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At least 1,063 records · Page 59Linked to original sources
PubMed2003

Design and synthesis of 4,6-di-tert-butyl-2,3-dihydro-5-benzofuranols as a novel series of antiatherogenic antioxidants.

Antioxidants have been considered as potential antiatherogenic agents by inhibiting oxidation of low-density lipoprotein (LDL), albeit vitamin E, a natural antioxidant, has failed to show reduction on atherosclerosis in clinical trials. We have rationally designed and synthesized a novel series of antioxidants, 4,6-di-tert-butyl-2,3-dihydro-5-benzofuranols, to overcome the clinical limitation of vitamin E. In vitro, the compounds showed a potent inhibitory effect on lipid peroxidation detected as 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyrazin-3-one (MCLA)-dependent chemiluminescence in linoleic acid autoxidation. They also inhibited the LDL oxidation induced by Cu(2+), and the inhibition is more potent than that of vitamin E and probucol. In vivo, 4,6-di-tert-butyl-2,3-dihydro-2,2-dipentyl-5-benzofuranol (BO-653, 1f), an optimal compound, showed the highest concentration in plasma and LDL fraction in Watanabe heritable hyperlipidemic rabbits, due to its high affinity to LDL. The isolated LDL samples from the 1f-treated rabbits showed potent resistibility to LDL oxidation. Compound 1f has been taken into clinical trials.

Animals↗
PubMed1997

Novel indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives. Structure-activity relationships for high inhibition of human LDL peroxidation.

Series of indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives were synthesized and evaluated in order to determine the necessary structural requirements for a high inhibition of human LDL copper-induced peroxidation. Various modulations were systematically performed on the indole and cycloalkeno[1,2-b]indole nuclei as well as on the carboxamide moiety. The best compounds (3c, 3e, 7c, 7f, 7h, 7g, and 7o) are between 5 and 30 times more active than probucol itself. Two of these compounds (3c and 7o) were selected for complementary in vitro and in vivo investigations, which have shown additional properties of interest for the treatment and the prevention of atherosclerosis injuries. Compound 3c was found to have some antiinflammatory properties while compound 7o was proved to protect endothelial cells from the direct cytotoxicity of oxidized LDL with some additional calcium channel blocking properties.

Amides↗
PubMed2001

Specific antioxidant activity of caffeoyl derivatives and other natural phenolic compounds: LDL protection against oxidation and decrease in the proinflammatory lysophosphatidylcholine production.

Specific antioxidant activity (SAA) (i.e., activity related to the molar or gallic acid equivalent amount of antioxidant) of natural polyphenolic mixtures or pure phenolic compounds was studied using their capacity to delay the conjugated diene production brought about by in vitro LDL copper-mediated or AAPH-mediated oxidation. The cinnamic acid series (caffeic, sinapic, ferulic acids) displayed a constant SAA over a large range of concentrations, whereas the benzoic acid series (gallic and protocatechuic acids) showed much higher SAA at low concentrations. The natural phenolic mixtures had a constant SAA. The highest SAA was obtained with caffeoyl esters (caffeoylquinic, rosmarinic, and caffeoyltartaric acids) and catechin for the copper-oxidation and the AAPH-oxidation system, respectively. Phenolic mixtures and acids delayed vitamin E depletion and decreased proinflammatory lysophosphatidylcholine production. As with polyphenols, probucol delayed lysophosphatidylcholine and conjugated dienes production, at higher concentrations, but was not effective at preventing vitamin E depletion. Polyphenols prevent the oxidation of LDL and its constituents (vitamin E, phosphatidylcholine), which is compatible with an antiinflammatory and antiatherosclerotic role in pathophysiological conditions.

Antioxidants↗
PubMed2002

Anti-lipid-peroxidative principles from Tournefortia sarmentosa.

Using the inhibition of Cu(2+)-induced low-density-lipoprotein (LDL) peroxidation to direct fractionation, four new benzenoids, tournefolal (1), tournefolic acids A (2) and B (3), and B ethyl ester (4), together with salvianolic acid A (5), isosalvianolic acid C (6), lithospermic acid (7), salvianolic acid F (8), and rosmarinic acid (9), were isolated from the stems of Tournefortia sarmentosa. The structures of the new compounds 1-4 were elucidated on the basis of spectral and chemical methods. Furthermore, the anti-LDL-peroxidative activity of the isolated compounds was determined. All isolated compounds exhibited more potent activity than probucol except for salvianolic acid F (8).

