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Biomedical subjects

B T Mossman

Publications and source records attributed to B T Mossman.

At least 109 records · Page 6Linked to original sources
PubMed1985

Chlorozocin. A diabetogenic analogue of streptozocin with dissimilar mechanisms of action on pancreatic beta cells.

Chlorozotocin (chlorozocin, CLZ), the 2-chloroethyl analogue of streptozocin (STZ), was evaluated in three species of rodents. The drug is currently being used in phase II chemotherapeutic trials in man, and appears to be effective in the treatment of certain tumors. In our studies, hyperglycemia was induced in hamsters as early as 2 days after a single intraperitoneal (i.p.) injection of 30-60 mg/kg and was most striking at 4 days. Greater concentrations of CLZ (greater than or equal to 50 mg/kg) were required to produce hyperglycemia in CD-1 mice. Degranulation and necrosis of beta cells developed in hamsters and mice, whereas alpha and acinar cells of the pancreas revealed no morphologic changes. Hyperglycemia was not induced in rats at any concentration tested; however, animals showed abnormal carbohydrate tolerance after administration of 100 mg/kg CLZ (LD50 dosage). The nature of damage by CLZ to beta cells was investigated both in vivo and in vitro. Pretreatment of hamsters with nicotinamide (500 mg/kg, i.p.) failed to alter the extent of CLZ-induced beta cell injury and associated hyperglycemia, but decreased the amount of beta cell necrosis and hyperglycemia in animals receiving STZ. The nonmetabolizable sugar, 3-O-methylglucose (3-O-MG), and 3-aminobenzamide, an inhibitor of the nuclear enzyme, polyADPribose synthetase, prevented STZ-associated damage to beta cells in islet cell cultures, but only 3-O-MG reduced CLZ-induced toxicity. Thus, in comparison to STZ, CLZ appears to be a diabetogenic agent with different species specificity and alternative mechanisms of cytotoxicity. The glucose moiety of both drugs appears critical in the induction of beta cell damage.

3-O-Methylglucose↗
PubMed1985

Therapeutic and diabetogenic potential of two newly synthesized nitrosoureido sugars.

Two newly synthesized nitrosoureido sugars have been evaluated for their antitumor activity and diabetogenic potential in a number of in vitro and in vivo preclinical tumor model systems. 2-Amino-2-deoxy-N'-methyl-N'-nitrosoureido-1,3,4,6-tetra-O-acetyl-alpha- D- mannopyranose (MAZ), a lipophilic mannosamine derivative, and ethyl-6-deoxy-3,5-di-O-methyl-6-(3-methyl-3-nitrosoureido)-alph a- D-glucofuranoside (EDOMEN or CGP 6'809), were both found to inhibit L1210 leukemia cell growth in vitro by 50% at approximately 5.0 X 10(-5) M. At these concentrations, little effect was noted immediately on L1210 cell radiolabeled precursor incorporation; however, at higher concentrations, EDOMEN inhibited [3H]leucine and [3H]mannose incorporation, while MAZ specifically decreased L1210 cell [3H]thymidine and [3H]leucine incorporation. Inhibition of Lewis lung carcinoma and B16 melanoma cell growth by 50% in vitro was achieved at higher concentrations of these agents (10(-4) to 10(-3) M). Since the currently available nitrosoureido sugars, streptozotocin and chlorozotocin, have been observed by us to be diabetogenic, EDOMEN and MAZ were evaluated for their specific toxicity to rat pancreatic beta-cells in vitro. Cytotoxicity in beta-cell cultures was monitored both by phase-contrast microscopy and the release of insulin into the culture medium. beta-Cells were found to be 10-fold more sensitive to the toxic effects of MAZ than were pancreatic fibroblasts. EDOMEN, on the other hand, did not damage beta-cells preferentially and therefore was not considered diabetogenic. Both MAZ and EDOMEN had moderate activity as antileukemic agents in mice. At 50 mg/kg/day i.p. for 5 days, MAZ increased the life span of female DBA/2J mice with L1210 leukemia by over 50%. Similarly, doses of EDOMEN at 125 to 250 mg/kg/day i.p. for 5 days increased L1210 leukemic life span by nearly 60%. At these doses, no effect of MAZ was observed on primary Lewis lung carcinoma growth or life span of tumor-bearing C57BL/6 mice. EDOMEN, however, increased life span in Lewis lung carcinoma mice by up to 33% and caused an apparent antimetastatic effect. These studies indicate that EDOMEN may have enhanced value as a cancer chemotherapeutic agent due to its therapeutic effectiveness, lack of diabetogenic potential, and other favorable formulation properties (water solubility) as compared with other clinically available nitrosoureas.

