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Biomedical subjects

G Shklar

Publications and source records attributed to G Shklar.

At least 19 recordsLinked to original sources
PubMed1992

The selective cytotoxic effect of carotenoids and alpha-tocopherol on human cancer cell lines in vitro.

This study compares the toxic effects of the carotenoids, beta-carotene and canthaxanthin, and alpha-tocopherol (vitamin E) on human tumor cells and their normal counterparts in vitro. Seven different malignant cell lines were examined: oral carcinoma (two cell lines), breast (two cell lines), lung carcinoma (two cell lines), and malignant melanoma. The in vitro cell culture assays showed a consistent morphologic change in the affected tumor cells following treatment with carotenoid or vitamin E. A rounding of the tumor cells and eventual lifting off the tissue culture plate were observed. These changes were apparent after 1 to 5 hours of treatment depending on the tumor cell line. Associated with these observable cellular changes were quantitative reductions in proliferation (3H-thymidine proliferation) and succinic dehydrogenase activity (MTT assay). In addition, there was a noticeable change in protein expression, with an increased expression of a 70-kD protein following treatment with beta-carotene. This protein was associated with tumor cells showing a decrease in proliferation (oral carcinoma, malignant melanoma) but not with normal keratinocytes or melanocytes. These studies substantiate a selective cytotoxic effect on human tumor cell growth by carotenoids and alpha-tocopherol in vitro, and may provide an explanation of the therapeutic activity of these agents and their possible use in the treatment of premalignancy or early oral carcinoma.

Breast Neoplasms↗
PubMed1991

Sequential mast cell infiltration and degranulation during experimental carcinogenesis.

Mast cell density, distribution, and ultrastructure were studied by light and electron microscopy in hamster buccal pouches undergoing chemically induced carcinogenesis. Epidermoid carcinomas in the pouches were induced by three topical applications per week of 0.5% 7,12-dimethylbenz[a]anthracene (DMBA) in oil using a brush. Four experimental, DMBA-treated and two normal, untreated hamsters were sacrificed after 8, 10, 12, 14, and 16 weeks. After 8 weeks of DMBA treatment, the epithelium showed the pathological signs of dysplasia and hyperkeratosis. In the dermis an increased number of mast cells were evident, some of which showed degranulation. A few mast cells had started to migrate upwards towards the dysplastic epithelium after 10 weeks of DMBA treatment. Rapid degranulation was also apparent in some mast cells. These processes of upward migration and degranulation continued progressively during the 12- and 14-week periods of DMBA application in correlation with the progression of the tumor. By 16 weeks of treatment with the carcinogen, more mast cells had migrated closer to the invasive carcinoma, and many had degranulated. In the connective tissue mast cells were fully packed with many granules, and some mast cells were in proximity to macrophages and eosinophils. Our observations demonstrate that there is a positive correlation between developing carcinomas and mast cell density. Mast cell migration towards the carcinoma and degranulation were also evident.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Directed lysis of experimental cancer by beta-carotene in liposomes.

The purpose of this study was to extend the knowledge of the antitumor activity of liposomes and to identify, for the first time, the antitumor effect of liposomes with the antioxidant beta-carotene. The administration of the carotenoid encapsulated in in liposomes has the advantages of quantitation, facilitation, and most importantly an increased therapeutic response, resulting in the accentuation of regression of carcinoma in the hamster pouch. Tumors induced after the application of the carcinogen 7,12-dimethylbenz[alpha]anthracene (0.5%) were injected with liposomes composed of phosphatidylcholine, phosphatidylserine, and phosphatidylethanolamine in a ratio of 1:1:1 (large unilamellar vesicles). Tumor-bearing animals were divided into four groups, each containing 10 hamsters. The group treated with the liposomes of beta-carotene exhibited a significantly lower tumor burden (approx 5,000-fold difference) than the control tumor group. Electron- and light-micrographic analyses were used to substantiate the gross observations of tumor regression. It was noted that the carcinoma cells endocytozed liposomes in increased numbers compared with normal mucosa treated with liposomes. In addition, non-tumor-bearing hamsters injected with beta-carotene liposomes or liposomes alone did not exhibit any pathological change to the normal mucosa. An inflammatory infiltrate consisting of mononuclear cells, mast cells, and some polymorphonuclear leukocytes was noted, and degranulating polymorphonuclear leukocytes and mast cells and eosinophils predominated in the tumor controls (7,12-dimethylbenz[alpha]anthracene treated only). Notably, not all areas of degenerating dysplasia or early carcinoma exhibited a dense inflammatory response adjacent to the mucosa after the injection of beta-carotene liposomes. The results demonstrate a selective nontoxic therapy to regress experimental oral cancer.

