicting the likely risk/benefit ratio for prophylactic tamoxifen treatment in otherwise healthy women, who have been calculated to be genetically predisposed to developing breast cancer. In the future, predisposition to breast cancer may be determined by genetic screening.

Antioxidants↗
PubMed1994

Tamoxifen decreases drug efflux from liposomes: relevance to its ability to reverse multidrug resistance in cancer cells?

Tamoxifen decreased the efflux of the fluorescent marker drug, chloroquine, from phosphatidylcholine liposomes. Tamoxifen is a known structural-mimic of cholesterol, which were both found to be similarly effective in preventing drug release from liposomes. This ability of tamoxifen and cholesterol to decrease drug efflux in a concentration-dependent manner is likely to arise from their known ability to decrease membrane fluidity both in liposomes and also in cancer cells. The possible importance of the ability of tamoxifen to inhibit drug efflux from liposomes in relation to its ability to reverse multidrug resistance in cancer patients caused by the efflux of cytotoxic therapeutic agents, is discussed.

Antineoplastic Agents↗
PubMed1994

The antioxidant action of a pure antioestrogen: ability to inhibit lipid peroxidation compared to tamoxifen and 17 beta-oestradiol and relevance to its anticancer potential.

The pure antioestrogen ICI 164,384, and nafoxidine (structurally related to tamoxifen) were good inhibitors of iron ion-dependent lipid peroxidation. In rat liver microsomes incubated with Fe(III)-ascorbate the overall order of effectiveness of the compounds tested as inhibitors of lipid peroxidation was 4-hydroxytamoxifen > 17 beta-oestradiol > nafoxidine > or = tamoxifen > ICI 164,384. When the microsomes were incubated with Fe(III)-ADP/NADPH, a similar order of effectiveness was observed. In ox-brain phospholipid liposomes incubated with Fe(III)-ascorbate the order was 4-hydroxytamoxifen > 17 beta-oestradiol > ICI 164,384 > tamoxifen > or = nafoxidine. The antioxidant ability of ICI 164,384, a steroidal oestrogen antagonist, is compared to that of tamoxifen (a non-steroidal antioestrogen and partial oestrogen agonist) and 17 beta-oestradiol and is discussed in relation to its anticancer action.

Animals↗
PubMed1994

Tamoxifen: new membrane-mediated mechanisms of action and therapeutic advances.

Tamoxifen protects membranes and lipoprotein particles against oxidative damage. This antioxidant action is likely to contribute to the observed cardioprotective action of tamoxifen and supports the use of this compound in treating and even preventing breast cancer. Membrane-mediated mechanisms of tamoxifen action, through a putative modulation of membrane fluidity, are likely to play an important role in its anticancer action and its ability to reverse multidrug resistance, and could also lead to clinical uses as an anti-Candida and anti-viral agent. In this review, Helen Wiseman discusses the interaction of tamoxifen with membranes and lipoprotein particles, and considers the possible clinical implications.

Animals↗
PubMed1994

Tamoxifen and related compounds protect against lipid peroxidation in isolated nuclei: relevance to the potential anticarcinogenic benefits of breast cancer prevention and therapy with tamoxifen?

Tamoxifen, 4-hydroxytamoxifen, nafoxidine, 17 beta-oestradiol and ICI 164,384 were all found to protect rat liver nuclei against Fe(III)-ascorbate dependent lipid peroxidation. The order of effectiveness of these compounds was 4-hydroxytamoxifen > 17 beta-oestradiol > nafoxidine > tamoxifen > ICI 164,384. This protection by tamoxifen against the formation of the genotoxic reactive-intermediates and products of lipid peroxidation in the nuclear membrane could be important in the prevention of nuclear DNA damage and thus carcinogenesis. This possible anticarcinogenic benefit of tamoxifen treatment could be important in long-term therapy with tamoxifen (and future derivatives) and in its proposed use in the prevention of breast cancer.

Animals↗
PubMed1994

The antioxidant action of synthetic oestrogens involves decreased membrane fluidity: relevance to their potential use as anticancer and cardioprotective agents compared to tamoxifen?

The synthetic oestrogens diethylstilboestrol, hexoestrol and 17 alpha-ethynyloestradiol are known to be good antioxidants, and we now report that they decrease membrane fluidity, in ox-brain phospholipid liposomes. The order of effectiveness was diethylstilboestrol > hexoestrol > 17 alpha-ethynyloestradiol and a good positive correlation was demonstrated between decreased membrane fluidity and antioxidant ability (measured as inhibition of liposomal lipid peroxidation: correlation coefficient, r = 0.99). This ability of diethylstilboestrol, hexoestrol and 17 alpha-ethynyloestradiol to decrease membrane fluidity is suggested, therefore, to be the mechanism of their antioxidant action. The membrane-modulating antioxidant action of these synthetic oestrogens is compared to that of tamoxifen and their potential use as anticancer and cardioprotective agents is discussed.

Antineoplastic Agents↗
PubMed1993

Carcinogenic antioxidants. Diethylstilboestrol, hexoestrol and 17 alpha-ethynyloestradiol.