Animals↗
PubMed1985

Cocarcinogenic and tumor promoting properties of asbestos and other minerals in tracheobronchial epithelium.

Epidemiologic and experimental studies document a synergistic effect of asbestos and smoking in the induction of bronchogenic carcinoma. Whereas the increased risk of these cancers in nonsmoking asbestos workers is 4-fold or less in comparison to nonsmokers in the general population, individuals who smoke and are exposed to asbestos occupationally have a 80-90 fold increased risk. The observations summarized above provide substantial insight into the interactions between asbestos and chemical carcinogens in cigarette smoke at the cellular level (Fig. 8). On the one hand, asbestos fibers and other particulates appear to act as condensation nuclei for PAH in the occupational setting or environment. They then facilitate the transfer of these chemical carcinogens into target cells, i.e., those destined to develop into tumor cells. As a result, the adduct formation of PAH to DNA is encouraged, an event linked intrinsically to initiation of transformation. Alternatively, asbestos appears to enhance and modulate the further development of initiated cells to neoplastic cells by a process resembling tumor promotion in mouse skin. In this regard, the most dramatic example illustrating the importance of asbestos in two-stage carcinogenesis is an experiment by Topping and Nettesheim. These investigators inserted the PAH, 7,12-dimethyl-benz(a)anthracene (DMBA) into the lumen of rat trachea which then were implanted on syngeneic animals. Subsequently, chrysotile asbestos was introduced, and grafts were removed for histology when palpable tumors occurred. At non-tumorigenic (i.e., initiating) amounts of DMBA, asbestos promoted the development of malignancies, although two neoplasms were observed with use of asbestos alone. Asbestos was not carcinogenic at these amounts, but a low incidence (5%) of squamous cell carcinoma was observed with use of chrysotile alone at much higher concentrations. These results suggest that asbestos is a weak carcinogen, but more importantly a promoter of carcinogenesis in the respiratory tract. Studies in this laboratory show striking effects of asbestos fibers on cell proliferation and differentiation although these responses appear to occur also after exposure of tracheobronchial cells to nonasbestos fibers including fiberglass.

Adsorption↗
PubMed1984

Mechanisms of streptozotocin- and alloxan-induced damage in rat B cells.

In studies to evaluate possible inhibitors of the B-cell toxin, streptozotocin, the superoxide scavenger, superoxide dismutase, did not prevent or reduce the toxic effects of streptozotocin as determined by loss of insulin secretion from rat pancreatic B cells in monolayer culture. However, 1,1-dimethyl urea, a scavenger of the hydroxyl radical, did afford significant protection. Both scavengers diminished the cytotoxic effects of alloxan. The inhibitors of poly (ADP-ribose) synthetase, 3-aminobenzamide and nicotinamide, also were effective in attenuating alloxan- and streptozotocin-induced B-cell toxicity. Tests of the hydroxyl-scavenging ability of the three streptozotocin antagonists revealed that 3-aminobenzamide, nicotinamide and 1,1-dimethyl urea were effective scavengers of this free radical. Conversely, 1,1-dimethyl urea, although not as potent as 3-aminobenzamide or nicotinamide, was found to inhibit poly (ADP-ribose) synthetase. These data indicate that these chemicals most likely attenuate alloxan-induced toxicity by scavenging the hydroxyl radical and diminish streptozotocin-induced toxicity by inactivation of the poly (ADP-ribose) system.

Alloxan↗
PubMed1984

Interaction of Mount St. Helens' volcanic ash with cells of the respiratory epithelium.