Animals↗
PubMed1990

Induction of a 70 kD protein associated with the selective cytotoxicity of beta-carotene in human epidermal carcinoma.

Beta-carotene and canthaxanthin at concentrations of 70 or 300 microM were shown to inhibit the proliferation of cultured human squamous cells (SK-MES lung carcinoma and SCC-25 oral carcinoma) in a 5 hr cell density assay. Responses were similar for both tumor cell lines, ranging from 71-84% inhibition. In contrast, equimolar concentrations of alpha-tocopherol gave only 19-36% inhibition of SCC-25, but 50-75% inhibition of SK-MES cell density. Equimolar reduced glutathione resulted in 4-15% stimulation of SCC-25 and 22-25% inhibition of SK-MES cell proliferation. With cultured normal keratinocytes, treated final cell densities did not differ significantly from those of controls. Two additional assays measuring the metabolic generation of formazan (MTT assay) and [5-3H]thymidine incorporation were in substantial agreement with the growth inhibition pattern. Thus both continuous and cyclic cellular processes are involved in the tumor-specific response. Onset of the response to beta-carotene alone or in combination with alpha-tocopherol is signalled within 1-2 hours of treatment by the appearance of a unique 70 kD heat-shock protein.

Canthaxanthin↗
PubMed1990

The administration of beta carotene to prevent and regress oral carcinoma in the hamster cheek pouch and the associated enhancement of the immune response.

In the past four years this laboratory has utilized the hamster cheek pouch tumor model to investigate the anticancer activities of antioxidants, such as beta carotene. These molecules, which have exhibited no evidence of toxicity, have been administered systemically (oral ingestion), and locally to the tumor site in the hamster cheek pouch. The results have been either the inhibition of tumor growth, or the regression of tumor. Adjacent to the degenerating tumors a dense inflammatory infiltrate was observed. Specifically, the cytokines, tumor necrosis factor alpha, and beta, have been immunohistochemically localized to the site of regressed oral carcinoma. Recently, liposomes composed of phosphaditylcholine, phosphaditylserine, and phosphodityelanolamine were combined with beta carotene and injected locally to oral squamous cell carcinoma of the hamster. The results indicated that tumor cells accumulated the liposomes and were lysed while normal mucosal cells did not demonstrate this effect. Therefore antioxidants such as beta carotene can be localized to a tumor site, without a toxic response. Future studies on the anticancer activity of the antioxidants need to focus on the cellular and molecular changes produced in the immune effectors and in the mucosal cells following administration of the antioxidants.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

An animal model for mucositis induced by cancer chemotherapy.

Mucositis induced by chemotherapy is a painful and often dose-limiting side effect of cancer therapy. Furthermore, loss of the integrity of the oral epithelium often provides a microbial portal of entry and leads to sepsis. The present study describes the first animal model for chemotherapy-induced mucositis. The combination of three intraperitoneal injections of 5-fluorouracil at 5-day intervals and superficial mechanical mucosal irritation resulted in clinical breakdown of the oral mucosa characterized by ulcerative mucositis in Golden Syrian hamsters. Both clinical and histologic evaluation demonstrated that these changes were similar to those described in human beings and followed a pattern influenced by the degree of myelosuppression. This model should be of significance in establishing the stomatotoxicity of new chemotherapeutic agents, in evaluating medicaments to treat mucositis, and in studying the influence of oral mucosal breakdown on sepsis in myelosuppressed persons.

