Effect of sodium butyrate in combination with X-irradiation, chemotherapeutic and cyclic AMP stimulating agents on neuroblastoma cells in culture.

Sodium butyrate, X-irradiation, chemotherapeutic agents and cyclic AMP-stimulating agents cuased reduction in the cell number (due to cell death and reduction in cell division) when added individually to mouse neuroblastoma cells in culture. However, the combination of sodium butyrate with X-irradiation, chemotherapeutic and cyclic AMP-stimulating agents produced a greater reduction in the cell number than that produced by the individual agents.     

Effect of sodium butyrate in combination with prostaglandin E1 and inhibitors of cyclic nucleotide phosphodiesterase on human amelanotic melanoma cells in culture.

Sodium butyrate and cyclic AMP-stimulating agents (prostaglandin E1, papaverine, theophylline, and RO20-1724) caused reductions in the cell number (primarily due to reduction in cell division) when added individually to human melanoma cells in culture. However, the combination of sodium butyrate with one of the cyclic AMP-stimulating agents produced a marked reduction in cell number (primarily due to cell death).     

Effect of sodium butyrate in combination with prostaglandin E1 and inhibitors of cyclic nucleotide phosphodiesterase on human amelanotic melanoma cells in culture

Summary Sodium butyrate and cyclic AMP-stimulating agents (prostaglandin E₁, papaverine, theophylline, and RO20-1724) caused reductions in the cell number (primarily due to reduction in cell division) when added individually to human melanoma cells in culture. However, the combination of sodium butyrate with one of the cyclic AMP-stimulating agents produced a marked reduction in cell number (primarily due to cell death).Supported in part by BRSG grant RR-05357 awarded by Biomedical Research Support Grant Program, Division of Research Resources, National Institutes of Health. We thank Marianne Gaschler for her technical help.     

Stimulation of pyruvate carboxylation by gastric secretagogues

Pyruvate carboxylation was stimulated by 2 gastric secretagogues, histamine and dibutyryl cyclic AMP, and by butyrate. Thiocyanate, an inhibitor of acid secretion, produced a slight decrease. Avidin significantly reduced acid secretion and this effect was overcome by biotin and oxalacetate. The results suggest that carboxylation of pyruvate is one of the reactions controlling oxidative metabolism and acid secretion in toad gastric mucosa.     

Stimulation of pyruvate carboxylation by gastric secretagogues

Summary Pyruvate carboxylation was stimulated by 2 gastric secretagogues, histamine and dibutyryl cyclic AMP, and by butyrate. Thiocyanate, an inhibitor of acid secretion, produced a slight decrease. Avidin significantly reduced acid secretion and this effect was overcome by biotin and oxalacetate. The results suggest that carboxylation of pyruvate is one of the reactions controlling oxidative metabolism and acid secretion in toad gastric mucosa.This investigation was supported by Consejo de Desarrollo Científico y Humanístico de la Universidad del Zulia, and by CONICIT Grant S1-0455.     

Effects of butyrate and insulin and their interaction on the DNA synthesis of rumen epithelial cells in culture

Rumen epithelial cells (REC) were incubated in the presence of various concentrations of butyrate or insulin or with both of them, to obtain information on their effect on the DNA synthesis of cultured cells. The 24-h values of 3H-thymidine incorporation into cellular DNA were measured in the presence of butyrate, insulin or butyrate plus insulin. While butyrate reduced DNA synthesis, insulin produced an increase over the control. Combined butyrate plus insulin treatment influenced the incorporation of label in accordance with the relative proportion of these two substances.     

Effects of butyrate and insulin and their interaction on the DNA synthesis of rumen epithelial cells in culture

Summary Rumen epithelial cells (REC) were incubated in the presence of various concentrations of butyrate or insulin or with both of them, to obtain information on their effect on the DNA synthesis of cultured cells. The 24-h values of³H-thymidine incorporation into cellular DNA were measured in the presence of butyrate, insulin or butyrate plus insulin. While butyrate reduced DNA synthesis, insulin produced an increase over the control. Combined butyrate plus insulin treatment influenced the incorporation of label in accordance with the relative proportion of these two substances.     