Respirable-sized dust from the Mount St. Helens (MSH) eruption of Spring 1980, and minerals similar to the major components of the volcanic ash, were examined comparatively for interactions with epithelial cells of rodent respiratory airways in vitro. MSH dust, Na feldspar, cristobalite, and alpha-quartz, in concentrations of 0.4 to 40 mg/ml, had neither significant effects on mucin release by tracheal explants nor acute toxic effects after exposure for 2 hr. Long-term incubation (1 and 3 weeks) of explants after a 1-hr exposure to MSH dust failed to elicit widespread toxic or proliferative changes in airway epithelial cells. In contrast, long-term exposure to Na feldspar, cristobalite, and alpha-quartz caused significant toxicity to the explants, although metaplastic changes were not observed. Ultrastructural evidence of associations (e.g., phagocytosis) between particulates and respiratory epithelium was not observed. The results of these studies suggest that volcanic ash from MSH interacts minimally with cells of the respiratory mucosa.

Animals↗
PubMed1984

Asbestos and benzo[a]pyrene act synergistically to induce squamous metaplasia and incorporation of [3H]thymidine in hamster tracheal epithelium.

When exposed to either crocidolite asbestos (single 1-h exposure to 0.4 mg/ml medium) or the polycyclic aromatic hydrocarbon, benzo[a]pyrene (BaP) (less than or equal to 2.5 micrograms/ml medium, 1x weekly for 4 weeks), the epithelium of hamster tracheal explants exhibits insignificant amounts of squamous metaplasia, an atypical lesion, in comparison to amounts observed in untreated tissues. Incorporation of [3H]thymidine, an indication of DNA synthesis by epithelial cells, likewise is unchanged. However, the extent of squamous metaplasia and numbers of labeled basal and suprabasal cells are increased substantially when BaP and asbestos are added in combination. These results suggest an important mechanism of co-carcinogenesis involving chemical and physical carcinogens and support epidemiologic observations documenting an increased risk of bronchogenic carcinoma in asbestos workers who smoke.

Animals↗
PubMed1983

Use of pancreatic beta cells in culture to identify diabetogenic N-nitroso compounds.

Epidemiological observations suggest that environmental factors play a role in the pathogenesis of insulin dependent diabetes mellitus (1). Several chemicals have been identified as specific beta cell toxins (2-4). We report here studies to determine the feasibility of using monolayer cultures of pancreatic beta cells from neonatal rat to screen potential diabetogenic chemicals. Cytotoxicity was monitored both by phase microscopy and the release of insulin into the culture medium. In comparative studies, cellular protein and release of 51chromium (51Cr) were measured after addition of test compounds to cultures of fibroblasts derived from pancreatic tissue. The nitrosoamides 1 methyl-l-nitrosourea (MNU), 1,3 bis (2-choroethyl) nitrosourea (BCNU), chlorozotocin (CLZ), and the beta cell toxin, streptozotocin (SZ), were examined. CLZ and SZ were more toxic to pancreatic beta cells than to fibroblasts. In contrast, MNU and BCNU damaged both beta cells and fibroblasts at identical concentrations. These results suggest that in vitro techniques can be used to identify chemicals that selectively injure beta cells. Although SZ-induced toxicity was ameliorated with addition of nicotinamide to cultures of beta cells, nicotinamide did not prevent damage caused by CLZ. This observation indicates different mechanisms of drug-induced cytotoxicity.

Animals↗
PubMed1983

Studies using lectins to determine mineral interactions with cellular membranes.

Chrysotile asbestos interacts with mucin-secreting cells of tracheal organ cultures, causing an increase in secretion of mucin into the culture medium. This response occurs in the absence of obvious morphologic damage to tracheal epithelial cells. We speculated that asbestos-induced hypersecretion was regulated by the interaction of fibers with specific carbohydrate residues on the cell surface. To test this hypothesis, lectins, i.e., proteins with a high affinity for mono- and oligosaccharides on the plasma membrane, were added to tissues 30 min before addition of chrysotile. Secretion of mucin into the medium was then determined over a 2-hr period by using incorporation of 3H-glucosamine. Blocking of alpha-D-mannose and alpha-D-glucose residues inhibited chrysotile-induced hypersecretion (p less than 0.05), whereas lectins blocking residues of alpha-D-N-acetylgalactosamine, beta-D-N-acetylglucosamine, alpha-L-fucose and sialic acids were ineffective. Preincubation of cultures with carboxypeptidase A or phospholipase A2, but not with neuraminidase, diminished mucin secretion caused by chrysotile. To determine if the positive surface charge of chrysotile was important in interaction with mucin cells, we examined comparatively the effects of various polycations (cationic ferritin, polylysine, DEAE-dextran) and chrysotile after leaching of fibers to remove Mg2+. Although use of polycations enhanced secretion of mucin, effects were not as striking as those observed with chrysotile. In contrast, leached chrysotile failed to elicit a hypersecretory response. These results suggest the interaction of a positively charged component (presumably Mg2+) of chrysotile with glycolipids and glycoproteins containing terminal residues of alpha-D-mannose or alpha-D-glucose.