Antioxidants↗
PubMed1995

Synthesis and evaluation of 3',5'-di-tert-butyl-4'-hydroxyflavones as potential inhibitors of low density lipoprotein (LDL) oxidation.

The novel flavones 6-28, which display structural analogies with the two well-known lipid peroxidation inhibitors, probucol [1] and butylated hydroxytoluene [2], were synthesized and studied in vitro for their ability to inhibit the copper sulfate or endothelial cell-induced lipid peroxidation of human low-density lipoprotein (LDL). Most of the flavones were active in the range of 0.1-1 microM.

Antioxidants↗
PubMed1999

Antioxidant principles from Ephemerantha lonchophylla.

One dihydrostilbene and three phenanthrene antioxidants were isolated from an ethanolic extract of the Chinese herbal Ephemerantha lonchophylla. One of these compounds, ephemeranthone (4) is a new natural product. Denbinobin (1) and 3-methylgigantol (3) have been previously isolated from this plant, and 3-ethoxy-5-hydroxy-7-methoxy-1,4-phenanthraquinone (2) is an artifact. The structures of these compounds were determined by spectroscopic analysis. The antioxidative activities for inhibiting human low density lipoprotein oxidation in vitro of compounds 1-4 were determined, and only 4 was active (5.3 times that of probucol).

Antioxidants↗
PubMed1997

NADPH-initiated cytochrome P450-dependent free iron-independent microsomal lipid peroxidation: specific prevention by ascorbic acid.

In this paper we demonstrate that ascorbic acid specifically prevents NADPH-initiated cytochrome P450 (P450)-mediated microsomal lipid peroxidation in the absence of free iron. Lipid peroxidation has been evidenced by the formations of conjugated dienes, lipid hydroperoxide and malondialdehyde. Other scavengers of reactive oxygen species including superoxide dismutase, catalase, glutathione, alpha-tocopherol, uric acid, thiourea, mannitol, histidine, beta-carotene and probucol are ineffective to prevent the NADPH-initiated P450-mediated free iron-independent microsomal lipid peroxidation. Using a reconstituted system comprised of purified NADPH-P450 reductase, P450 and isolated microsomal lipid or pure L-alpha-phosphatidylcholine diarachidoyl, a mechanism has been proposed for the iron-independent microsomal lipid peroxidation and its prevention by ascorbic acid. It is proposed that the perferryl moiety P450 Fe3+.O2.- initiates lipid peroxidation by abstracting methylene hydrogen from polyunsaturated lipid to form lipid radical, which then combines with oxygen to produce the chain propagating peroxyl radical for subsequent formation of lipid peroxides. Apparently, ascorbic acid prevents initiation of lipid peroxidation by interacting with P450 Fe3+.O2.-.

Animals↗
PubMed2003

Tumor necrosis factor-alpha in low doses preactivates and activates macrophages by increasing their ability to produce reactive oxygen species and oxidize low-density lipoproteins: protective effect of antioxidants.

Tumor necrosis factor-alpha in low doses activated rat peritoneal macrophages and intensified production of reactive oxygen species (zymosan-depended chemiluminescence). Single or 2-fold incubation with tumor necrosis factor-a activated and preactivated human blood macrophages and promoted oxidative modification of low-density lipoproteins (increased their mobility in agarose gel). Antioxidants (potassium phenosan, probucol, and desferal) suppressed oxidative modification of low-density lipoproteins induced by nonactivated, preactivated, and activated macrophages. Our results show that antioxidants hold much promise for the prevention and therapy of atherosclerosis.

Animals↗
PubMed2000

Paraquat-induced membrane dysfunction in pulmonary microvascular endothelial cells.