The synthetic oestrogens diethylstilboestrol, hexoestrol and 17 alpha-ethynyloestradiol are known to be carcinogenic, yet they all exert antioxidant properties in vitro in that they are good inhibitors of iron ion-dependent lipid peroxidation. In rat liver microsomes incubated with Fe(III)-ascorbate or Fe(III)-ADP/NADPH and also in ox-brain phospholipid liposomes incubated with Fe(III)-ascorbate; the overall order of effectiveness of the compounds tested as inhibitors of lipid peroxidation was diethylstilboestrol > hexoestrol > 17 alpha-ethynyloestradiol > 4-hydroxytamoxifen > 17 beta-oestradiol > tamoxifen. Compounds acting as antioxidants towards lipids may also exert pro-oxidant effects towards other molecules such as DNA and thus must never be assumed to be safe for human use.

Animals↗
PubMed1993

Tamoxifen and related compounds decrease membrane fluidity in liposomes. Mechanism for the antioxidant action of tamoxifen and relevance to its anticancer and cardioprotective actions?

Tamoxifen and related compounds decrease membrane fluidity in ox-brain phospholipid liposomes: their order of effectiveness is, 4-hydroxytamoxifen > 17 beta-oestradiol > tamoxifen > cis-tamoxifen > N-desmethyltamoxifen > cholesterol. A good positive correlation was demonstrated between the decrease in membrane fluidity by these compounds and their antioxidant ability as inhibitors of liposomal and microsomal lipid peroxidation (correlation coefficient, r = 0.99, P < 0.001, in both cases). The ability of tamoxifen to decrease membrane fluidity is suggested to be the mechanism of its antioxidant action and is discussed in relation to its anticancer and cardioprotective actions.

Animals↗
PubMed1993

Vitamin D is a membrane antioxidant. Ability to inhibit iron-dependent lipid peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to anticancer action.

Vitamin D is a membrane antioxidant: thus Vitamin D3 (cholecalciferol) and its active metabolite 1,25-dihydroxycholecalciferol and also Vitamin D2 (ergocalciferol) and 7-dehydrocholesterol (pro-Vitamin D3) all inhibited iron-dependent liposomal lipid peroxidation. Cholecalciferol, 1,25-dihydroxycholecalciferol and ergocalciferol were all of similar effectiveness as inhibitors of lipid peroxidation but were less effective than 7-dehydrocholesterol; this was a better inhibitor of lipid peroxidation than cholesterol, though not ergosterol. The structural basis for the antioxidant ability of these Vitamin D compounds is considered in terms of their molecular relationship to cholesterol and ergosterol. Furthermore, the antioxidant ability of Vitamin D is compared to that of the anticancer drug tamoxifen and its 4-hydroxy metabolite (structural mimics of cholesterol) and discussed in relation to the anticancer action of this vitamin.

Animals↗
PubMed1993

Enhancement by tamoxifen of the membrane antioxidant action of the yeast membrane sterol ergosterol: relevance to the antiyeast and anticancer action of tamoxifen.

The anticancer drug tamoxifen inhibits lipid peroxidation in ox-brain phospholipid liposomes, and is a good antiyeast agent, with clinical potential. We now report that the ergosterol-containing lipid fraction derived from yeast microsomal membranes (and the ergosterol separated from it) inhibited lipid peroxidation when introduced into ox-brain phospholipid liposomes. Inhibition of lipid peroxidation by the lipid fraction was greatly enhanced when yeast cell growth was inhibited with tamoxifen prior to lipid extraction. The ability of tamoxifen to enhance the membrane antioxidant ability of ergosterol is expressed in terms of a tamoxifen enhancement coefficient. Enhancement by tamoxifen of the membrane antioxidant action of ergosterol is discussed in relation to the antifungal and anticancer actions of tamoxifen.

Animals↗
PubMed1993

Protective actions of tamoxifen and 4-hydroxytamoxifen against oxidative damage to human low-density lipoproteins: a mechanism accounting for the cardioprotective action of tamoxifen?

Tamoxifen and 4-hydroxytamoxifen protect isolated human low-density lipoproteins (LDLs) against copper-ion-dependent lipid peroxidation: 4-hydroxytamoxifen is more protective than tamoxifen or 17 beta-oestradiol. 4-Hydroxytamoxifen and 17 beta-oestradiol also prevent the increase in the electrophoretic mobility of LDL caused by exposure to copper ions, presumably by protection of the apoprotein B of LDL against oxidative modification. Our observations may help to account for the cardioprotective benefits reported to be associated with tamoxifen therapy and prophylaxis in breast cancer.

Copper↗
PubMed1993

Tamoxifen inhibits lipid peroxidation in cardiac microsomes. Comparison with liver microsomes and potential relevance to the cardiovascular benefits associated with cancer prevention and treatment by tamoxifen.

Tamoxifen and 4-hydroxytamoxifen were both good inhibitors of iron-dependent lipid peroxidation in rat cardiac microsomes. Tamoxifen was also a good inhibitor of lipid peroxidation in liposomes prepared from the phospholipid obtained from rat liver microsomes. In a modified rat liver microsomal system containing a sufficiently low amount of peroxidizable phospholipid to make it comparable with the rat cardiac microsomal system, tamoxifen and 4-hydroxytamoxifen were of similar effectiveness as in the cardiac system. Tamoxifen is known to lower serum cholesterol levels, and the findings reported here indicate that the drug might also protect heart cell membranes against peroxidative damage. Potential cardioprotective and antiatherosclerotic benefits of tamoxifen are discussed in relation to the drug's use in cancer prevention and treatment.

Animals↗
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↗