Biomedical subjects

M Athar

Publications and source records attributed to M Athar.

At least 73 records · Page 4Linked to original sources

PubMed1993

Asbestos induced oxidative injury to DNA.

DNA-damaging effects of asbestos in the presence of organic peroxides and hydroperoxides were investigated. The destabilization of the secondary structure of DNA, damage to deoxyribose sugar and DNA fidelity were measured, respectively, by S-1 nuclease hydrolysis, the formation of thiobarbituric acid (TBA)-reacting species and a melting temperature (Tm) profile using calf thymus DNA. S-1 nuclease hydrolysis and Tm determinations have shown that the presence of benzoylperoxide (BOOB), cumene hydroperoxide (COOH) or tertiary-butyl hydroperoxide (t-BOOH) increased asbestos-mediated DNA damage by a large factor compared either to asbestos alone or to peroxide or hydroperoxide alone. However, no formation of TBA-reacting species could be observed in this system. The quenchers of reactive oxygen species (ROS) afforded protection against DNA damage. These results suggest that asbestos in the presence of organic peroxides and hydroperoxides damage the DNA which is mediated by the generation of oxygen free radicals. The significance of these results in relation to the development of cancer of the respiratory tract among the asbestos exposed population is discussed.

Animals↗

PubMed1992

Gallbladder perforation: preoperative diagnosis by combined imaging techniques.

Gallbladder perforation represents the most serious complication of cholecystitis. Rapid preoperative diagnosis is necessary because of the high morbidity and mortality associated with it. The authors present a case of gallbladder perforation in a 64-year-old man who had been on high doses of steroids. This case was diagnosed preoperatively by combined radiologic imaging methods.

Cholecystitis↗

PubMed1992

Photodynamic effects of chloroaluminum phthalocyanine tetrasulfonate are mediated by singlet oxygen: in vivo and in vitro studies utilizing hepatic microsomes as a model membrane source.

Chloroaluminum phthalocyanine tetrasulfonate (AlPcTS) is a promising photosensitizer for the photodynamic therapy (PDT) of cancer. In this study, we investigated the in vivo and in vitro photodestruction of hepatic microsomal membranes by AlPcTS and studied the role of reactive oxygen species in this process. Irradiation of hepatic microsomes prepared from AlPcTS-pretreated SENCAR mice to approximately 675 nm light resulted in rapid destruction of cytochrome P450 and associated monooxygenase activities, and enhancement of lipid peroxidation in a light-dose-dependent manner. The specificity of AlPcTS and light dependency on photodestruction of microsomal membranes was confirmed by Western blot analysis. Similar results were obtained when AlPcTS was added in vitro to a suspension of hepatic microsomes prepared from control animals followed by irradiation to approximately 675 nm light. Among the quenchers of singlet oxygen, superoxide anion, hydrogen peroxide, and hydroxyl radical, only the quenchers of singlet oxygen such as sodium azide, histidine, and 2,5-dimethyl furan afforded substantial protection in a dose-dependent manner against AlPcTS-mediated photodestruction of cytochrome P450 and associated monooxygenase activities, and photoenhancement of lipid peroxidation under both in vivo and in vitro conditions. These results suggest that lipid-rich microsomal membranes may be the potential targets of cell injury by AlPcTS-based PDT and that this process is mediated by singlet oxygen.

Animals↗

PubMed1992

Photodynamic therapy of chemically- and ultraviolet B radiation-induced murine skin papillomas by chloroaluminum phthalocyanine tetrasulfonate.