Animals↗
PubMed1990

Prevention of experimental cancer and immunostimulation by vitamin E (immunosurveillance).

Eighty young adult male Syrian hamsters were divided into four equal groups. Group 1 animals had the right buccal pouches painted with a 0.1% solution of 7,12 dimethylbenz(a)anthracene (DMBA) three times per wk for 28 wk. Group 2 animals were similarly painted with DMBA for 28 wk but were also given 140 micrograms vitamin E in 0.4 ml mineral oil three times weekly on days alternate to DMBA painting. Group 3 animals were used as DMBA-vehicle controls. Group 4 animals were vitamin E controls. Animals were killed after 28 wk, the pouches photographed and tumors counted, measured. The pouches were fixed in formalin, sectioned in paraffin and studied histologically and histochemically for tumor necrosis factors alpha and beta. All animals in Group 1 and 3 had gross tumors of the right buccal pouch. None of the animals in Group 2 had grossly visible tumors. Microscopic studies revealed that, while no gross tumors were seen in the Group 2 animals, there was histologic evidence of dysplasia and early carcinoma-in-situ undergoing degeneration. Immunohistochemical staining revealed a dense infiltrate of mononuclear cells adjacent to tumor sites with a large number of cytotoxic T lymphocytes and macrophages. Vitamin E appears to prevent tumor formation by stimulating a potent immune response to selectively destroy tumor cells as they begin to develop into recognizable microscopic foci of carcinoma.

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

Detection of Ki-ras messenger RNA in normal and chemically transformed hamster oral keratinocytes.

The cheek pouch of the Syrian hamster is an excellent model for the experimental study of oral carcinogenesis. The carcinogenic chemical 7,12-dimethylbenz[a]anthracene consistently produces epidermoid carcinomas in the cheek pouch of the Syrian hamster, giving rise to characteristic histopathological lesions in a time-dependent manner. We now present experimental evidence that c-Ki-ras mRNA can be detected in all 7,12-dimethylbenz[a]anthracene-induced tumors examined (in vivo and in vitro) in this experimental oral cancer model while no detectable c-Ki-ras mRNA can be found in the normal hamster cheek pouch epithelium. Cellular synchronization experiments using a cell line (hamster cheek pouch carcinoma cell line 1) derived from one of these 7,12-dimethylbenz[a]anthracene-induced hamster oral tumors revealed that the c-Ki-ras protooncogene is expressed during the G1 phase of the cell cycle (proliferation dependent). Serum starvation and RNA synthesis inhibition experiments using hamster cheek pouch carcinoma cell line 1 cells suggest that the c-Ki-ras protooncogene is indeed quiescent in the normal hamster cheek pouch epithelium and that failure to detect its mRNA is not related to the slower proliferation of the normal epithelial cells. These results suggest that the transcription of the c-Ki-ras protooncogene is associated with malignant transformation in the cheek pouch of the Syrian hamster.

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

Regression of experimental cancer by oral administration of combined alpha-tocopherol and beta-carotene.

alpha-Tocopherol (vitamin E) and beta-carotene have been shown to be capable of regressing established epidermoid carcinomas of hamster buccal pouch when injected locally into the tumor site. Neither has yet been shown to be effective in regressing cancer when administered by oral route. However, a combination of both alpha-tocopherol and beta-carotene was shown to be effective in regressing epidermoid carcinomas of hamster buccal pouch when the mixture was administered orally in vegetable oil. The epidermoid carcinomas were induced in the right buccal pouch of 100 Syrian hamsters by painting three times weekly for 14 weeks with a 0.5% solution of 7,12-dimethylbenz[a]anthracene in mineral oil. The animals were then divided into five equal groups of 20 animals. Group 1 animals received no further treatment and represented tumor controls. Group 2 animals received 200 micrograms beta-carotene and 200 micrograms dl-alpha-tocopherol acid succinate combined in 0.2 ml vegetable oil. Animals received the mixture daily by mouth using a 1-ml syringe. Groups 3 and 4 received beta-carotene and alpha-tocopherol individually in double amounts (400 micrograms in 0.2 ml vegetable oil). Group 5 animals received only the vegetable oil (0.2 ml daily) and were controls for vehicle. The animals in Groups 1, 3, 4, and 5 were killed after 22 weeks because the tumors were extensive, large, and necrotic and the animals were weak and cachectic. After 22 weeks, the tumors in Group 2 animals were small in 15 out of 20 animals. The tumors were reduced in size compared with tumor burden at 14 weeks, the point at which the beta-carotene/alpha-tocopherol was started.

