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PubMed1982

Epidermal-dermal junction during experimental skin carcinogenesis and cocarcinogenesis as revealed by scanning electron microscopy.

During epidermal carcinogenesis important changes in the epidermal-dermal junction take place. Because of methodological difficulties may be these changes, especially those concerned with three-dimensional organization of the junction, remain unsatisfactorily investigated. To obtain new information, we studied with scanning electron microscopy (SEM) the development of carcinogenic changes in the epidermis of mice induced by DMBA-TPA, DMBA alone, and by the cocarcinogen TPA alone. We correlated the results with those from transmission electron microscopy and light microscopy. Although the epidermal changes morphologically showed similarities, biologically they differed. With them, distinct changes in the epidermal-dermal junction developed, that could be followed through early, hyperplastic and neoplastic phases. With the SEM the first changes were seen in the basal layer of the epidermis and concerned the cell arrangement. SEM provided information about the localization and development of incipient epidermal carcinomas induced by DMBA-TPA and DMBA treatment, as well as about the changes in the basal lamina. These can be classified by their surface, their extent and their frequency throughout large regions. Our studies indicate that these changes vary greatly, depending upon the treatment used and the time of their development. Only the progressive disintegration of the basal lamina is characteristic of carcinogenesis.

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

Cocarcinogenesis between cadmium and Aroclor 1254 in planarians is enhanced by inhibition of glutathione synthesis.

Asexual Dugesia dorotocephala planaria continuously exposed to 50 micrograms/beaker of Aroclor 1254 (A1254) and cadmium (Cd) developed tumors after 11 days of continuous exposure to 0.65 or 1.3 mg/liter Cd and after 23 days to 0.13 mg/liter Cd. The tumor rate at 14 days averaged 53% for the survivors in both 0.65 and 1.3 mg/liter Cd + A1254 and 40% at 0.13 mg/liter Cd + A1254. Other groups were either preexposed or coexposed to L-buthionine-S,R-sulfoximine (BSO), a specific inhibitor of glutathione synthesis. In the presence of A1254 (50 micrograms/beaker), animals continuously exposed to BSO and 0.13 mg/liter Cd first developed tumors at 18 days, with a tumor yield equal to 41% of the survivors. Tumors developed by 6 days at 0.65 mg/liter Cd, with a yield equal to 75% of survivors. At 1.3 mg/liter Cd, BSO did not change the rate or frequency of planarian tumor production. Continuous BSO always produced high mortality over 20 days. In contrast, a 24-h preexposure to BSO caused little mortality. In these groups, tumor yields increased with cadmium concentration (0.13, 0.25, 0.65 mg/liter), and the large cocarcinogenic effect of A1254 was clearly evident. No tumors developed in animals exposed only to 50 micrograms/beaker of Aroclor 1254 or continuously only to 1 mM BSO.

Animals↗
PubMed1983

Free oxygen radicals: necessary contributors to tumor promotion and cocarcinogenesis.

The two stage model of carcinogenesis postulates that agents which lead to tumor formation are either initiating or promoting agents. Initiating agents induce chemical modifications of DNA. Promoting agents have been assumed to induce cell proliferation and thereby establish a milieu in which the initiated cells can express their irreversibly altered genotype. Promoters can induce both the migration of leukocytes to the skin and stimulate their respiratory activity leading to the formation of active O2 species which cause lipid peroxidation and thereby change membrane properties. However, it was recently found that the O2 species emanating from promoter-activated leukocytes also cause formation of strand breaks both in the DNA of the leukocytes themselves and in the DNA of cells cocultivated with such leukocytes. The contribution of activated O2 species to tumor promotion has been confirmed by the finding that antioxidants and copper containing superoxide dismutase (SOD)-mimetic compounds, protease inhibitors and retinoids (which block free radical formation) inhibit promotion. Furthermore, cocarcinogens such as gossypol and pyrogallol may also cause conversion of O2 to the superoxide anion radical. The heritable change caused by initiators may render the cell more vulnerable to promoter-mediated DNA damage. Experimental investigation of these hypotheses may elucidate our understanding of the contribution of promoter-mediated DNA damage in tumorigenesis and identify preventive agents for carcinogenesis.

Animals↗
PubMed2002

Arsenite cocarcinogenesis: an animal model derived from genetic toxicology studies.

Although epidemiologic evidence shows an association between inorganic arsenic in drinking water and increased risk of skin, lung, and bladder cancers, no animal model for arsenic carcinogenesis has been successful. This lack has hindered mechanistic studies of arsenic carcinogenesis. Previously, we and others found that low concentrations (< or =5 microm) of arsenite (the likely environmental carcinogen), which are not mutagenic, can enhance the mutagenicity of other agents, including ultraviolet radiation (UVR) and alkylating agents. This enhancing effect appears to result from inhibition of DNA repair by arsenite, but not via inhibition of DNA repair enzymes. Rather, low concentrations of arsenite disrupt p53 function and upregulate cyclin D1. Failure to find an animal model for arsenic carcinogenesis might be because arsenite is not a carcinogen per se but acts as an enhancing agent (cocarcinogen) with a genotoxic partner. We tested this hypothesis with solar UVR in hairless but immunocompetent Skh1 mice. Mice were given 10 mg/L sodium arsenite in drinking water (or not) and irradiated with 1.7 KJ/m(2) solar UVR 3 times weekly. As expected, no tumors appeared in any organs in control mice or in mice given arsenite alone. After 26 weeks irradiated mice given arsenite had a 2.4-fold increase in skin tumor yield compared with mice given UVR alone. The tumors were mostly squamous cell carcinomas, and those occurring in mice given UVR plus arsenite were much larger and more invasive. These results are consistent with the hypothesis that arsenic acts as a cocarcinogen with a second (genotoxic) agent by inhibiting DNA repair and/or enhancing positive growth signaling. Skin cancers in populations drinking water containing arsenic may be caused by the enhancement by arsenic compounds of carcinogenesis induced by UVR (or other environmental agents). It is possible that lung and bladder cancers associated with arsenic in drinking water may also require a carcinogenic partner.

Animals↗
PubMed1979

Biochemical evidence of cocarcinogenesis: tumor promoting agent enhances methylnitrosourea activation of rat guanylate cyclase activity.

The two-stage or cocarcinogenic hypothesis of carcinogenesis involves an initiator (carcinogen) and a promotor (cocarcinogen) being utilized in combination to produce more tumors than either would alone. This theory was tested at the cellular level utilizing Tumor Promoting Agent, 12-0-tetradecanoly-phorbol-13-acetate, (promotor) in combination with submaximal and maximal doses of methylnitrosourea (initiator). Tumor promoting agent, which can cause some tumors itself, was found to enhance the activity of guanylate cyclase (E.C.4.6.1.2.), an enzyme that has been associated with normal and abnormal growth. Tumor promoting agent when utilized in combination with submaximal stimulatory doses of methylnitrosourea had an additive effect on guanylate cyclase activity, but the agent had no further additive effect on guanylate cyclase activation when methylnitrosourea was utilized in maximal stimulatory doses. These results indicate a carcinogen acting alone without a promoter can maximally activate guanylate cyclase and would suggest that at the cellular level a promotor is not absolutely necessary for the changes observed morphologically in canerous cells. The promotor, however, did enhance the enzyme's activity when a submaximal dose of the carcinogen was used indicating that promoting agents, at least biochemically, appear capable of potentially contributing to the development of a cancerous cell.

Animals↗