Photodynamic therapy (PDT) of cancer combines irradiation of tumors with visible light following selective uptake of the photosensitizer by the tumor cells. PhotofrinR-II (Pf-II) is the only photosensitizer which is in clinical use in PDT, whereas chloroaluminum phthalocyanine tetrasulfonate (AlPcTS) has also shown promise in preclinical studies. In most such studies, the effectiveness of the photosensitizers has been assessed in implanted tumor model systems rather than in model systems where tumors are allowed to grow in their own connective tissue matrix. In this study the pharmacokinetics, tumor ablation capability and cutaneous photosensitization response of AlPcTS have been assessed in mice bearing chemically- and ultraviolet B radiation (UVB)-induced benign skin papillomas. When tumor-bearing animals were injected intraperitoneally with AlPcTS (5 mg/kg body wt), maximum tumor:normal skin ratio of 2.4 was observed at 48 h, at which time the mice were irradiated within the absorption spectrum of the photosensitizer. In tumor ablation studies with SENCAR mice bearing chemically-induced skin tumors, AlPcTS resulted in greater than 80% ablation in tumor volume at 20 days post-irradiation. In cutaneous photosensitization response, AlPcTS produced only transient effects (no effect after 24 h) in SENCAR mice. Pharmacokinetics data, tumor ablation effects and cutaneous photosensitization response of AlPcTS were comparable in SKH-1 hairless mice bearing UVB-induced skin tumors. Our data indicate that AlPcTS produces significant photodynamic effects towards the ablation of murine skin tumors, and that it does not produce prolonged cutaneous photosensitivity.

Animals↗

PubMed1991

Involvement of singlet oxygen in chloroaluminum phthalocyanine tetrasulfonate-mediated photoenhancement of lipid peroxidation in rat epidermal microsomes.

In recent studies chloroaluminum phthalocyanine tetrasulfonate (AlPCTS) has been shown to be an effective photosensitizer for the tumor necrosis in a modality known as photodynamic therapy, but the mechanism of photodynamic effect of AlPCTS is poorly understood. In this study, in vitro incubation of rat epidermal microsomes with AlPCTS followed by exposure to red light (approximately 675 nm) resulted in an increase in ADP/iron-supported lipid peroxidation, a measure of membrane damage. This photodestructive effect was found to be dependent on both the duration of light exposure and the dose of AlPCTS. Studies employing various quenchers of reactive oxygen species revealed that scavengers of singlet oxygen (histidine, 2,5-dimethylfuran, beta-carotene and sodium azide) afforded substantial protection (up to 90%) of photoenhancement whereas the scavengers of hydrogen peroxide (catalase), superoxide anion (superoxide dismutase), and hydroxyl radical (sodium benzoate, mannitol and ethanol) were ineffective in this regard. Our data indicate that AlPCTS-mediated photodestruction mainly involves a type II reaction via singlet oxygen formation and suggest that the latter could play a significant role in the tumor necrosis evoked by AlPCTS and light.

Animals↗

PubMed1991

All-trans retinoic acid protects against conversion of chemically induced and ultraviolet B radiation-induced skin papillomas to carcinomas.

It is becoming increasingly clear that cutaneous carcinogenesis in murine skin is a stepwise process comprising of initiation, promotion and progression. Most of the papillomas induced by an initiation-promotion protocol regress, while a few of them progress to malignant carcinomas. Progression of benign tumors into malignant cancer is critical since the latter lesions are capable of metastatic spread and eventual death. Inhibitors of the conversion process are therefore likely to be useful as cancer chemopreventive agents. All-trans retinoic acid (RA) is a known regulator of cellular proliferation and differentiation, and a known inhibitor of tumor promotion in murine skin. In this study we assessed the effect of topical application of RA on conversion of benign skin papillomas to malignant carcinomas. Papillomas were induced in SENCAR mice by topical application of 7,12-dimethylbenz[a]anthracene (DMBA) as tumor initiator followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) as tumor promoter. In SKH-1 hairless mice papillomas were induced by thrice weekly exposure to ultraviolet B (UVB) radiation. At 18 (DMBA/TPA group) and 25 (UVB group) weeks papilloma yield stabilized and no new tumors developed. Beginning at the 20th week (DMBA/TPA group) and at the 27th week (UVB group), malignant conversion was achieved by twice weekly topical application of TPA or free radical-generating compounds benzoyl peroxide (BPO), 2,2-azobis(2-amidinopropane) (ABP) and tert-butyl peroxybenzoate (BPB). Application of RA (10 micrograms/animal) 1 h prior to skin application of TPA, BPO, ABP or BPB afforded significant protection (up to 70%) only against malignant conversion mediated by free radical-generating compounds in both chemically induced and UVB-induced benign skin papillomas. On the other hand, preapplication of RA was less effective in the suppression of spontaneous malignant conversion in vehicle-treated animals. These results suggest that, in addition to their anti-tumor promoting effects, retinoids may also act as anti-carcinogens by inhibiting the process of malignant conversion induced by free radical-generating compounds.

