Ultrastructure of 1,2-dimethylhydrazine-induced adenocarcinomas in rat colon.
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Adenocarcinoma↗
Biomedical subjects
D H Barkla
Publications and source records attributed to D H Barkla.
The influence of adrenoceptor activity on cell proliferation in colonic crypt ipithelium and in colonic adenocarcinomata.
The effects of chemical sympathectomy and of the injection of amines or amine-receptor blocking drugs on cell proliferation in colonic crypts and in dimethylhydrazine-induced colonic carcinomata is examined in rats using a stathmokinetic technique. In animals which had been chemically sympathectomized by injection of 6-hydroxydopamine cell proliferation essentially ceased in the colonic crypts but continued at a normal rate in the tumours. Stimulation of alpha-adrenoceptors by metaraminol, a drug with properties similar to noradrenaline, caused acceleration of cell proliferation in colonic crypts but not in tumours. Conversely, blockade of alpha-adrenoceptors by phentolamine inhibited cell proliferation in crypts but not in tumours. Injection of adrenaline, predominantly a beta-adrenergic agonist, inhibited cell proliferation in the tumours but not in colonic crypts whereas blockade of beta-adrenoceptors by propranolol accelerated cell proliferation in tumours but not in colonic crypts. It is postulated that cell proliferation in the crypts of Lieberkühn in rat colon resembles that in rat jejunum in being controlled by the autonomic nervous system. However, tumour cell proliferation does not appear to be subject to such regulation.
Adenocarcinoma↗
Cytotoxicity of cyproheptadine and methysergide to chemically induced carcinomas of rat colon.
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Animals↗
Surface changes in the descending colon of rats treated with dimethylhydrazine.
Male Sprague-Dawley rats were given weekly s.c. injections of 1,2-dimethylhydrazine (21 mg/kg) for period of up to 20 weeks. The descending colon of treated animals killed at 2 weekly intervals was examined for morphological change, over a 30-week period, after commencement of treatment using scanning electron microscopy, light microscopy, transmission electron microscopy, and freeze-fracture techniques. Scanning electron microscopy showed that 1,2-dimethylhydrazine treatment resulted in the progressive replacement of the normal arrangement of epithelial cells covering the luminal surface of intestinal glands with enlarged and irregularly shaped arrangements of epithelial cells, so that the entire mucosa was atypical and disorganized at 30 weeks after commencement of treatment. The changes were not readily observable using other methods of microscopy. Multiple tumors that were apparently unrelated to sites of specific morphological change erupted into the intestinal lumen through the atypical epithelium. Tumor surface cells and normal absorptive cells were compared using scanning electron microscopy and transmission electron microscopy of thin sections and freeze-fracture replicas. The results showed that tumor cells were usually smaller, more rounded, showed less regularly shaped microvilli, and had fewer particles in the apical surface membrane than on normal absorptive cells.
Animals↗
Cytotoxicity of 5,6-dihydroxytryptamine in dimethylhydrazine-induced carcinomas of rat colon.
Male Sprague-Dawley rats were given weekly s.c. injections of 1,2-dimethylhydrazine (21 mg/kg) for 20 weeks. The injections were then discontinued, and, after an interval of 2 to 8 weeks, experimental animals were given i.p. injections of 5,6-dihydroxytryptamine (5,6DHT) at a dose of 40 mg/kg and sacrificed at intervals of 1, 2, 6, 16, and 48 hr later. Specimens of descending colon and carcinomas of the descending or transverse colon from sacrificed animals were examined using light microscopy and transmission electron microscopy. The results show that 5,6DHT at a dose of 40 mg/kg is cytotoxic to malignant colonic epithelial cells but not cytotoxic to adjacent nonmalignant colonic epithelial cells. In malignant colonic epithelial cells, ultrastructural changes in cytoplasmic membranes and mitochondria were evident at 1 hr after 5,6DHT treatment. At 6 hr after 5,6DHT treatment, light microscopy of sections of tumor showed areas of cell necrosis and disrupted tumor morphology. Sections of specimens taken 16 hr after treatment showed widespread destruction of malignant cells.
