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Biomedical subjects

J Hofmann

Publications and source records attributed to J Hofmann.

At least 127 records · Page 7Linked to original sources
PubMed1988

Enhancement of the antiproliferative effect of cis-diamminedichloroplatinum(II) and nitrogen mustard by inhibitors of protein kinase C.

Quercetin (3,3',4',5,7-pentahydroxyflavone) has been shown to inhibit a variety of enzymes including the calcium- and phospholipid-dependent protein kinase (protein kinase C) in vivo and in vitro. We show that this compound synergistically enhances the antiproliferative activity of cis-diamminedichloroplatinum(II) (cis-DDP) and nitrogen mustard. Quercetin does not affect the repair of DNA interstrand cross-links introduced by cis-DDP. Long-term exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA), which reduces total protein kinase C activity, also amplifies the growth-inhibitory effect of cis-DDP and acts synergistically with quercetin. A synergism is also observed if tamoxifen or staurosporine are combined with cis-DDP. For both drugs the dose-effect curves for the inhibition of protein kinase C closely resemble the dose-effect curves for the antiproliferative activities. Although alternative mechanisms cannot be definitively excluded, the effects of quercetin, TPA, tamoxifen and staurosporine may result from the inhibition of protein kinase C.

Alkaloids↗
PubMed1988

Protection of Ehrlich ascites tumor cells against the antiproliferative effect of mechlorethamine (nitrogen mustard) by 5-N,N-dimethylamiloride.

5-N,N-Dimethylamiloride protects Ehrlich ascites tumor cells against the antiproliferative effect of nitrogen mustard. The drug reduces the frequency of DNA interstrand cross-links introduced by nitrogen mustard. Cells with a defective choline carrier are not protected against nitrogen mustard by dimethylamiloride. As nitrogen mustard is taken up by the choline carrier, it is concluded that the recently reported inhibition of the choline transport system by amiloride and its dimethyl derivatives (W. Doppler et al., Biochem. Pharmacol., 36: 1645-1649, 1987) is responsible for the protection against the alkylating agent.

Amiloride↗
PubMed1988

Stimulatory effects of androgen and antiandrogen on the in vitro proliferation of human mammary carcinoma cells.

The proliferation of three mammary carcinoma cell lines was explored for the effectiveness of dihydrotestosterone (DHT) and the antiandrogenic substances cyproterone acetate (CPA) or hydroxyflutamide. The cell growth, determined in multiple experimental cultures of the estrogen-sensitive lines MCF-7 and EFM-19, was stimulated by 10(-9) M to 10(-6) M DHT, whereas estrogen-resistant MFM-21 cells were unresponsive to the hormonal factors applied. Growth-promoting effects of 10(-8) M to 10(-6) M CPA were detected in cultures of those cell lines which were sensitive to estrogen and androgen. Competition experiments with DHT and the antiandrogens suggested involvement of the androgen receptor in the stimulation of cell growth by CPA. Participation of the estrogen receptor was excluded by lack of competition between CPA and the enhancement of proliferation by estradiol-17 beta. At the receptor level the antiandrogens were able to compete with androgen binding. The results of the study demonstrate androgenic properties of CPA in regard to the growth of human mammary carcinoma cells.

Androgen Antagonists↗
PubMed1988

Differential sensitivity of histone acetylation in nitrogen-mustard sensitive and resistant cells. Relation to drug uptake, formation and repair of DNA-interstrand cross-links.

Cultivation of Ehrlich-ascites tumor cells in the presence of N-mustard leads to a selection of cells with a defective choline carrier. As N-mustard employs the choline carrier for transport, this results in reduced drug uptake and in a decrease in drug sensitivity which is specific for N-mustard. Walker carcinoma cells with a stable pleiotropic resistance to a variety of alkylating agents and adriamycin exhibit no evidence for an impaired drug transport and show the same frequency of DNA-interstrand cross-links as the sensitive parental line. Both sensitive and resistant Walker cells exhibit equal capacities for repair of N-mustard induced DNA-interstrand cross-links. The inhibition of histone acetylation by N-mustard, however, was found to be significantly lower in the resistant Walker or Ehrlich cells compared to sensitive counterparts. Although the difference between N-mustard concentrations leading to half maximal inhibition of histone acetylation in sensitive and resistant cells is considerably smaller than the difference between N-mustard doses required for half maximal inhibition of cell proliferation the data suggest that--besides DNA-DNA cross-linking--the inhibition of histone acetylation has to be considered as an important alternative mechanism responsible for the cytotoxic activity of alkylating agents. Inhibition of histone acetylation is not due an accelerated deacetylation and is predominantly expressed in chromatin fractions soluble in 0.1 M NaCl after digestion with micrococcal nuclease.

Acetylation↗
PubMed1988

Desensitization of the Ca2+-mobilizing system to serum growth factors by Ha-ras and v-mos.