Animals↗

PubMed1991

Cadmium-mediated induction of cellular defence mechanism: a novel example for the development of adaptive response against a toxicant.

Early response to the exposure of cadmium includes the enhancement in lipid peroxidation with the concomitant impairment in antioxidative defence mechanism. This investigation deals with the delayed response of cadmium induced stimulation of endogenous defence response against its oxidative damage. The administration of cadmium led to an increase in the hepatic enzymatic and nonenzymatic defence armory in a dose dependent manner 72 hrs post its administration. This includes respectively an increase in the activities of superoxide dismutase, glutathione peroxidase, glucose-6-phosphate dehydrogenase and in the levels of glutathione, metallothionein and zinc. Cadmium administration also stimulated serum ceruloplasmin activity in a dose dependent manner. These changes are accompanied by the concomitant decrease in the peroxidative damage to lipids. Our results suggest the development of a delayed adaptive/defence response as a result of exposure to cadmium.

Animals↗

PubMed1991

Photodynamic therapy of murine skin tumors using Photofrin-II.

Photodynamic therapy (PDT) is a new experimental cancer therapy in which a photosensitizing chemical that selectively localizes within tumors is given to a tumor-bearing individual and the tumor is then irradiated by wavelengths within the visible spectrum of the photosensitizer. The only photosensitizer currently approved for human clinical trials is Photofrin-II (Pf-II). In most preclinical studies, the effectiveness of Pf-II has been assessed in implanted tumor models rather than in systems in which tumors are grown in their own connective tissue matrix. In this study, the pharmacokinetics, tumor ablation capability and cutaneous photosensitizing capacity of Pf-II were assessed in mice bearing chemically induced or ultraviolet B radiation (UVB)-induced benign skin neoplasms. Intraperitoneal administration of Pf-II (5 mg/kg body weight) to tumor-bearing animals showed maximum tumor: normal skin ratio of the photosensitizer at 72 h. When SENCAR mice bearing chemically induced tumors were irradiated with visible light corresponding to the absorption spectrum of the photosensitizer, up to 89% ablation in tumor volume at 20 d post-irradiation was observed. Animals treated with Pf-II and exposed to visible light showed significant cutaneous photosensitization for at least 6 d after-irradiation. Treatment of SKH-1 hairless mice bearing UVB-induced cutaneous neoplasms with Pf-II exhibited similar pharmacokinetics, skin tumor ablation effects and cutaneous photosensitivity. Our data indicate that Pf-II has significant activity towards the ablation of murine skin benign tumors grown in their own tissue matrix, suggesting that such a murine skin tumor model system could be valuable in evaluating the photodynamic effects of newly developed photosensitizers.

Animals↗

PubMed1990

Evidence for the involvement of singlet oxygen in the photodestruction by chloroaluminum phthalocyanine tetrasulfonate.

In recent years, choloroaluminum phthalocyanine tetrasulfonate (A1PCTS) has been shown to be a promising photosensitizer for the photodynamic therapy (PDT) of cancer. Although its mechanism of photodynamic action is not well defined, A1PCTS is going to be under clinical trials of PDT. In this study, in vitro addition of A1PCTS to a suspension of rat epidermal microsomes followed by irradiation with red light (approximately 675 nm) resulted in significant destruction of cytochrome P-450 and associated monooxygenase activities. The photodestructive effect was dependent on both the dose of A1PCTS and the duration of light exposure. Studies using various quenchers of reactive oxygen species showed that only scavengers of singlet oxygen such as histidine, 2,5-dimethylfuran, beta-carotene and sodium azide afforded substantial protection against photodestruction. Our data indicate the direct involvement of singlet oxygen in the A1PCTS-mediated photodestructive process.

