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Biomedical subjects

B Lippert

Publications and source records attributed to B Lippert.

36 records · Page 2Linked to original sources
PubMed1992

From cisplatin to artificial nucleases--the role of metal ion-nucleic acid interactions in biology.

Metal ions and metal coordination compounds bind to nucleic acids in a variety of ways, ranging from weak electrostatic interactions via hydrogen bonding and/or van der Waals forces to strong covalent binding. Metal ions naturally take part in the formation and the degradation of nucleic acids, and the propensity of certain metal coordination compounds to bind to nucleic acids, notably DNA, is exploited in cancer chemotherapy. Moreover, metal compounds have a wide potential as chemical probes for nucleic acid structures and as tools for nucleic acid processing.

Animals↗
PubMed1991

2'-Deoxy-2'-methylenecytidine and 2'-deoxy-2',2'-difluorocytidine 5'-diphosphates: potent mechanism-based inhibitors of ribonucleotide reductase.

It has been found that 2'-deoxy-2'-methyleneuridine (MdUrd), 2'-deoxy-2'-methylenecytidine (MdCyd), and 2'-deoxy-2',2'-difluorocytidine (dFdCyd) 5'-diphosphates (MdUDP (1) MdCDP (2) and dFdCDP (3), respectively) function as irreversible inactivators of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). 2 is a much more potent inhibitor than its uridine analogue 1. It is proposed that 2 undergoes abstraction of H3' to give an allylic radical that captures a hydrogen atom and decomposes to an active alkylating furanone species. RDPR also accepts 3 as an alternative substrate analogue and presumably executes an initial abstraction of H3' to initiate formation of a suicide species. Both 2 and 3 give inactivation results that differ from those of previously studied inhibitors. The potent anticancer activities of MdCyd and dFdCyd indicate a significant chemotherapeutic potential. The analogous RDPR of mammalian cells should be regarded as a likely target and/or activating enzyme for these novel mechanism-based inactivators.

Cytosine↗
PubMed1990

Lactate dehydrogenase isoenzymes in squamous cell carcinomas of the oral cavity.

Lactate dehydrogenase (LDH; EC 1.1.1.27) isoenzymes in human epithelial cells from squamous cell carcinomas and healthy tissues of the oral cavity of five patients were analyzed using isoelectric focussing. A new basic isoenzyme and high LDH-7 and LDH-9 activity were found in tumor cells in contrast to epithelial cells of adjoining nontumor tissue. These findings indicate that gradual changes in the percentage distribution of LDH isoenzymes may represent a useful parameter of disease activity in patients with squamous cell carcinomas.

Adult↗
PubMed1989

Inhibited methionine incorporation in human squamous carcinomas of the oral cavity as a measure for response to 5-fluorouracil.

Human epithelial cells and fibroblasts from malignant tumors and healthy tissues of the oral cavity were exposed in vitro to increasing concentrations of 5-fluorouracil. In order to determine whether the two cell types showed a difference in uptake, accumulation was measured over time using tritiated fluorouracil. Maximal drug uptake occurred in highly proliferative epithelial cells from cancerous tissue at 3 h, whereas fibroblasts from the same tissue and other cell types from healthy tissue exhibited a steadily increasing uptake over a long period of time. By use of [3H]methionine, a direct correlation could be demonstrated between the amount of incorporated drug and the fall in the rate of de novo protein synthesis. Furthermore, suppression of protein synthesis was closely related to the inhibition of cell division. These results indicate that the level of de novo protein synthesis can be a direct measure of the anticancer effect of fluorouracil.

Carcinoma, Squamous Cell↗
PubMed1986

Effect of dextran-bound acetazolamide on rabbit corneal endothelial ion fluxes.