Effect of human serum on alkaline phosphatase induction in cultured human tumor cells

The continuous cell lines T 24 and HT-29, derived from human bladder and colon carcinomas, produce term-placental and intestinal alkaline phosphatase, respectively. Growth in hyperosmolar medium or exposure to prednisolone or sodium butyrate induces increased enzyme levels, and combinations of inducers elicit synergistic activity increases. The effect of the inducing agents is strikingly diminished when cells are grown in the presence of high concentrations of human serum, and the synergistic increases are essentially abolished. Major human serum protein fractions do not affect alkaline phosphatase induction.     

Beta-adrenergic-stimulated adenylate cyclase activity in normal and EBV-transformed lymphocytes

Beta-adrenergic-associated cyclic AMP accumulation was studied in intact lymphocytes before and after transformation with Epstein-Barr virus into immortal cell lines. Although a marked reduction in isoproterenol-stimulated cyclic AMP synthesis was observed in transformed cells, forskolin-stimulated cyclic AMP accumulation was preserved. A parallel loss of 125-iodocyanopindolol binding sites suggests that the reduction in beta-adrenergic-stimulated AMP synthesis is due to receptor down-regulation.     

Sexual dimorphism of mouse fetal brain lesions after X-irradiation prior to gonadal differentiation

Fractionated X-irradiation of gestational days 11-13 in the mouse, with doses between 3 x 1.05 and 3 x 1.33 Gy resulted in rosette-like clusters of primitive ependym-resembling cells dispersed within the cortex walls. Quantification of these abnormalities showed a general prevalence in the female fetuses, especially due to the larger number of rosettes in the females than in the males. It was concluded that X-irradiation acts on sex-specific differentiation steps, which are fully developed at the beginning of the fetal period. As it was recently speculated that these are linked to an early divergence of gene expression between the sexes, we suggest that X-chromosome damage may be involved in the pathogenesis of the dimorphic lesion pattern. While, in principle, this will valid for any fetal tissue, it only becames evident in the forebrain because of the outstanding relationship between cell necrosis and rosette development in this specific organ.     

Beta-adrenergic-stimulated adenylate cyclase activity in normal and EBV-transformed lymphocytes

Summary Beta-adrenergic-associated cyclic AMP accumulation was studied in intact lymphocytes before and after transformation with Epstein-Barr virus into immortal cell lines. Although a marked reduction in isoproterenol-stimulated cyclic AMP synthesis was observed in transformed cells, forskolin-stimulated cyclic AMP accumulation was preserved. A parallel loss of¹²⁵-iodocyanopindolol binding sites suggests that the reduction in beta-adrenergic-stimulated AMP synthesis is due to receptor down regulation.     

Effect of human serum on alkaline phosphatase induction in cultured human tumor cells

Summary The continuous cell lines T 24 and HT-29, derived from human bladder and colon carcinomas, produce term-placental and intestinal alkaline phosphatase, respectively. Growth in hyperosmolar medium or exposure to prednisolone or sodium butyrate induces increased enzyme levels, and combinations of inducers elicit synergistic activity increases. The effect of the inducing agents is strikingly diminished when cells are grown in the presence, of high concentrations of human serum, and the synergistic increases are essentially abolished. Major human serum protein fractions do not affect alkaline phosphatase induction.     

Histone deacetylase inhibitors augment doxorubicin-induced DNA damage in cardiomyocytes

Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutics with suberoylanilide hydroxamic acid (Vorinostat) and depsipeptide (Romidepsin) already being approved for clinical use. Numerous studies have identified that histone deacetylase inhibitors will be most effective in the clinic when used in combination with conventional cancer therapies such as ionizing radiation and chemotherapeutic agents. One promising combination, particularly for hematologic malignancies, involves the use of histone deacetylase inhibitors with the anthracycline, doxorubicin. However, we previously identified that trichostatin A can potentiate doxorubicin-induced hypertrophy, the dose-limiting side-effect of the anthracycline, in cardiac myocytes. Here we have the extended the earlier studies and evaluated the effects of combinations of the histone deacetylase inhibitors, trichostatin A, valproic acid and sodium butyrate on doxorubicin-induced DNA double-strand breaks in cardiomyocytes. Using γH2AX as a molecular marker for the DNA lesions, we identified that all of the broad-spectrum histone deacetylase inhibitors tested augment doxorubicin-induced DNA damage. Furthermore, it is evident from the fluorescence photomicrographs of stained nuclei that the histone deacetylase inhibitors also augment doxorubicin-induced hypertrophy. These observations highlight the importance of investigating potential side-effects, in relevant model systems, which may be associated with emerging combination therapies for cancer.     