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

Prevention and inhibition of oral cancer in the hamster buccal pouch model associated with carotenoid immune enhancement.

Beta carotene, canthaxanthin, and a carotenoid mixture from an extract of algae were shown to prevent or inhibit the gross development of squamous cell carcinoma induced in the hamster buccal pouch by 7,12-dimethylbenz(a)anthracene. The carotenoids, dissolved in mineral oil, were administered by oral ingestion on days alternate to the carcinogen. Animals fed similar amounts of canthaxanthin, beta carotene or algae extract exhibited a statistically significant reduction in the development of tumors, both in number and size. The feeding of carotenoids, besides inhibiting gross tumor development, also produced a histologically unique picture. Microscopic areas of dysplasia, carcinoma in situ histologically unique picture. Microscopic areas of dysplasia, carcinoma in situ, or early carcinoma showed areas of tumor lysis and an inflammatory infiltrate consisting of lymphocytes and histiocytes. Characterization of this infiltrate disclosed a significant increase in cytotoxic lymphocytes, and cytotoxic macrophages producing tumor necrosis factor alpha. To confirm the presence of cytotoxic lymphocytes and macrophages a 51Cr release assay was performed. The results indicate that the immune response of the hamster was directed to the developing areas of dysplasia and carcinoma and was associated with the observations of prevention and inhibition of the growth of oral squamous cell carcinoma.

Administration, Oral↗
PubMed1988

Transforming growth factor alpha in chemically transformed hamster oral keratinocytes.

The cheek pouch of the Syrian hamster is an excellent tissue for the experimental induction of oral cancer by carcinogenic chemicals. Lysate prepared from a cell line (HCPC-1) derived from one of these hamster oral tumors greatly increased the growth of these oral tumor cells in vitro. We now show that the mitogenic substance, transforming growth factor alpha (TGF-alpha), is present in all of the chemically transformed hamster oral tumors examined (in vitro and in vivo). In no adult normal tissue of the Syrian hamster can we detect expression of TGF-alpha. TGF-alpha could be partly or wholly responsible for the mitogenic activity detected in the lysate of the chemically transformed hamster oral keratinocytes. Both normal and chemically transformed hamster oral keratinocytes express the receptor to epidermal growth factor. The consistent detection of TGF-alpha and epidermal growth factor receptor mRNAs in these hamster oral tumor cells suggests that an autocrine growth mechanism might be operative. This hamster cheek pouch oral cancer model can be used for the molecular analysis of how TGF-alpha and epidermal growth factor receptor might be involved in the malignant transformation of epithelial tissues.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

The effect of chemotherapeutic agents on human oral squamous cell carcinoma transplanted to nude mice: a histologic study.

Clearly differentiated squamous cell carcinomas were transplanted to the backs of nude mice; tumor cells of a human tongue carcinoma cell line were used. Animals bearing tumors that measured at least 4 mm in diameter were treated with either methotrexate (MTX), cis-diamminedichloroplatinum II (CDDP) or bleomycin intraperitoneally for 5 days. Histologic evaluation of tumors obtained 24 hours after the last injection revealed degenerative and necrotic morphology in all treatment groups. The histologic alterations were observed prior to any clinical evidence of tumor shrinkage. The most impressive changes were found in CDDP-treated tumors, with creation of large pseudocysts containing necrotic material and cell debris. Pseudocyst formation was less obvious in MTX-treated animals and was absent in bleomycin-treated tumors. Drug treatment had no obvious influence on the keratinization in tumors. The findings suggest that the nude mouse model may be useful for the histologic determination of drug-induced effects on tumors in human beings.