Aluminum↗

PubMed1990

Inhibition of benzoyl peroxide-mediated tumor promotion in 7,12-dimethylbenz(a)anthracene-initiated skin of Sencar mice by antioxidants nordihydroguaiaretic acid and diallyl sulfide.

Benzoyl peroxide (BPO), a free radical generating compound, is widely used in topical medications prescribed for acne vulgaris and in cosmetic products. It has been shown to possess tumor-promoting activity in murine skin initiated with chemical carcinogens such as 7,12-dimethylbenz(a)anthracene (DMBA). In the present study we assessed the effect of the antioxidants nordihydroguaiaretic acid (NDGA) and diallyl sulfide (DAS) against BPO-mediated tumor promotion in murine skin. Pretreatment of Sencar mice with NDGA and DAS prior to skin application of BPO resulted in a time- and dose-dependent inhibition of epidermal ODC induction caused by BPO. Tumor initiation was achieved by a single topical application of DMBA (10 micrograms/animal) to Sencar mice. Ten days later tumor promotion was begun by twice-weekly topical application of BPO (20 mg/animal). The anticarcinogenic effects of NDGA (25 mumol/mouse) and DAS (20 mumol/mouse) were evaluated by administering these agents topically 60 min prior to each BPO application. After 26 weeks on test, the number of benign papillomas/mouse were 0.10 +/- 0.07 and 2.15 +/- 0.30 in the NDGA and DAS pretreated group of animals as compared to 4.40 +/- 1.14 in animals receiving BPO alone. After 51 weeks on test, the number of squamous cell carcinomas/mouse were 0.00 +/- 0.00, 0.35 +/- 0.10 in the NDGA and DAS pretreated group of animals as compared to 0.65 +/- 0.12 in animals receiving BPO alone. From these data we suggest that the antioxidants NDGA and DAS can abrogate the tumor-promoting effects of BPO in murine skin and that NDGA is substantially more effective than DAS in this regard.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1990

Nickel-mediated inhibition in the glutathione-dependent protection against lipid peroxidation.

Glutathione protects liver microsomes against the rapid onset of lipid peroxidation via a sulfhydryl dependent heat labile factor known as free radical reductase. The administration of nickel to mice resulted in an inhibition in the activity of free radical reductase, and enhanced lipid peroxidation and the activity of glutathione S-transferase in a dose dependent manner. The pretreatment of cyclam, a known specific chelator of nickel restored free radical reductase and glutathione S-transferase activities and alleviated nickel mediated enhancement of lipid peroxidation. Our results indicate that nickel-mediated inhibition in free radical reductase activity and activation of glutathione S-transferase may be due to the interaction of nickel with sensitive-SH groups located on these proteins.

Animals↗

PubMed1989

Effect of dietary tannic acid on epidermal, lung, and forestomach polycyclic aromatic hydrocarbon metabolism and tumorigenicity in Sencar mice.

Tannic acid inhibits the mutagenicity of several polycyclic aromatic hydrocarbons (PAHs) and their bay-region diol-epoxides. Our prior studies have shown that when applied topically to Sencar mice, tannic acid caused substantial inhibition of epidermal PAH metabolism, subsequent PAH-DNA adduct formation, and PAH-induced skin tumorigenesis (H. Mukhtar et al., Cancer Res., 48:2361-2365, 1988, and references therein). In this study the effects of tannic acid supplementation in the diet (1%, w/w, in AIN-76 diet) of Sencar mice on benzo(a)pyrene (BP) metabolism and its subsequent DNA binding and tumorigenesis in lung and forestomach were evaluated. Animals receiving a tannic acid-containing diet showed diminished aryl hydrocarbon hydroxylase and 7-ethoxy-resorufin O-deethylase activities in the forestomach and lung. Elevated glutathione S-transferase and NAD(P)H:quinone reductase activities were observed in these tissues. Maximum effects occurred after 45 days of feeding. Administration of [3H]BP p.o. to animals resulted in lower covalent binding to DNA in forestomach and lung of animals receiving tannic acid-containing diet as compared to animals receiving AIN-76 control diet. Tumor induction studies in forestomach and lung revealed significant protection against BP-induced tumorigenesis in animals fed tannic acid-supplemented diet as compared to animals fed control diet. The mice fed tannic acid-supplemented diet developed 3.3 forestomach tumors/mouse compared to 5.2 tumors/mouse in animals receiving control diet. The numbers of pulmonary tumors per mouse in animals fed tannic acid-supplemented diet and control diet were 1.6 and 3.1, respectively. Topical application of 7,12-dimethylbenz(a)anthracene to animals fed tannic acid-supplemented diet did not result in significant protection against skin tumorigenesis. However, a slight delay in the onset of skin tumor formation occurred in tannic acid-fed animals when compared to animals receiving control diet. Our data suggest that dietary supplementation with tannic acid affords protection against BP-induced forestomach and lung tumorigenesis in rodents.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1989

