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Biomedical subjects

D R Bickers

Publications and source records attributed to D R Bickers.

At least 55 records · Page 3Linked to original sources
PubMed1991

Inhibition of mutagenicity in Salmonella typhimurium and skin tumor initiating and tumor promoting activities in SENCAR mice by glycyrrhetinic acid: comparison of 18 alpha- and 18 beta-stereoisomers.

Licorice has been used as medicine and as sweetening agent in food products. The major water-soluble constituent of licorice is glycyrrhizin (GL), an oleanane triterpenoide, which is known to be partly hydrolyzed by glucuronidase to its aglycone glycyrrhetinic acid (GA) which exists in 18 alpha (alpha-GA) and 18 beta (beta-GA) stereoisomeric forms. In this study alpha-GA and beta-GA were found to inhibit the mutagenicity of benzo[a]pyrene (B[a]P), 2-aminofluorene and aflatoxin B1 in Salmonella typhimurium TA98 and TA100. beta-GA was more effective than alpha-GA as an antimutagen. In the two-stage skin tumorigenesis protocol using 7,12-dimethylbenz[a]anthracene (DMBA) as the tumor initiating agent followed by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate as tumor promoter, pretreatment of SENCAR mice with alpha-GA or beta-GA resulted in significant protection against tumor initiation as well as tumor promotion. As an anti-tumor initiating agent, beta-GA was found to be more effective than alpha-GA. Similarly, topical application of beta-GA was found to be more effective than alpha-GA in inhibiting the binding of both [3H]B[a]P and [3H]DMBA to epidermal DNA. However, as an anti-tumor promoter, alpha-GA and beta-GA showed comparable effects. Our results suggest that both alpha-GA and beta-GA possess substantial anti-skin tumor initiating and anti-skin tumor promoting activities.

Animals↗
PubMed1991

Protection against ultraviolet B radiation-induced photocarcinogenesis in hairless mice by green tea polyphenols.

Our recent studies have shown that polyphenols present in green tea (GTP) possess significant antigenotoxic activity and afford protection against polycyclic aromatic hydrocarbon-induced skin tumor initiation in mice. In this study we assessed the effect of oral feeding and topical application of GTP on ultraviolet B (UVB) radiation-induced skin carcinogenesis in female SKH-1 hairless mice. Chronic oral feeding of GTP (0.1%, w/v) in drinking water resulted in significantly (P less than 0.01) lower tumor yield (percent of animals with tumors and number of tumors per mouse) and extended TDT50 (P less than 0.05), as compared to animals receiving normal drinking water. Topical application of GTP before UVB irradiation also afforded protection against photocarcinogenesis; however, the protective response was lower than that observed by oral feeding of GTP in drinking water. These results, in conjunction with our prior publications, suggest that consumption of green tea may reduce the risk of some forms of human cancer induced by both physical and chemical environmental carcinogens.

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

[Principles of photobiology and photochemistry].

The relationship between light exposure and UV induced skin diseases is presented. The basic law is: "No photobiology--no photochemistry". Photoaging, phototoxic and photoallergic reactions, porphyria, UV-carcinogenesis, and alterations of immune functions are discussed.

Humans↗
PubMed1989

Protection against chemically induced skin tumorigenesis in SENCAR mice by tannic acid.

Tannic acid, a naturally occurring dietary polyphenol, was evaluated as a possible anticarcinogen in an initiation-and-promotion skin tumorigenesis protocol. In the 2-stage tumor protocol in SENCAR mice, using DMBA, BP and MNU as the initiating agents followed by twice-weekly applications of TPA as tumor promotor, tannic acid was found to be an effective inhibitor of tumor formation whether the tumor data are considered as cumulative number of tumors, percentage of mice with tumors or tumors/mouse. After 9 weeks of TPA application, the number of tumors/mouse in the groups receiving DMBA, BP and MNU were 32.10 +/- 3.18, 3.70 +/- 0.55 and 2.00 +/- 0.53, respectively, whereas the corresponding numbers in the DMBA, BP and MNU groups receiving prior applications of tannic acid were 11.50 +/- 2.38, 0.35 +/- 0.15 and 0.35 +/- 0.13, respectively. These results suggest that tannic acid may prove useful in reducing the risk of chemically-induced skin tumorigenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Effect of topical application of clotrimazole to rats on epidermal and hepatic monooxygenase activities and cytochrome P-450.