Animals↗
PubMed1985

Alpha tocopherol alters the distribution of Langerhans cells in DMBA-treated hamster cheek pouch epithelium.

Thirty-seven adult male and female golden hamsters (Mesocricetus auratus) were divided into four experimental groups. In Group A, the animals served as untreated controls, having the left buccal pouches painted with mineral oil. In Group B, the animals received 10 mg vitamin E (alpha tocopherol) in peanut oil by the oral route, with a fine pipette, twice weekly. In Group C animals, the left buccal pouch was painted three times weekly with DMBA (0.5% solution of 7,12 dimethylbenz(a)anthracene in heavy mineral oil). Group D animals received both vitamin E and DMBA in the amounts indicated for Groups B and C, with the vitamin E being administered on days alternate to the DMBA painting, also in the manner described for the above groups. All animals were killed after eight weeks of treatment. Epithelial whole mounts were prepared from the left buccal pouches. These specimens were then stained for ATPase to demonstrate the presence of Langerhans cells (LCs). A notably decreased density of LCs was observed after treatment with DMBA. Vitamin E administration in addition to DMBA treatment resulted in a less dramatic decrease in LC density. Since vitamin E has been shown to retard experimental oral carcinogenesis, vitamin E may retard carcinogenesis by maintaining the number of Langerhans cells.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

Jawbone cavities and trigeminal and atypical facial neuralgias.

The possible role of dental and oral disease in the etiology of idiopathic trigeminal and atypical facial neuralgias has been examined. Among thirty-eight patients with idiopathic trigeminal neuralgia and twenty-three patients with atypical facial neuralgia, there was in nearly all instances a close relationship between pain experienced and the existence of cavities in alveolar bone and jawbone of the patients. The cavities were at the sites of previous tooth extractions and, although at times more than 1 cm. in a given diameter, were usually not detectable by x-rays. A new method for their detection and localization was developed empirically, based on the observation that peripheral infiltration of local anesthetic into or very close to the bone cavity rapidly abolished trigger and pain perception by patients during persistence of the anesthetic action. Histopathologic examination of bone removed from cavities by curettage revealed, in both idiopathic trigeminal and atypical facial neuralgias, a similar pattern characterized by a highly vascular abnormal healing response of bone. Some lesions presented a mild chronic inflammatory (lymphocytic) infiltration. Preliminary microbiologic studies of material from the walls of the cavities showed the existence within them of a complex, mixed polymicrobial aerobic and anaerobic flora. Treatment consisted of vigorous curettage of the bone cavities, repeated if necessary, plus administration of antibiotics to induce healing and filling-in of the cavities by new bone. Responses of patients to the above treatment consisted of marked to complete pain remissions, the longest of which has been for 9 years. Complete healing leads to complete and persistent pain remissions. It was concluded that in both idiopathic trigeminal and atypical facial neuralgias, dental and oral pathoses may be major etiologic factors.

Adult↗
PubMed1979

Ultrastructural alterations in experimental lingual leukoplakia and carcinoma.

Epidermoid carcinomas, preceded by dysplastic leukoplakic lesions, were produced on the right lateral borders of the tongues of Syrian hamsters by the application, three times per week, of DMBA in acetone after the area had been scratched with a root canal broach. Animals were killed at 12 to 13 weeks and 15 to 16 weeks. Electron microscopic studies of both the dysplastic leukoplakic lesions and the well-differentiated epidermoid carcinomas revealed clumping of tonofilaments and widening of intercellular spaces, in addition to the cellular pleomorphism, altered nuclear-cytoplasmic ratio, and prominent nucleoli observed with the light microscope. In the carcinomas, there were variations in the morphology of mitochondria, with tubular forms in evidence. The basal lamina in the carcinomas was discontinuous. Pseudopodia arising from basal cells were seen in areas of basal lamina discontinuity.

9,10-Dimethyl-1,2-benzanthracene↗