Inhibition of the high affinity Fc receptor (Fc gamma RI) on human monocytes by porphyrin photosensitization is highly specific and mediated by the generation of superoxide radicals.

p72 high affinity receptors (Fc gamma RI) for the Fc portion of IgG molecules on human peripheral blood monocytes mediate a variety of beneficial functions, but also have deleterious effects in certain clinical situations. In the present study, the photosensitizing porphyrins hematoporphyrin derivative and dihematoporphyrin ether (DHE), which are known to preferentially affect the cell membrane, were found to significantly inhibit binding of mouse IgG2a antibodies to the ligand binding site of Fc gamma RI on human peripheral blood monocytes and the U937 human monocytic cell line. Fc gamma RI receptors could be identified with a monoclonal antibody which recognizes an epitope distinct from the ligand binding site, indicating that photosensitization induced a structural alteration rather than loss of the receptor molecule from the cell surface. The effect of DHE and light appeared to be highly specific, since binding of monoclonal antibodies to other surface structures was not decreased. DHE plus light-induced modulation of Fc gamma RI was found to be mediated by superoxide anions, since addition of a mimic of superoxide dismutase restored both binding of mouse IgG2a to Fc gamma RI as well as human monocyte accessory cell function. These studies identify porphyrin photosensitization as a unique mechanism by which to selectively down-regulate Fc gamma RI-mediated functions.

Antibodies, Monoclonal↗

PubMed1989

Antimutagenic activity of green tea polyphenols.

For centuries green tea has been a widely consumed beverage throughout the world. It is known to contain a number of pharmacologically active compounds. In this study water extracts of green tea (WEGT) and their major constituents, green tea polyphenols (GTP), were examined for antimutagenic activity. WEGT and GTP were found to significantly inhibit the reverse mutation induced by benzo[alpha]pyrene (BP), aflatoxin B1 (AFB1), 2-aminofluorene, and methanol extracts of coal tar pitch in Salmonella typhimurium TA100 and/or TA98 in the presence of a rat-liver microsomal activation system. GTP also inhibited gene forward mutation in V79 cells treated with AFB1 and BP, and also decreased the frequency of sister-chromatid exchanges and chromosomal aberrations in V79 cells treated with AFB1. The addition of GTP during and after nitrosation of methylurea resulted in a dose-dependent inhibition of mutagenicity. Studies to define the mechanism of the antimutagenic activity of GTP suggest that it may affect carcinogen metabolism, DNA adduct formation, the interaction of ultimate carcinogen or the scavenging of free radicals.

Aflatoxin B1↗

PubMed1989

Malignant conversion of UV radiation and chemically induced mouse skin benign tumors by free-radical-generating compounds.

It is known that the free-radical-generating compound, benzoyl peroxide (BPO) enhances malignant conversion of murine skin benign papillomas into carcinomas. To further define the role of free radicals in malignant conversion, we studied the effect of various free-radical-generating compounds on the conversion of benign papillomas into carcinomas in murine skin. Papillomas were induced in Sencar mice by 7,12-dimethylbenz[a]anthracene (DMBA) initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion and in SKH-1 hairless mice by biweekly exposure to UVB radiation. After 20 and 27 weeks respectively, papilloma yield stabilized and no new tumors developed. Skin application of acetone, TPA, BPO, 2,2-azobis(2-amidino-propane) (ABP) and tert-butyl hydroperoxybenzoic acid (BPB) increased the rate of malignant conversion in both Sencar and SKH-1 mice. In general, the rate of malignant conversion was faster in UVB-induced tumors compared with DMBA-induced tumors. The relative efficacy of each agent was similar in both groups and was in the order: acetone less than TPA less than BPB less than BPO less than ABP. Our data suggest that free-radical-generating compounds may accelerate the malignant conversion of benign papillomas into carcinoma, indicating that epigenetic mechanism(s) may also be involved in this process.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1989

Evidence for the metabolism of tumor promoter organic hydroperoxides into free radicals by human carcinoma skin keratinocytes: an ESR-spin trapping study.