Clotrimazole, an N-substituted imidazole, is a widely used topical agent for the treatment of superficial fungal infections. In this study, the effect of application of clotrimazole to the skin of neonatal rats on the induction response of the cytochrome P-450-dependent monooxygenase system in epidermis and liver has been examined. A single topical application of clotrimazole (10 mg/100 g) to rats resulted in a 53% increase in hepatic cytochrome P-450 content. Clotrimazole treatment also resulted in significant induction of epidermal 7-ethoxycoumarin-O-deethylase activity. Hepatic p-nitrophenol hydroxylase, an enzyme, catalyzed principally by the ethanol inducible cytochrome P-450 isozyme, was also significantly induced (58%) by topically applied clotrimazole. This enzyme activity was undetectable in epidermal microsomes. Further characterization of the cytochrome P-450 isozymes induced in liver by clotrimazole treatment was based on monoclonal antibodies (MAbs) raised against purified rat liver cytochrome P-450 isozymes induced by phenobarbital (MAb 2-66-3) and ethanol (MAb 1-98-1). Hepatic microsomes prepared from clotrimazole-treated rats showed significant immunoreactivity on Western blot with both the MAbs whereas no reactivity occurred in epidermal microsomes. Our data indicate that topical application of clotrimazole to rats results in the induction of selected cytochrome P-450 isozyme(s) in liver and epidermis which may have implications for the therapeutic use of this compound.

Administration, Topical↗
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

Topical capsaicin treatment of chronic postherpetic neuralgia.

Uncontrolled studies have indicated that topically applied capsaicin may be a safe and effective treatment for postherpetic neuralgia. In a double-blind study 32 elderly patients with chronic postherpetic neuralgia were treated with either capsaicin cream or its vehicle for a 6-week period. Response to treatment was evaluated by visual analogue scales of pain and of pain relief, together with changes in a categoric pain scale and in a physician's global evaluation. Significantly greater relief in the capsaicin-treated group compared with vehicle was observed for all efficacy variables. After 6 weeks almost 80% of capsaicin-treated patients experienced some relief from their pain. Because capsaicin avoids problems with drug interactions and systemic toxicity, we suggest that topical capsaicin be considered for initial management of postherpetic neuralgia.

Administration, Topical↗
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

Protection against polycyclic aromatic hydrocarbon-induced skin tumor initiation in mice by green tea polyphenols.

Green tea is a popular beverage in China and Asia and has been shown to possess antipyretic, diuretic and several other pharmacological activities. The major constituents of green tea are polyphenols which have been found to possess antioxidant and antimutagenic properties. In this study green tea polyphenols (GTP) were evaluated as an anti-initiating agent against the skin tumorigenicity induced by polycyclic aromatic hydrocarbons (PAHs) in mice. In a complete skin tumorigenesis protocol using 3-methylcholanthrene the topical application of GTP to female BALB/c mice resulted in substantial protection against the onset and subsequent development of tumors. In the two-stage skin tumorigenesis protocol using 7,12-dimethylbenz[a]anthracene (DMBA) as the initiating agent followed by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate; (TPA) as tumor promoter, topical application of GTP to female SENCAR mice afforded significant protection against skin tumorigenicity. Oral feeding of GTP in drinking water to female SENCAR mice also protected against skin tumorigenesis in DMBA - TPA-treated animals. GTP when administered topically or orally significantly inhibited PAH - DNA adduct formation in epidermis after topical application of [3H]benzo[a]pyrene or [3H]DMBA. Our results suggest that GTP has substantial anti-skin-tumor-initiating activity against PAHs and could prove useful in protecting against some forms of human cancer.

Animals↗
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

Monoclonal antibodies directed characterization of epidermal and hepatic cytochrome P-450 isozymes induced by skin application of therapeutic crude coal tar.

A single application of crude coal tar (CCT) solution (USP) to the skin of neonatal rats was shown to induce epidermal and hepatic cytochrome P-450(P-450)-dependent monooxygenase activities. To further characterize the induction response, in this study we have utilized highly specific monoclonal antibodies (MoAb) 1-7-1, 2-66-3, and 1-98-1 directed against highly purified rat liver P-450s induced by 3-methyl-cholanthrene, phenobarbital and ethanol, respectively. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of hepatic microsomes prepared from CCT-treated animals showed a significant increase in the coomassie blue stainable proteins in the P-450 region; however, this was not evident in epidermal microsomes. Immunoblot analysis of epidermal and hepatic microsomes with MoAb 1-7-1 revealed strong immunoprecipitin bands in both tissues. MoAb 2-66-3 showed significant immunoreactivity only with hepatic microsomes. Interestingly, CCT treatment resulted in suppression of immunoreactivity with MoAb 1-98-1 in hepatic microsomes. MoAb 1-7-1 and 2-66-3 exhibited concentration-dependent inhibitory effects in aryl hydrocarbon hydroxylase and 7-ethoxycoumarin-O-deethylase activities induced by CCT application. MoAb 1-7-1 was substantially more effective in this respect. Epidermal and hepatic microsomes prepared from CCT-treated rats showed significantly greater metabolism of benzo(a)pyrene (BP). MoAb 1-7-1 and MoAb 2-66-3 inhibited BP metabolism in both the tissues. However, MoAb 1-7-1 was more inhibitory in this regard as compared to MoAb 2-66-3. These studies indicate that topical application of therapeutic CCT to the skin of neonatal rats results in induction of P-450 isozyme c in epidermis and isozymes b and c in liver, and that this induction is associated with the suppression of P-450 isozyme j in liver.