The effects of a carbonic anhydrase inhibitor, acetazolamide, bound to a 72,000 dalton dextran (DBI) on bicarbonate and sodium fluxes across the isolated rabbit corneal endothelium have been examined. When DBI was present on the aqueous-facing endothelial surface, there was a marked inhibition of both the stromal to endothelial unidirectional and net flux of bicarbonate. This suggests that the exit of bicarbonate from the cell into the aqueous-facing solution is influenced by the enzyme carbonic anhydrase. No change was found in sodium fluxes under these same incubation conditions. When DBI was present on the stromal-facing surface of the endothelium, no changes were found in unidirectional or net bicarbonate fluxes; the sodium flux from stroma to endothelium was increased, however, with no change in net flux. This data implies that the link between sodium and bicarbonate movement across the endothelium is not a direct coupling between the transport of the two ions in the form of a symport (Na+:HCO3-) at the apical cell border.

Acetazolamide↗
PubMed1979

Stereochemistry of reactions catalysed by mammalian-brain L-glutamate 1-carboxy-lyase and 4-aminobutyrate: 2-oxoglutarate aminotransferase.

Deamination of 4-aminobutyrate by mammalian or bacterial 4-aminobutyrate aminotransferases involves the abstraction of the pro-S hydrogen on C-4 of 4-aminobutyrate. Decarboxylation of L-glutamate by rat brain glutamate decarboxylase occurs with retention of configuration. Inhibition of this enzyme by (S)-4-aminohex-5-ynoic acid involves the abstraction of the proton at C-4 of the inhibitor. On the basis of this finding, we postulate the existence of an abnormal reaction of glutamate decarboxylase in which the proton at C-4 of (S)-4-aminohex-5-ynoic acid is removed in a manner similar to the one which normally occurs in enzymatic transaminations of L-amino acids. This reaction is presumably facilitated by the acetylenic group adjacent to the eliminated proton.

4-Aminobutyrate Transaminase↗
PubMed1978

The effect of gamma-acetylenic GABA, an enzyme-activated irreversible inhibitor of GABA-transaminase, on dopamine pathways of the extrapyramidal and limbic systems.

gamma-Acetylenic GABA (100 mg/kg i.p.) inhibited GABA-transaminase activity and caused a several-fold increase in the concentration of GABA in rat brain. This increased GABA concentration was associated with a decreased rate of dopamine depletion following alpha-methyl-p-tyrosine treatment and a decrease in homovanillic acid in extrapyramidal and limbic structures suggesting a decrease in dopamine turnover in both pathways. In addition, gamma-acetylenic GABA injected into the ventral mesencephalic tegmentum decreased dopamine turnover in the mesolimbic forebrain. These results are consistent with a modulatory function of GABAergic neurons on extrapyramidal and limbic dopamine pathways. Inhibitory effects on dopaminergic functions of the extrapyramidal and limbic systems were also indicated by the amphetamine and apomorphine-induced ipsilateral turning after unilateral substantia nigral injections of gamma-acetylenic GABA and by the attenuation of dopamine-induced hypermotility after bilateral injections of gamma-acetylenic GABA into the nucleus accumbens.

4-Aminobutyrate Transaminase↗
PubMed1978

Mechanism of the stereospectific irreversible inhibition of bacterial glutamic acid decarboxylase by (R)-(--)-4-aminohex-5-ynoic acid, an analogue of 4-aminobutyric acid.

4-Aminohex-5-ynoic acid inhibits bacterial glutamic acid decarboxylase in a time-dependent irreversible manner. The inhibition is stereospecific and requires the abstraction of the propargylic hydrogen from 4(R)-(--)-4-aminohex-5-ynoic acid. This leads to the generation of a reactive alkylating agent in the active site which can react with a nucleophilic residue. At complete inhibition, there is incorporation of one molecule of inhibitor per pyridoxal binding site. If the decarboxylation of glutamate occurs with retention of configuration, the irreversible inhibition of this enzyme by the 4-(R) isomer can be rationalized on the basis of reversibility of the protonation step in the normal catalytic mechanism.

Aminocaproates↗
PubMed1978

Molecular properties of the adrenergic alpha-receptor. I--Structural requirements for specific covalent occupancy by N,N'-bis--(5-aminopentyl)cystamine derivatives.