Inhibition of pancreatic cancer cell growth

Pancreatic cancer cells are resistant to the growth-inhibitory and apoptosis-inducing effects of conventional chemotherapeutic agents. There are multiple genetic and epigenetic events during the process of carcinogenesis that enable the cancer cells to avoid normal growth constraints and apoptosis. Investigation of the mechanisms involved has led to multiple strategies that encourage cell death and apoptosis to occur. The pathways involved are summarized in this review, together with some recently developed strategies to promote cell death in this cancer.     

Sexual dimorphism of mouse fetal brain lesions after X-irradiation prior to gonadal differentiation

Summary Fractionated X-irradiation of gestational days 11–13 in the mouse, with doses between 3×1.05 and 3×1.33 Gy resulted in rosette-like clusters of primitive ependym-resembling cells dispersed within the cortex walls. Quantification of these abnormalities showed a general prevalence in the female fetuses, especially due to the larger number of rosettes in the females than in the males. It was concluded that X-irradiation acts on sex-specific differentiation steps, which are fully developed at the beginning of the fetal period. At is was recently speculated that these are linked to an early divergence of gene expression between the sexes, we suggest that X-chromosome damage may be involved in the pathogenesis of the dimorphic lesion pattern. While, in principle, this will be valid for any fetal tissue, it only becames evident in the forebrain because of the outstanding relationship between cell necrosis and rosette development in this specific organ.We are greatly indebted for the technical assistance of Mrs E. Senft, Mrs I. Hempfling and Mrs K. Pfaff.     

Adenosine promoted accumulation of adenosine 3',5'-monophosphate in rabbit vagus nerve.

Desheathed rabbit vagus nerve has been found to form cyclic AMP when incubated with adenosine. This accumulation of cyclic AMP is inhibited by theophylline but not by antiadrenergic agents, anticholinergic agents or local anaesthetics. Depolarizing media are not able to promote cyclic AMP accumulation in this preparation.     

Increase in membrane conductance by adrenaline in parotid acinar cells.

It is shown that excitation of the alpha- or beta-adrenoceptors in mouse parotid acinar cells causes a marked reduction of surface cell membrane resistance. The alpha-adrenoceptor induced membrane effect is an increase in K conductance. The beta-adrenoceptor induced membrane effect does not seem to be mediated by cyclic AMP.     

Biophysikalische Studien mit synthetischem Lecithin als Weg zu neuartigen Chemotherapeutika

Summary Based on the behaviour of lecithin in a biophysical cell model, novel compounds have been developed which are regarded as phosphatide blockers in the membrane of the living cell. They inhibit neoplasms in animal experiments to a high degree, and are therefore potential chemotherapeutic agents of great interest.     

Critical period for induction of congenital hydrocephalus and dysplasia of subcommissural organ by prenatal X-irradiation in rats

A single whole-body X-irradiation of pregnant Wistar rats at a dose of 1.05 Gy at 10.30, 12.30 and 14.30 h respectively, of gestational day 10 resulted in significantly high incidences of hydrocephalic offspring. No hydrocephalic offspring resulted from X-irradiation of pregnant rats with 1.05 Gy at 16.30 h, whereas a dose of 1.22 Gy at 16.30 h resulted in a low but statistically significant incidence of hydrocephalus. Neither 1.05 Gy nor 1.22 Gy X-irradiation of pregnant rats at 18.30 h resulted in any hydrocephalic offspring. Dysplasia of the subcommissural organ was noticed in all the hydrocephalic brains histologically examined.     

Increase in the survival time of mice exposed to ionizing radiation by a new class of free radical scavengers

N-acyl dehydroalanines react with and scavenge mainly superoxide radical (O-2.) and hydroxyl radical (HO.). The ortho-methoxyphenylacetyl dehydroalanine derivative, indexed as AD-20, protects mice against damage resulting from total body X-irradiation, as measured by the increase in their survival time. AD-20 increases the LD50 at 30 days from 6.1 to 7.3 Gy in animals exposed to a wide range of X-rays (6 to 10 Gy). The dose reduction factor (D R F) of AD-20 is 1.20. We postulate that such radioprotective effect may result from its free radical scavenging activity.