Membrane dysfunction monitored by lactate dehydrogenase release from cultured pulmonary microvascular endothelial cells of pigs, which were exposed to paraquat at different concentrations (0.1-2 mM), was examined. Paraquat caused a time-dependent increase in lactate dehydrogenase release. Lactate dehydrogenase releases after 72 hr, 32, 58, and 84% by 0.1, 0.5, and 2 mM paraquat, respectively, were well correlated with cell viability measured by cell adherence. In contrast, reductions of two tetrazolium compounds were depleted profoundly by 72 hr after exposure to 0.5 mM paraquat, suggesting depletion of intracellular reductive substances. Extracellular hydrogen peroxide began to significantly increase 56 hr or 32 hr after exposure to 0.5 mM or 1.5 mM paraquat, respectively, preceding the initial increase of lactate dehydrogenase release (64 hr by 0.5 mM or 48 hr by 1.5 mM). Lactate dehydrogenase release 72 hr after exposure to 0.5 mM paraquat was prevented strongly by catalase (1000 units/ml), but weakly by superoxide dismutase (1000 units/ml). These enzymes failed to restore the reduced acid phosphatase activity. Also, 0.1 mM desferal or alpha,alpha'-dipyridyl protected lactate dehydrogenase release. Similarly, 1 mM thiourea or dimethylthiourea, and 0.5 mM alpha-tocopherol or trolox, were effective, but diethylenetriaminepentaacetic acid (0.1 mM) and probucol (5 or 10 microM) were ineffective. Exposure of 0.5 or 1.5 mM paraquat suppressed levels of lipid peroxidation. These results indicate that membrane dysfunction by paraquat is ascribed to an iron-catalyzed reaction of extracellularly increased hydrogen peroxide. A deleterious species for the membrane dysfunction is discussed.

Acid Phosphatase↗
PubMed1998

Investigation of oxidant stress and vasodepression to glyceryl trinitrate in the obese Zucker rat in vivo.

1. We examined the relationship between oxidant stress and the vasodepressor activity of glyceryl trinitrate (GTN) in vivo, including rapid GTN tolerance development, in 13-week old obese and age-matched lean Zucker rats which had been maintained for 4 weeks on either control diet or diets enriched with the lipophilic, chain-breaking antioxidants vitamin E (0.5% w w(-1)) or probucol (0.5% w w(-1)) or the superoxide anion scavenger tiron (1% w v(-1) in drinking water). 2. The basal plasma level of the isoprostane 8-epi-PGF2alpha, an in vivo marker of lipid peroxidation, was elevated by approximately 5 fold in the obese Zucker rat and markedly reduced by dietary lipophilic antioxidants and depressed by dietary tiron. 3. Vasodepression to bolus does GTN (0.1-100 microg kg(-1) i.v.), but not endothelium-dependent vasodepression to bolus dose acetylcholine (ACh, 0.02-2.0 microg kg(-1) i.v.), was impaired in obese animals and completely restored by dietary antioxidants. 4. Nitrate tolerance developed in vivo during a I h infusion of GTN (40 microg kg(-1) min(-1) i.v.) appeared more severe in obese animals. However, rapid nitrate tolerance was not affected by dietary antioxidants in either the obese or lean Zucker rat. 5. We therefore provide evidence that elevated oxidant stress in the obese Zucker rat is associated with an impairment in nitrate vasodepressor activity. However, our data are not consistent with either a role for oxidant stress in rapid nitrate tolerance development in the anaesthetized Zucker rat or the aggravation of this tolerance by pre-existing oxidant stress.

Acetylcholine↗
PubMed2001

Vascular dysfunction induced by AGE is mediated by VEGF via mechanisms involving reactive oxygen species, guanylate cyclase, and protein kinase C.

OBJECTIVE: These experiments were designed to elucidate mechanisms mediating vascular dysfunction induced by advanced glycation end products (AGEs). METHODS: Skin chambers were mounted on the backs of Sprague-Dawley rats and 1 week later, granulation tissue that formed in the bottom of the chamber was exposed twice daily for 7 days to glycated rat serum albumin in the presence and absence of inhibitors of reactive oxygen intermediates, nitric oxide synthase and guanylate cyclase, protein kinase C (PKC), and a neutralizing vascular endothelial growth factor (VEGF) antibody. Vascular (125)I-albumin clearance and blood flow were quantified by use of a double isotope-dilution technique and radiolabeled microspheres, respectively. RESULTS: Albumin permeation and blood flow were increased dose-dependently to a maximum of 2 to 3 times controls by increasing the extent of glucose modification, the concentration, or the duration of exposure to glycated albumin. These increases were significantly attenuated by probucol and superoxide dismutase; N(G)-nitro-L-arginine-methyl ester (L-NAME), a nitric oxide synthase inhibitor; LY83583, a guanylate cyclase inhibitor; and LY333531, a beta-isoform-selective protein kinase C inhibitor. A neutralizing VEGF monoclonal antibody also markedly attenuated the permeability and blood flow increases induced by glycated albumin. CONCLUSIONS: These observations indicate potentially important roles for oxygen free-radicals and nitric oxide in mediating permeability and blood flow changes induced by glycated proteins via mechanisms involving increased protein kinase C activity and VEGF production. Striking similarities in the mechanism by which hyperglycemia and glycated proteins induce vascular dysfunction suggest that a common pathway mediates effects of these different metabolic imbalances on vascular dysfunction.