An elevation of the intracellular pH and a rise in the cytoplasmic Ca2+ concentration are considered important mitogenic signals which are observed after stimulation by various growth factors. In a preceding report it was demonstrated that the expression of Ha-ras or v-mos in cells transfected with Ha-ras or v-mos, respectively, leads to an activation of the Na+/H+ antiporter and a concomitant rise in intracellular pH (W. Doppler, R. Jaggi, and B. Groner, Gene 54:145-151, 1987). This report describes the effect of the Ha-ras and v-mos oncogenes on intracellular Ca2+ release. The expression of Ha-ras in NIH 3T3 cells carrying a glucocorticoid-inducible transforming Ha-ras gene caused a desensitization of the Ca2+-mobilizing system to serum growth factors. The induction of p21ras in cells carrying the corresponding glucocorticoid-inducible proto-oncogene did not affect the Ca2+ response to growth factors. Conditions leading to the expression of the transforming Ha-ras gene but not those causing the induction of the normal Ha-ras gene yielded an increase in phosphatidylinositol turnover and a concomitant rise in inositol phosphates. Results similar to those obtained with the transforming Ha-ras gene were seen after the expression of v-mos. The data are consistent with a mechanism in which expression of the transforming Ha-ras gene leads to a release of Ca2+ from intracellular stores via elevated levels of inositol trisphosphate.

Animals↗
PubMed1987

Temperature dependence of membrane ion conductance analyzed by using the amphiphilic anion 5/6-carboxyfluorescein.

The rate of efflux of trapped 5/6-carboxyfluorescein from sealed lipid vesicles showed a marked dependence on (a) temperature, (b) phospholipid acyl chain composition, and (c) the nature of co-trapped counterions. When the dye was salted with sodium, at pH greater than 7, the rate of dye permeation showed a discrete maximum at the melting point of the lipid bilayer (Tc); in the case of membranes composed of dipalmitoylphosphatidylcholine, this discontinuity extended over a very broad temperature range, being detectable at least 10 degrees C above and below Tc. The peak in dye permeation rate was superimposed on a permeation profile that showed a simple exponential relationship to temperature. Studies with a homologous series of saturated lecithin bilayers revealed a consistent pattern of behavior: a logarithmic dependence of dye permeation rate on temperature with a superimposed discontinuity at Tc. For thin membranes (12-14-carbon acyl chains), the discontinuity was severe, exerting an influence over a very broad temperature range and leading to extremely high overall dye leakage rates. As the acyl chains were lengthened, the discontinuity became less pronounced, almost disappearing at a chain length of 20 carbons. In sharp contrast to these results, dye salted with N-methylglucamine [or with tris(hydroxymethyl)aminomethane] showed no efflux maximum at Tc, and base-line leakage rates were generally slower. When dye was salted with ammonium, efflux was too rapid to monitor, even at temperatures well below Tc. The results indicate that the rate of release of electrically charged dyes, such as 5/6-carboxyfluorescein, from sealed lipid vesicles can be tightly coupled to the counterion leakage rate and hence can provide an accurate and convenient assay of relative ion flux across phospholipid bilayers.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1987

Amiloride and 5-N,N-dimethylamiloride inhibit the carrier mediated uptake of choline in Ehrlich ascites tumor cells.

Amiloride and 5-N,N-dimethylamiloride (DMA) inhibit the choline uptake of Ehrlich ascites tumor cells. The inhibition by DMA is competitive with a KI value of 20 microM. The apparent KM value for choline was determined as 15 microM. Amiloride is approximately three times less potent. Amiloride uptake is not antagonized by choline or impaired in cells characterized by a deficient choline carrier. This indicates that amiloride is not transported into the cell by the choline carrier. The inhibition of the choline uptake by DMA cannot be attributed to a depression of choline kinase (EC 2.7.1.32) and is therefore considered to be due to a direct interaction between DMA and the choline carrier. DMA does not compete with sodium ions for its effect on the choline carrier. It is suggested that the choline carrier of Ehrlich ascites tumor cells exhibits a binding site for DMA similar to the one on the Na+/H+ antiporter.

Amiloride↗
PubMed1986

Alkylating antitumor agents reduce histone acetyl-transferase activity.

N-Mustard depresses the acetylation of histones in Ehrlich ascites and Walker carcinoma cells. It is demonstrated that this effect is not caused by an accelerated deacetylation but is due to an inhibition of the acetyl-transferase reaction. Employing 4-sulphonatoethylthio-cyclophosphamide it is demonstrated that the alkylating agent affects predominantly the acetylation of a chromatin fraction which is soluble in 0.1M NaCl after digestion with micrococcal nuclease. After removal of the alkylating agent, the recovery of histone acetylation is relatively slow and--in contrast to the repair of DNA cross-links--characterized by a 4-hr lag period. The reduction of histone acetylation by N-mustard is much less expressed in cells which are resistant to the drug than in the sensitive parental lines. This is in contrast to DNA-interstrand cross-links in Walker cells where both N-mustard sensitive and resistant cells inhibit the same cross-link frequency and identical repair rates. Based on these data it is concluded that the inhibition of histone acetylation may be an important part of the mechanism by which alkylating agents inhibit tumor growth.