Animals↗
PubMed1983

Interaction of asbestos with metaplastic squamous epithelium developing in organ cultures of hamster trachea.

The normal mucociliary epithelium of the respiratory tract in chronic cigarette smokers often is replaced focally by a metaplastic squamous epithelium. Because asbestos workers who smoke have a substantially greater risk of bronchogenic carcinoma than nonsmokers, we hypothesized that interaction of asbestos with squamous epithelium might be a contributing factor. To address this question, an in vitro model was developed to study the interaction of asbestos with both mucociliary and squamous epithelium. Explants of tracheas from hamsters were cultured in either a chemically defined minimal essential medium, which maintains a differentiated epithelium, or a nutritionally complex medium, which encourages the development of squamous metaplasia. Scanning electron microscopy (SEM) was used to measure quantitatively the development of a squamous epithelial surface on the explants. The interaction of chrysotile and crocidolite asbestos with cells of the mucociliary and squamous epithelium was studied using both SEM and transmission electron microscopy (TEM). Long fibers of asbestos were cleared, whereas shorter fibers were phagocytized by cells of the mucociliary epithelium. In contrast, asbestos was phagocytized by superficial squamous cells regardless of fiber length, and fibers penetrated between intercellular junctions in the metaplastic epithelium. The relevance of these interactions to the induction of bronchogenic carcinoma is discussed.

Animals↗
PubMed1983

Effects of crocidolite and chrysotile asbestos on cellular uptake and metabolism of benzo(a)pyrene in hamster tracheal epithelial cells.

The incidence of bronchogenic carcinoma is increased substantially in asbestos workers who smoke. We used several approaches to determine possible mechanisms of synergism at the cellular level between asbestos and the polycyclic aromatic hydrocarbon (PAH), benzo(a)pyrene (BaP), a chemical carcinogen in cigarette smoke. Specifically, we hypothesized that cellular uptake and metabolism of BaP might be facilitated when the hydrocarbon was coated on asbestos. In addition, we were interested in whether asbestos, alone or in combination with BaP, caused single strand breakage of DNA in epithelial cells of the airway. UICC reference samples of crocidolite and chrysotile were coated with 3H-BaP before their addition to monolayers of hamster tracheal epithelial cells. In comparative studies, 3H-BaP at identical amounts was added to cells in culture medium. At intervals thereafter, uptake of BaP by cells was documented by scintillation spectrometry and by autoradiography. In addition, cells and media were assayed by use of high pressure liquid chromatography (HPLC) to demonstrate the water-soluble metabolites of BaP. The integrity of DNA was monitored by alkaline elution at intervals after exposure of tracheal cells to various concentrations of asbestos, BaP and BaP-coated asbestos. A rapid transfer of BaP to cells occurred after addition of BaP-coated asbestos to cultures. When BaP was adsorbed to both types of fibers before their addition to cultures, 70% of the total BaP introduced entered the cell within 1 hr; 50% remained intracellular after 8 hr. In contrast, if identical amounts of BaP were added directly to medium, an initial influx of 20% was observed and cells retained only 5% of the initial amount at 8 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗
PubMed1983

In vitro approaches for determining mechanisms of toxicity and carcinogenicity by asbestos in the gastrointestinal and respiratory tracts.

Organ and cell cultures of gastrointestinal and tracheobronchial epithelium have been used to document both the interaction of asbestos with mucosal cells and the sequence of cellular events occurring after exposure of cells to fibers. The biological activity of various types of asbestos in vitro is related to surface charge, crystallization, and dimensional characteristics. These factors also influence adsorption of natural secretions and serum components to fibers, a process that ameliorates cytotoxicity. Although mechanistic studies at the cellular level are lacking using epithelial cells of the digestive tract, asbestos appears to elicit a constellation of morphologic and biochemical changes in tracheal epithelium that resemble effects of classical tumor promoters on target cells.