Animals↗
PubMed2000

A nonfibrillar form of the fusogenic prion protein fragment [118-135] induces apoptotic cell death in rat cortical neurons.

Neuronal loss is a salient feature of prion diseases. However, its cause and mechanism, particularly its relationship with the accumulation and precipitation of the pathogenic, protease-resistant isoform PrP(Sc) of the cellular prion protein PrP(C), are still an enigma. Several studies suggest that neuronal loss could occur through a process of programmed cell death, which is consistent with the lack of inflammation in these conditions. By analogy with the pathological events occurring during the development of Alzheimer's disease, controversies still exist regarding the relationship between amyloidogenesis, prion aggregation, and neuronal loss. We recently demonstrated that a prion protein fragment (118-135) displayed membrane-destabilizing properties and was able to induce, in a nonfibrillar form, the fusion of unilamellar liposomes. To unravel the mechanism of prion protein neurotoxicity, we characterize the effects of the human Pr[118-135] peptide on rat cortical neurons. We demonstrate that low concentrations of the Pr[118-135] peptide, in a nonfibrillar form, induce a time- and dose- dependent apoptotic cell death, including caspase activation, DNA condensation, and fragmentation. This toxicity might involve oxidative stress, because antioxidant molecules, such as probucol and propyl gallate, protect neurons against prion peptide toxicity. By contrast, a nonfusogenic variant Pr[118-135, 0 degrees ] peptide, which displays the same amino acid composition but several amino acid permutations, is not toxic to cortical neurons, which emphasizes the critical role of the fusogenic properties of the prion peptide in its neurotoxicity. Taken together, our results suggest that the interaction between the Pr[118-135] peptide and the plasma membrane of neurons might represent an early event in a cascade leading to neurodegeneration.

Amino Acid Chloromethyl Ketones↗
PubMed1998

Interstitial fibrosis in hypercholesterolemic rats: role of oxidation, matrix synthesis, and proteolytic cascades.

Uninephrectomized rats with diet-induced hypercholesterolemia develop interstitial inflammation and fibrosis after 8 to 12 weeks. Fibrosis has been associated with the accumulation of lipid peroxidation products within the tubulointerstitium, along with increased renal mRNA levels for transforming growth factor beta-1 (TCF-beta 1), some matrix proteins, and the tissue inhibitor of metalloproteinases (TIMP-1). However, mRNA levels for urokinase-type plasminogen activator (uPA) have been found to be decreased. The purpose of the present study was to determine whether antioxidant therapy could attenuate interstitial fibrosis in hypercholesterolemic rats and to determine changes in the pattern of renal gene expression induced by antioxidant therapy. Three groups of uninephrectomized rats were studied after 12 weeks of feeding standard rat chow, an atherogenic diet (standard chow plus 4% cholesterol/1% cholic acid), or an atherogenic diet supplemented with high doses of the antioxidants probucol and vitamin E. Rats fed the atherogenic diet developed hypercholesterolemia and a 56% increase in total kidney collagen compared with rats fed standard chow. In comparison, the hypercholesterolemic rats treated with antioxidants had normal levels of renal lipid peroxidation products and a normal kidney collagen content. In contrast, there were no significant differences in urinary albumin excretion rates or the number of interstitial macrophages between the two hypercholesterolemic groups. Compared with the untreated hypercholesterolemic group, antioxidant therapy induced significant reductions in renal mRNA levels for procollagen III (to 60% of untreated levels), collagen IV (60%), and TIMP-1 (20%), while uPA levels were significantly increased (to 210%). Paradoxically, antioxidant therapy was associated with a significant increase in renal TGF-beta 1 mRNA levels (to 150%), although TGF-beta 1 protein expression shifted from interstitial to tubular epithelial cells in predominance. The results of the present study demonstrate the efficiency of antioxidant therapy in preventing renal interstitial fibrosis in hypercholesterolemic rats with a single kidney. Based on changes in renal gene expression at the mRNA level, impaired matrix protein synthesis and increased intrarenal activity of the metalloproteinases and uPA/plasmin may play a role in the attenuation of fibrosis.

Animals↗
PubMed1999

Ongoing clinical trials of lipid reduction therapy in patients with renal disease.