Administration, Topical↗
PubMed1989

Cytochrome P-450-dependent omega-oxidation of leukotriene B4 in rodent and human epidermis.

Leukotriene B4 (LTB4,5-12-dihydroxy 6,8,10,14-eicosatetraenoic acid), an enzyme-catalyzed oxidation product of arachidonic acid, is a major inflammatory mediator. Human polymorphonuclear leukocytes and rodent hepatic microsomes catabolize LTB4 to 20-OH-LTB4 and 20-COOH-LTB4, which is mediated by a cytochrome P-450 catalyzed reaction termed the LTB4 omega-hydroxylase. In this study we investigated the catabolism of LTB4 in rat, guinea pig, and human epidermis. The incubation of 3H-LTB4 (9 microM) for 60 min in the presence of oxygen, NADPH, and epidermal microsomes prepared from neonatal fat (3.0 mg) or adult guinea pig (2.6 mg) resulted in the formation of 20-OH-LTB4 and 20-COOH-LTB4. Metabolite identification was based on co-chromatography on high pressure liquid chromatography with highly purified reference standards. The formation of 20-OH-LTB4 and 20-COOH-LTB4 was accompanied by the disappearance of LTB4. The rate of formation of 20-OH-LTB4 was 9-12-fold higher than that of 20-COOH-LTB4. Product formation was negligible with boiled microsomes, required NADPH and oxygen, was linear with respect to incubation time and protein, and was maximal at pH 7.4. LTB4-omega-hydroxylase activity was inhibited (greater than 90%) by carbon monoxide or 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF-525A) (1 mM), whereas alpha-naphthoflavone produced only moderate (13%) or no effects. Topical application of 3-methylcholanthrene and other conventional inducers of epidermal monooxygenase activities to neonatal rats (100 mg/kg, single treatment) did not result in an increase in epidermal LTB4-omega-hydroxylase activity. The addition of 3H-LTB4 (30 nmoles) to primary human keratinocytes followed by incubation at 37 degrees C resulted in time-dependent disappearance of LTB4 and appearance of 20-OH-LTB4 and 20-COOH-LTB4 in the medium. These results suggest that LTB4 is catabolized by the cytochrome P-450-dependent enzyme system in rodent and human skin and that this may participate in modulating the effects of this proinflammatory lipid in this tissue.

Animals↗
PubMed1989

Benzo(a)pyrene metabolism, DNA-binding and UV-induced repair of DNA damage in cultured skin fibroblasts from a patient with unilateral multiple basal cell carcinoma.

The metabolism of benzo(a)pyrene (BP), a ubiquitous environmental carcinogen, and its subsequent binding to DNA, and the repair of UV-induced DNA damage were studied in fibroblasts cultured from the skin of a 61-year-old male who had multiple BCC (greater than 100) on his left upper trunk. Biopsies were obtained and fibroblasts cultured from clinically normal tumour-free skin adjacent to tumour-bearing sites (TBS) and from visibly uninvolved normal skin (UNS) at distant sites. The cultured cells were incubated with [3H]-BP for 24 h and BP metabolism was assessed by HPLC and the formation of BP-diols, quinones and phenols verified. Total BP metabolism was 45% lower in TBS fibroblasts than in UNS fibroblasts. The formation of BP-7,8-diol, the precursor of the carcinogenic end product of BP metabolism, was 53% lower in TBS cells than in UNS cells. Pretreatment of UNS cells with benz(a)anthracene (BA) (x 10(-4) M) did not significantly affect BP metabolite formation whereas BA-treatment of TBS cells resulted in 55% and 76% increases in total BP metabolism and BP-7,8-diol formation, respectively. Treatment of TBS cells with BA also caused a substantial increase (95%) in BP-DNA adduct formation. Whereas DNA-binding in UNS cells was unaffected by this treatment. In response to irradiation with 2J/m2 UVC, total DNA repair was similar in both cell types; on alkaline elution it appeared that the TBS cells were more efficient in repairing UV-induced DNA strand breaks. These results suggest that BP metabolism and repair of DNA are altered in TBS cells and that patients with this type of metabolic profile may be at higher risk of the development of cutaneous neoplasms. It is also possible that fibroblasts from tumour bearing skin undergo some as yet unexplained alteration in carcinogen metabolism as a consequence of the induction of neoplasia.

Benz(a)Anthracenes↗