The synthesis and alpha-adrenoreceptor blocking activity of several substituted analogs of the prototype alpha-blocker N,N'-bis-(5-aminopentyl)cystamine (APC) are described. The three optical forms of the analog carrying methyl groups on the carbons alpha- to the sulfurs were synthesized and shown to be equipotent and somewhat less active than APC. The omega, omega'-bis-guanidino analog of APC was less active. Significant improvement in potency was observed only with APC analogs carrying benzyl and substituted benzyl groups on the terminal nitrogens. Linking the terminal nitrogens of APC with a p.xyledenyl group so as to give the 26-membered analog caused a sharp drop in activity. The significance of these results as regards the alpha-receptor topography is discussed.

Adrenergic alpha-Antagonists↗
PubMed1977

4-amino-hex-5-enoic acid, a selective catalytic inhibitor of 4-aminobutyric-acid aminotransferase in mammalian brain.

Incubation of rat brain 4-aminobutyrate aminotransferase with 4-amino-hex-5-enoic acid, a substrate analog of 4-aminobutyric acid, results in a time-dependent irreversible loss of enzymatic activity. In the presence of 0.1 mM inhibitor the half-life of the inactivation process is approximately 6 min. Low concentrations of L-glutamic acid or 4-aminobutyric acid protect against this inactivation, while 2-oxoglutarate prevents this protection, suggesting that only the pyridoxal form of the enzyme is susceptible to inhibition by 4-amino-hex-5-enoic acid. The irreversible inhibition of mammalian 4-aminobutyrate aminotransferase by 4-amino-hex-5-enoic acid is selective. There is no inhibition of this enzyme from Pseudomonas fluorescens with the inhibitor at mM concentrations. Even at 10 mM there is no irreversible inhibition of mammalian glutamate decarboxylase or of aspartate aminotransferase, while alanine aminotransferase is inhibited over 500 times more slowly than rat brain 4-aminobutyrate transaminase.

4-Aminobutyrate Transaminase↗
PubMedDate not supplied

Sequential neuropathology of dogs treated with vigabatrin, a GABA-transaminase inhibitor.

Vigabatrin (Sabril) is a gamma-aminobutyric acid-transaminase (GABA-T) inhibitor that is effective in the treatment of certain types of drug-resistant or uncontrolled epilepsy but is known to cause microscopic vacuolation (intramyelinic edema) in the brains of treated rats, mice, and dogs. The effects of high oral doses (300 mg/kg/day) of vigabatrin administered orally to Beagle dogs were studied during treatment weeks 1-12 and recovery weeks 13, 14, 16, 20, 24, and 28. Emesis, loose stools, and anorexia and 3 drug-related deaths were observed during the first 4 wk of treatment but were virtually nonexistent thereafter because of adaptation to the drug aided by food supplementation. In more sensitive areas of the brain (columns of the fornix, thalamus, and hypothalamus), microscopic quantitative differences between background vacuolation in controls and drug-related vacuolation in treated dogs could be delineated after 4 wk, generally reached highest levels of severity between 8 and 12 wk, and were reversible upon cessation of dosing. Inhibition of brain GABA-T and elevation of brain GABA were noted after 1 wk of treatment. During the course of treatment vigabatrin ranged between 4-17 nmol/ml (plasma) and 42-1,570 nmol/ml [cerebrospinal fluid (CSF)] while CSF GABA concentrations were 4-32 nmol/ml (treated dogs) and 0.1-0.6 nmol/ml (control dogs). Although the cause of vigabatrin-induced microvacuolation is unknown, the results of the study demonstrated that GABA-T inhibition with subsequent GABA elevation occurred within the first week of treatment and was followed by the onset of detectable microvacuolation several weeks later.

4-Aminobutyrate Transaminase↗
PubMedDate not supplied

[Resistance of isolated cells from squamous cell carcinomas of the oral cavity to cytotoxic drugs].

Human tumor cells from 22 patients with squamous cell carcinomas of the oral cavity were cultivated in vitro and then subjected to sensitivity tests to cytotoxic drugs such as methotrexate, 5-fluorouracil, cisplatin and bleomycin. Tumor cell proliferation showed drug-specific reaction patterns and time-dose-dependent variations. While the effect of methotrexate on cell proliferation was insignificant, 5-fluorouracil caused a growth suppression of 50%. Cisplatin and bleomycin suppressed cell growth by more than 90%.

Antineoplastic Agents↗