5,6-Dihydroxytryptamine↗
Cell proliferation in the descending colon of dimethylhydrazine treated rats and in dimethylhydrazine induced adenocarcinomata.
A stathmokinetic technique which has estimable precision has been used to estimate mitotic rates in the crypts of Lieberkühn in the descending colon of normal, and of dimethylhydrazine (DMH)-treated rats, as well as in DMH-induced adenocarcinomata. Estimates of the mean number of proliferating and of non-proliferating cells per crypt of Lieberkühn were also made in normal and in DMH-treated rats. In normal rats, epithelial cell proliferation was found to be relatively slow in the basal one-fifth of the crypts of Lieberkühn and to be most rapid in the second one-fifth of the crypt. In DMH-treated rats the number of cells around the circumference of transversely sectioned crypts was significantly increased, as was the number of proliferating cells present in longitudinally sectioned crypts. The region of relatively slow cell proliferation in the base of the crypts was expanded to occupy the lower two-fifths of the crypt in DMH-treated rats whilst the region of most rapid cell proliferation was displaced upwards to occupy the third one-fifth of the crypt. In DMH-induced adenocarcinomata cell proliferation occurred at a rate similar to that in the relatively quiescent zone at the bases of the colinic crypts in normal animals. However, tumour cell proliferation was substantially slower than that in the second one-fifth of the crypt in normal animals.
Adenocarcinoma↗
A comparison of cell proliferation in normal and neoplastic intestinal epithelia following either biogenic amine depletion or monoamine oxidase inhibition.
Epithelial cell proliferation was studied in the jejunum and in the colon of normal rats, in the colon of dimethylhydrazine-treated rats and in dimethylhydrazine-induced adenocarcinoma of the colon using a stathmokinetic technique. Estimates of cell proliferation rates in these four tissues were then repeated in animals which had been depleted of biogenic animes by treatment with reserpine and in animals whose monoamine oxidase was inhibited by treatment with nialamide. In amine-depleted animals cell proliferation essentially ceased in all four tissues examined. Inhibition of monoamine oxidase did not significantly influence cell proliferation in nonmalignant tissues but accelerated cell division in colonic tumours.
Adenocarcinoma↗
Proceedings: Experimentally induced accumulation and depletion of Paneth cell granules.
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Animals↗
Possible sex differences in incidence of caries in human deciduous canines and molars.
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Australia↗
The level of the larynx during childhood.
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Cephalometry↗
The influence of serotonin on the mitotic rate in the colonic crypt epithelium and in colonic adenocarcinoma in rats.
1. The mitotic rate in the crypts of Lieberkühn of the descending colon and in dimethylhydrazine-induced adenocarcinomata of the descending colon of rat was measured using a stathmokinetic technique. 2. Intraperitoneal injection of a small dose (10 microgram/kg) of serotonin resulted in an increase in the tumour cell mitotic rate. 3. Blockade of serotonin receptors by 2-bromolysergic acid diethylamide and depletion of tissue serotonin levels following injection of DL-6-fluorotryptophan both result in a decrease in the tumour cell mitotic rate. 4. Treatment with serotonin, 2-bromolysergic acid diethylamide and DL-6-fluorotryptophan were all without effect on the colonic crypt cell mitotic rate.
Adenocarcinoma↗
The influence of dibutyryl adenosine cyclic monophosphate on cell proliferation in the epithelium of the jejunal crypts, the colonic crypts and in colonic carcinomata of rat.
1. Cell proliferation in the jejunal crypts, the colonic crypts and in dimethylhydrazine (DMH)-induced adenocarcinomata of rat colon was measured using a stathmokinetic technique. 2. Dibutryl cyclic adneosine monophosphate (dibutyryl cAMP) was found to inhibit cell proliferation in colonic crypts and in colonic adenocarcinomata. 3. Dibutryl cAMP at very high doses was found to inhibit jejunal crypt cell proliferation but at lower doses was found to accelerate jejunal crypt cell proliferation. 4. Neither bilateral adrenalectomy nor chemical sympathectomy was found to abolish the ability of dibutryl cAMP to stimulate jejunal crypt cell proliferation. 5. The present results are difficult to interpret in terms of known hormonal influences on cell proliferation in the tissues examined and of established actions, of these hormones on cyclic nucleotide metabolism in other tissues.