BACKGROUND: Lipid abnormalities in renal disease are associated with both a progressive decline in renal function and cardiovascular complications. Whether or not lipid anomalies are causal is not yet clear. Experimental studies have demonstrated that potentially atherogenic lipoproteins, such as low density lipoproteins (LDL), are associated with renal pathophysiological changes that result in progressive glomerular and interstitial damage and an ultimate reduction in renal function. These findings indicate that hyperlipidemia accelerates glomerular and interstitial damage in renal disease. Clinical studies also show that renal function declines more rapidly among patients with primary renal disease or diabetic nephropathy who have hyperlipidemia. However, few reports have demonstrated the effect of hypolipidemic agents on the progression of renal function among patients with renal disease, and those renal patients who were treated with lipid-lowering agents have not been clinically studied under large-scale controlled conditions. In addition, although cardiovascular complications are the most important factors associated with mortality in dialysis patients, randomized, large-scale trials studying the relationship between therapeutic intervention by lipid-lowering agents and prevention of cardiovascular complications have not been implemented. METHODS: We reviewed controlled and uncontrolled reported studies that examined the effects of lipid-lowering therapy in patients with renal disease. RESULTS: Most studies showed that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce cholesterol-rich apolipoprotein (apo)B-containing lipoproteins with no effects on renal function or proteinuria among patients with progressive renal disease. Small uncontrolled studies show that simvastatin and probucol moderately reduce proteinuria among patients with membranous nephropathy. One small retrospective study showed that long-term vitamin E therapy reduces aortic calcification in dialysis patients. CONCLUSIONS: Prospective, randomized large-scale trials including ongoing clinical trials of lipid reduction therapy and therapeutic interventions such as the use of the combination therapy with hypolipidemic agents and angiotensin converting enzyme (ACE) inhibitors, vitamins, or LDL apheresis are urgently required. Such trials will clarify the effect of treating dyslipidemia on the progression of renal insufficiency and dialysis-related cardiovascular complications.

Blood Component Removal↗
PubMed1999

Phospholipase A2 activity in ox-LDL-stimulated mesangial cells and modulation by alpha-tocopherol.

BACKGROUND: Oxidized LDL increases the production of both prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) in rat mesangial cells. These increases were suppressed by antioxidants such as alpha-tocopherol (alpha-Toc) or probucol. METHODS: We investigated the mechanism by which oxidized LDL leads to an increase in PGE2 production using rat mesangial cells in culture. We also examined how alpha-Toc supresses this augmentation, by measuring intracellular Ca2- and phospholipase A2 (PLA2) activity. RESULTS: In rat mesangial cells, oxidized LDL increased PLA2 activity by increasing the intracellular calcium ion content, which resulted in the induction of PGE2 production. On the other hand, pretreatment of cells with alpha-Toc, which resulted in a large uptake of alpha-Toc in cell membranes, markedly suppressed the augmentation of PGE2 production and PLA2 activity by oxidized LDL in a dose dependent manner. However, cytosolic PLA2 partially purified from mesangial cells was not inhibited by alpha-Toc despite an increase of alpha-Toc. CONCLUSION: These results suggest that the augmentation of PLA2 activity in mesangial cells by oxidized LDL in a result of oxidative stresses, and that the antioxidant action of alpha-Toc is responsible for the suppression of augmentation of PLA2 activity observed in mesangial cells exposed to oxidized LDL.

Animals↗
PubMed2001

Apheresis technology for prevention and regression of atherosclerosis.

Familial hypercholesterolemia (FH) is a congenital disorder of cholesterol metabolism, which is due to a deficiency in low-density lipoprotein (LDL) receptors. The homozygous form of FH is especially liable to coronary artery disease (CAD) in youth because of the very high LDL-cholesterol levels. It is resistant to drug therapy, and LDL-apheresis is the only practical way of treatment for these patients. Some patients with heterozygous FH also have high LDL-cholesterol levels that cannot be brought down into the optimum range by any combination drug therapy. We have treated or are treating 10 homozygous and 28 heterozygous FH patients in our hospital or in affiliated hospitals expert in blood purification. Among the 10 homozygous patients, 2 died of myocardial infarction. Only one young female patient is still free of symptoms, and the other patients have been suffering from regurgitation through the aortic valve although they have not experienced myocardial infarction. Rapid rebound of LDL-cholesterol after each apheresis treatment limits the period during which LDL-cholesterol is in the optimum range. The use of atorvastatin at a high dose (40 mg/day) was attempted to suppress this rebound. In contrast with good results in receptor-defective-type patients, receptor-negative-type patients did not show a response in LDL-cholesterol levels to the statin therapy although there was a slight increase in high-density lipoprotein (HDL)-cholesterol with a decrease in very-low-density lipoprotein-triglyceride and -cholesterol. Follow-up study of the patients with heterozygous FH revealed that LDL-apheresis was effective in lengthening the life expectancy of the patients with pre-existing CAD, especially those who had received intervention coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA). It was also shown that the use of probucol in combination with LDL-apheresis was effective in reducing coronary events as shown by the necessity of CABG or PTCA. Clinical data on the effect of LDL-apheresis, recently reported from some other institutions in Japan, will also be reviewed.