Acetylation↗
PubMed1986

Acetylcholinesterase activities in association with congenital malformation of the terminal ureter in infants and children.

Acetylcholinesterase activity was found to be higher than normal in intravesical segments of ureters taken from children with vesicoureteral reflux. The ratio of acetylcholinesterase activity to total cholinesterase activity was also found to be high. Acetylcholinesterase activity was normal in intravesical segments taken from the constricted area of ureters from children with obstructive megaureter but it was high in segments taken from the juxtavesical part, immediately adjacent to the constricted area. These findings complement histological studies which have revealed a hyperplasia of cholinergic nerve fibres in the tunica muscularis of reflux ureters whereas obstructive megaureters show a hypoplasia of the beta-adrenergic system.

Acetylcholinesterase↗
PubMed1986

[Tumor biochemistry as basis for advances in tumor chemotherapy].

Oncogenes, onc-gene products and the concept of autonomous self-stimulation of tumor growth by autocrine production of growth factors are discussed with regard to the development of new antitumor agents. The significance of the plasma membrane as an attractive target in tumor chemotherapy is emphasized. Membrane bound enzymes and related reactions which are involved in growth factor dependent regulation of cell proliferation offer new targets for antitumor chemotherapy. Examples demonstrating the antiproliferative effects of phospholipase-C and calmodulin inhibitors are presented. A synergistic effect of these drugs with alkylating agents is observed. Studies devoted to the improvement of alkylating antitumor agents have also led to the plasma-membrane as a particularly suited target. The same may be true for other antitumor agents like anthracyclines and platinum complexes for which evidence exists implicating the involvement of cellular membranes in the mechanism of cytotoxic action.

Alkylating Agents↗
PubMed1986

[Experiences with oral immunization of foxes against rabies in Hesse].

Since spring 1983 a field trial to immunize foxes by the oral route against rabies has been carried out in a heavily infected area of Hessen measuring about 1,500 km2. The vaccine strain SAD B 19, produced by the Federal Research Institute for Animal Virus Diseases at Tübingen and filled into 2 ml aliquots, was inserted into chicken heads and distributed by forest rangers in the trial area, 15 baits per km2. Up to the present day five baiting campaigns, two per year in spring and autumn, have been completed and in all 110,000 vaccine baits additionally marked with 150 mg tetracycline were layed out. Four baitings have been previously evaluated. With the exception of some rabies cases on the border to the unvaccinated region in the northwest, rabies was reduced impressively. A secondary outbreak in the region of Hausen/Kiedrich, caused by an extremely high density of the fox population, was eradicated by increasing the baits to 25 per km2. The number of rabies cases, which amounted to 238 within 15 months prior to the vaccination trial, went down from 38 in the first 6 months to 6 cases after the fourth baiting. As innocuity control 2,273 wild and domestic animals from the vaccination area were examined for the presence of the vaccine virus. The results were always negative indicating that rabies strain SAD B 19 had not established an infective cycle in wildlife. As could be shown by the marker studies, an average of 78 per cent of the foxes (variation of the baitings from 62 per cent to 82 per cent) had taken up one or more baits. Seroconversion had been achieved in 65 per cent of the foxes (variation from 43 per cent to 70 per cent) as demonstrated by the presence of neutralizing antibodies. From experiences in Switzerland it can be expected, that rabies will be extinguished, if 50 per cent of the population are successfully immunized. This value has been surpassed in the field trial in Hessen. These very promising results have led to the project of an enlargement of the vaccination area to 12,000 km2. The neighbouring states of Rheinland-Pfalz and Nordrhein-Westfalen have joined in this effort, which has started in autumn 1985 with a new artificial vaccine bait developed at the Tübingen research institute.

Administration, Oral↗
PubMed1985

The organism as bioreactor. Interpretation of the reduction law of metabolism in terms of heterogeneous catalysis and fractal structure.

Organisms and bioreactors are open, dissipative systems in steady state. They are functionally equivalent with respect to turnover and kinetics, and structurally analogous with respect to fractal organization and self-similar scaling. As heterogeneous catalytic systems both are governed by interaction of mass transport and reaction. The structural equivalent to turbulence in the reactor, yielding high efficiency, is the fractal folding and branching of the transport systems of the organism. Dimensionally and in terms of fractals, organisms and reactors are therefore area-volume hybrids. The physiological consequence of this is the reduction law of metabolism. Introducing limits into allometric functions describing scale-up of similar organisms yields probability density distributions of their realization.

Animals↗