Animals↗
PubMed1983

Influence of asbestos on the uptake of benzo(a)pyrene and DNA alkylation in hamster tracheal epithelial cells.

The objective of these experiments was to understand the mechanism of cocarcinogenicity of asbestos and polycyclic aromatic hydrocarbons. Benzo(a)pyrene [B(a)P] was coated onto crocidolite or chrysotile asbestos fibers, resuspended in serum-free medium, and added to cultures of hamster tracheal epithelial cells. The fibers markedly enhanced cell uptake of B(a)P. Although considerable metabolism occurred, approximately 40% of the applied B(a)P was retained by the cells after 8-hr incubation as opposed to 5% after incubation with B(a)P in the absence of asbestos. The hydrocarbon-containing medium was replaced by fresh medium. Four days later, approximately 3% of the B(a)P that had been applied when adsorbed to asbestos was still persistent in cells as compared to 0.5% in cells treated with B(a)P alone. DNA from hamster tracheal epithelial cells was purified, and the amount of B(a)P alkylation was assessed. At 8 hr, the extent of alkylation after treatment of the cells with either B(a)P or B(a)P:asbestos was similar. However, the retained unmetabolized B(a)P was subsequently metabolized and contributed to further alkylation so that the B(a)P-asbestos treated cells demonstrated considerably higher levels of alkylation throughout the 4-day posttreatment period. None of these effects was observed if asbestos was added 1 hr before the addition of B(a)P. The enhanced uptake of B(a)P and subsequent additional alkylation of DNA might represent a mechanism of asbestos-induced cocarcinogenesis.

Alkylation↗
PubMed1983

Squamous metaplasia of the respiratory tract. Possible pathogenic role in asbestos-associated bronchogenic carcinoma.

Asbestos workers who smoke have a substantially greater risk of developing bronchogenic carcinoma than nonsmokers. Squamous metaplasia often replaces the mucociliary epithelium in the respiratory tract of chronic users of cigarettes. As a result, clearance mechanisms are altered. Using both scanning and transmission electron microscopy, we examined the interaction of chrysotile and crocidolite asbestos with the metaplastic mucosa found in the bronchi of cigarette smokers and produced in cultures of hamster trachea by enriched, serum-free medium. After deposition on the squamous epithelium, both "long" and "short" fibers were either phagocytosed by, or moved between, the cells of the mucosa. The interaction of asbestos with the mucociliary epithelium differed. Most long fibers were cleared, whereas short fibers were taken up by the mucosa. The apparent increase in uptake of long asbestos fibers by the metaplastic squamous mucosa could contribute to the synergism between this unique mineral and cigarette smoke in the causation of bronchogenic neoplasms.

Animals↗
PubMed1983

Induction of squamous metaplasia in organ cultures of hamster trachea by naturally occurring and synthetic fibers.

Asbestos exhibits many properties of classical tumor promoters. These characteristics include the ability to stimulate proliferation and inhibit normal differentiation of cells. In organ cultures of trachea, crocidolite and amosite asbestos stimulate squamous metaplasia, a pathological process in which a rapidly proliferating squamous epithelium replaces the normal epithelium. We hypothesized that the induction of metaplasia depends upon the fibrous nature of asbestos. Accordingly, several naturally occurring and synthetic fibrous materials and their nonfibrous analogues were assessed for their ability to induce metaplastic changes in tracheal mucosa of the Syrian hamster. Exposure to both crocidolite asbestos and fiberglass resulted in significant increases (p less than 0.05) in squamous metaplasia over a range of dosages (1.0, 4.0, 16.0 mg/ml). Attapulgite (palygorskite) and both "long-" and "short-" fiber preparations of chrysotile asbestos had similar but less marked effects. Nonfibrous analogues of each material (riebeckite, antigorite, and glass particles) failed to produce metaplasia. Asbestos, and fibrous materials in general, appear to stimulate squamous metaplasia because of their fibrous geometry.

Animals↗