Atorvastatin↗
PubMed2002

Application of quantitative competitive polymerase chain reaction for measurements of mRNA from antioxidative enzymes in the diabetic rat retina and kidney.

This present study applied quantitative competitive polymerase chain reaction (QC-PCR) in the analyses of mRNA expression of the endogenous antioxidative enzymes CuZn superoxide dismutase (SOD), MnSOD, catalase, and glutathione peroxidase in tissue samples from the retina and kidney cortex of diabetic rats. RNA was extracted from snap-frozen retinas and pieces of the kidney cortex of male Wistar rats with streptozotocin (STZ)-induced diabetes and control rats. The mRNA levels were analyzed using QC-PCR. The animals were kept in the laboratory for 1 and 6 months, respectively, and fed a normal or probucol- (1% wt/wt) enriched diet. By using QC-PCR, relative mRNA levels of all antioxidative enzymes could be estimated in the retina and kidney cortex. In the retina, the relative catalase mRNA concentration was about 1/10 that of the other enzymes. After 6 months of diabetes, there was a 100% increase of the catalase (median, 0.012 [range, 0.008 to 0.017] v 0.006 [0.005 to 0.010]; P =.011) and a 50% increase of the glutathione peroxidase mRNA levels (0.88 [0.44 to 1.12] v 0.52 [0.31 to 0.79]; P =.044). In the kidney cortex, the relative glutathione peroxidase mRNA level was 10 to 15 times higher, and catalase mRNA level about half of those of CuZnSOD and MnSOD. After 1 month of diabetes, there was an increase only of the glutathione peroxidase mRNA levels, by 170% (17.59 [6.19 to 29.49] v 6.96 [2.34 to 9.04]; P =.047). We conclude that quantification of mRNA can provide difficulties when the amount of sample RNA is limited and/or the gene expression is low. The present study shows QC-PCR to be useful as a tool for measuring expression of mRNA not only in the kidney cortex but also in small tissue samples like the retina. Our results indicate modestly increased mRNA expression of catalase and glutathione peroxidase in the retina and likewise modestly increased mRNA expression of glutathione peroxidase in the kidney cortex of rats with STZ-induced diabetes. Extended studies, also including enzyme activities, are needed before any effect of hyperglycemia on the overall enzyme activity can be established.

Animals↗
PubMed2002

Esophageal cancer and the esophagus: challenges and potential strategies for selective cytoprotection of the tumor-bearing organ during cancer treatment.

Esophageal cancer is treated optimally with a combined-modality approach according to most clinical investigators. Cytotoxic chemotherapy and ionizing radiotherapy, given in a concomitant schedule, has yielded superior survival rates compared with radiotherapy alone. However, mucosal toxicity from such treatment may compromise quality of life and may mandate an unscheduled break in therapy in some patients who do not respond readily to standard treatments such as antacids; combinations of viscous xylocaine, aluminum hydroxide-magnesium carbonate, and diphenhydramine hydrochloride; oral liquid morphine sulfate, hydrocodone bitartrate, or acetaminophen. Hence, a number of alternative strategies that are designed to either prevent or limit toxicity to normal tissues without diminishing the antitumor effect are being tested. These include the use of conformal radiotherapy treatment planning techniques, amifostine (Ethyol, WR-2721), gene therapy via intratumoral injection of manganese superoxide dismutase-plasmid/liposome, glutamine, melatonin, omega-3-polyunsaturated fatty acids, transforming growth factor, flavonoid compounds, probucol, and keratinizing growth factor. An ongoing phase 2 trial by the North Central Cancer Treatment Group (NCCTG) may help clarify a role for cytoprotectants in patients receiving combined-modality therapy for esophageal cancer.

Amifostine↗