Humans are exposed to various peroxy and hydroperoxy compounds which are in use in the cosmetic, pharmaceutical and polymer industries and which are also generated as a result of the peroxidative metabolic conversion of certain lipids. This study was designed to determine whether the organic hydroperoxides, tert-butyl hydroperoxide, cumene hydroperoxide and tert-butyl peroxybenzoate are metabolized by human carcinoma skin keratinocytes to free radicals. Incubation of keratinocytes prepared from cutaneous squamous cell carcinoma in phosphate-buffered saline (pH 7.4) containing desferrioxamine with tert-butyl hydroperoxide, cumene hydroperoxide and tert-butyl peroxybenzoate in the presence of spin trap (3,5-dibromonitrosobenzene sulfonic acid) resulted in the generation of corresponding methyl radical adducts. Prior heating of the cells to 100 degrees C abolished the generation of radical adducts. The addition of ethanol to the reaction mixture also inhibited formation of radical adducts. These data provide the first direct evidence that human carcinoma skin cells can generate free radicals from organic hydroperoxides. Since free radicals are suggested to be involved in the cascade of events occurring during tumor promotion this metabolic capacity may be an important determinant of human cancer risk for hydroperoxides.

Benzene Derivatives↗

PubMed1989

Colonic filiform polyposis and a malignant adenomatous polyp.

We have reported a case of pseudopolyposis in the unusual form of filiform polyps in the transverse colon with an adenomatous polyp in the sigmoid colon that had a focus of malignant degeneration. The patient did not have any significant past history of inflammatory bowel disease.

Adenoma↗

PubMed1989

A novel mechanism for the generation of superoxide anions in hematoporphyrin derivative-mediated cutaneous photosensitization. Activation of the xanthine oxidase pathway.

Prior studies, both in vitro and in vivo, have suggested that cutaneous porphyrin photosensitization requires the generation of superoxide anion (.O2-) and various other reactive oxygen metabolites. No unifying concept has emerged, however, that unequivocally demonstrates the source of generation of these species. Since xanthine oxidase is known to generate .O2- in reperfused ischemic tissue and in certain inflammatory disorders, we attempted to assess its role in porphyrin photosensitization. C3H mice were rendered photosensitive by the intraperitoneal administration of dihematoporphyrin ether (DHE) (5 mg/kg) followed by irradiation with visible light. Murine ear swelling was used as a marker of the acute photosensitization response and involvement of oxygen radicals was evaluated using electron spin resonance (ESR) spectroscopy. The administration of allopurinol, a potent inhibitor of xanthine oxidase, afforded 90% protection against DHE-mediated acute photosensitivity in vivo. Furthermore, xanthine oxidase activity was twofold higher in the skin of photosensitized mice than in unirradiated animals. ESR spectra of 5,5-dimethyl-1-pyrroline N-oxide-trapped radicals from the skin of photosensitized mice verified the presence of .O2- and .OH, while neither of these species was detected in the skin of control mice or mice receiving allopurinol. The administration of a soybean trypsin inhibitor or verapamil before irradiation also partially blocked the photosensitivity response, suggesting that calcium-dependent proteases play a role in the activation of xanthine oxidase in this photodynamic process. These data provide in vivo evidence for the involvement of .O2- in DHE-mediated cutaneous photosensitization and suggest that these radicals are generated through the activation of the xanthine oxidase pathway. The administration of allopurinol and calcium channel blockers may thus offer new approaches for the treatment of cutaneous porphyrin photosensitization.

Allopurinol↗