Adrenalectomy↗
Further studies on the effect of adenosine cyclic monophosphate derivatives on cell proliferation in the jejunal crypts of rat.
1. Cell proliferation in the jejunal crypt epithelium of rat was measured using a stathmokinetic technique. 2. Sodium butyrate was found to promote jejunal crypt cell proliferation. 3. N6, O2'-Dibutyryl cyclic adenosine monophosphate (cAMP), N6-monobutyryl-cAMP and N6-monobutyryl-8-bromo-cAMP were found to inhibit cell proliferation when compared to sodium butyrate treated tissues. 4. 8-Chlorophenylthio-cAMP was found to inhibit cell division when compared to untreated animals. 5. O2'-Monobutyryl cAMP and 8-bromo-cAMP were not found to inhibit cell proliferation.
Animals↗
Adrenergic factors involved in the control of crypt cell proliferation in jejunum and descending colon of mouse.
The mitotic rates in the crypts of Lieberkühn of the proximal jejunum and descending colon of mouse, following different treatments, were measured using a stathmokinetic technique. Regression coefficients, representing mitotic rates, were then calculated by the method of least squares. Treatment with adrenaline, isoprenaline, phenylephrine, phentolamine, and yohimbine all resulted in decreased mitotic rate of jejunal and colonic crypt cells. Chemical sympathectomy and cryosympathectomy had a similar effect, and chemical sympathectomy was followed by a supersensitivity to clonidine. Intraperitoneal injection of metaraminol, clonidine, propranolol, prazosin, labetolol and simultaneous injection of propranolol and adrenaline all resulted in an increased rate of crypt cell proliferation in both jejunum and colon. A significant increase in mitotic rate was observed in both tissues at night. The amplitude of this diurnal variation was decreased in both jejunum and colon following chemical sympathectomy. In addition, the amplitude of this variation in jejunum was decreased after treatment with yohimbine or phentolamine. The results of the study suggest that the sympathetic nervous system stimulates epithelial cell proliferation in both the small and large intestine and that this effect is mediated by an alpha 2-adrenoceptor. By contrast, stimulation of alpha 1- and beta-adrenoceptors is inhibitory to cell proliferation in these tissues.
Animals↗
Effects of histamine and 5-hydroxytryptamine on the growth rate of xenografted human bronchogenic carcinomas.
1. The influence of histamine and 5-hydroxytryptamine (5-HT) antagonists and agonists on the volume doubling times (Td) of human bronchogenic carcinomas propagated as s.c. xenografts in immunosuppressed mice was examined. 2. The H2-receptor antagonists, cimetidine and ranitidine, increased Td. 3. Treatment with the H2-receptor agonist, 4-methyl histamine, had no effect on Td. 4. Co-administration of 4-methyl histamine and cimetidine abolished the effects of cimetidine. 5. The 5-HT2-receptor antagonists, cinanserin and ketanserin, both increased Td. 6. Treatment with the 5-HT1/2-receptor agonist quipazine (0.1 mg/kg, reflecting 5-HT2 agonist activity) decreased Td, while a higher dose (10.0 mg/kg) had no effect. 7. The 5-HT1/2-receptor antagonist, methiothepin, decreased Td. 8. The 5-HT uptake inhibitor, fluoxetine, increased Td in one tumour line but not in another, while the 5-HT releaser/depletor, fenfluramine, increased Td. 9. Histamine may stimulate tumour growth through the histamine H2-receptor, while the dominant effect of 5-HT is 5-HT1-receptor inhibition. 10. Tumour growth in some bronchogenic carcinomas may involve 5-HT uptake mechanisms.
Animals↗
Morphological changes in human melanoma cells following irradiation with thermal neutrons.
Morphological changes in two human melanoma cell lines, MM96 and MM418, following irradiation with thermal neutrons, were studied using light and electron microscopy. The results show that the response of human malignant melanoma cells to neutron irradiation is both cell line dependent and dose dependent, and that in any given cell line, some cells are more resistant to irradiation than others, thus demonstrating heterogeneity in respect to radiosensitivity. Cells repopulating MM96 flasks after irradiation were morphologically similar to the cells of origin whereas in MM418 flasks cells differentiated into five morphologically distinct subgroups and showed increased melanization. The results also show that radiation causes distinctive morphological patterns of damage although ultrastructural changes unique to the high LET particles released from boron 10 neutron capture are yet to be identified.
Boron Compounds↗
Biogenic amines as regulators of the proliferative activity of normal and neoplastic intestinal epithelial cells (review).
The role of extracellular amines such as noradrenaline and serotonin and their interaction with cyclic nucleotides and intracellular polyamines in the regulation of intestinal epithelial cell proliferation is reviewed with particular reference to the differences between normal and neoplastic cells. In respect to the normal epithelium of the small intestine there is a strong case to support the notion that cell proliferation is controlled by, amongst other things, sympathetic nerves. In colonic carcinomas, antagonists for certain serotonin receptors, for histamine H2 receptors and for dopamine D2 receptors inhibit both cell division and tumour growth. Because of the reproducible variations between tumour lines in the response to these antagonists, this inhibition appears to be due to a direct effect on the tumour cells rather than an indirect effect via the tumour host or stroma. This conclusion is supported by the cytocidal effects of toxic congeners of serotonin on the tumour cells. The most salient difference between the amine responses of normal and neoplastic cells relates to the issue of amine uptake. Proliferation of crypt cells is promoted by amine uptake inhibitors, presumably because they block amine re-uptake by the amine secreting cells--sympathetic neurones and enteroendocrine cells. However, tumour cell proliferation is strongly inhibited by amine uptake inhibitors, suggesting that neoplastic cells can, and need to take up the amine before being stimulated by it. Recent revelations in the field of oncogenes also support an important association between amines, cyclic nucleotides and cell division. The ras oncogenes code for a protein that is a member of a family of molecules which relay information from extracellular regulators, such as biogenic amines, to the intracellular regulators, including cyclic nucleotides. Evidence is presented suggesting that enteroendocrine cells, enterocytes, carcinoid tumour cells and adenocarcinoma cells all have the same embryonic origin and that cells exhibiting an admixture of endocrine and proliferative properties exist in colonic tumours, but not in the normal intestinal epithelium. Thus, it appears that in the normal intestine a clear structural and functional distinction exists between the regulating cells (i.e. the sympathetic neurones and enteroendocrine cells) and the regulated cells (i.e. the undifferentiated crypt cells): cells that have acquired a regulating role are no longer able to divide and cells which are able to divide do not take up or store amines.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Steroid hormones as regulators of the proliferative activity of normal and neoplastic intestinal epithelial cells (review).
Glucocorticoid and mineralocorticoid receptors are present in normal epithelial cells of both the small and large intestine and there have also been contentious reports of androgen, oestrogen and progesterone receptors in the epithelium of the normal large intestine. The majority of reports suggest that stimulation of the intestinal glucocorticoid receptors results in increased proliferation of epithelial cells in the small bowel, as does stimulation of androgen receptors and possibly mineralocorticoid receptors. The proliferative response of the normal intestine to oestrogens is difficult to evaluate and that to progestigens appears not to have been reported. Epidemiological studies reveal a higher incidence of bowel cancer in premenopausal women than in men of the same age and yet there is a lower incidence of these tumors in women of higher parity. These findings have been atributted to a variety of non-epithelial gender characteristic such as differences in bile metabolism, colonic bacterial and fecal transit times. In experimental animals, androgens have also been shown to influence carcinogenesis and this could well be attributed to changes in food intake etc. However, many studies have now revealed steroid hormone receptors on colorectal tumor cells and thus a direct effect of the steroid hormones on the epithelium during and after malignant transformation must now be considered.
Animals↗