Biomedical subjects

N Seiler

Publications and source records attributed to N Seiler.

223 records · Page 13Linked to original sources

PubMedDate not supplied

Inhibition of the growth of U-251 human glioblastoma in nude mice by polyamine deprivation.

An almost complete prevention of tumor growth was achieved in U-251 human glioblastoma xenografted nude mice, by partial decontamination of the gastrointestinal tract and feeding of a polyamine-free diet containing inhibitors of ornithine decarboxylase (DFMO) and of polyamine oxidase (MDL 72527). After one week of polyamine deprivation, spermidine concentrations were lowered, and spermine levels were increased in all tissues. In contrast, putrescine concentrations were only reduced in tumor and in brain. Erythrocyte polyamine determinations revealed differences similar to those observed in tissues: spermidine concentration was lowered by 50% and spermine level was 3-fold increased. If this or related treatments should become of therapeutic importance in the future, then the determination of erythrocyte polyamine levels might be of diagnostic value.

Animals↗

PubMedDate not supplied

Effect of polyamine deprivation on the survival of intracranial glioblastoma bearing rats.

It has previously been shown that systematic polyamine deprivation results in the almost complete inhibition of the growth of several solid tumors. The same polyamine deficient diet (containing antibiotics for the decontamination of the gastrointestinal tract, the ornithine decarboxylase inhibitor 2-(difluoromethyl)ornithine, and the polyamine oxidase inhibitor N1, N4-bis-(2,3-butadienyl)putrescine; "drug-containing polyamine deficient chow", DC-PDC) was applied for the first time to the treatment of rats with an intracranial tumor. Rats received intracortical grafts of C6 rat glioblastoma cells, and the length of their survival was determined. Treatment with DC-PDC, starting four days after tumor cell inoculation, significantly prolonged the median survival of the glioblastoma-bearing rats. The results underline the general growth inhibitory effect of systematic polyamine deprivation. Since the effect of polyamine restriction on tumor growth is reversible, combinations with cytotoxic drugs have to be found which exploit the changed functions of polyamine deficient tumor cells.

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PubMedDate not supplied

The gastrointestinal tract as polyamine source for tumor growth.

It has previously been demonstrated that decarboxylation of ornithine in tumors, and the oxidative splitting of N1-acetylspermidine in tumor and normal tissues, are important sources of putrescine. Both these sources are utilised by tumors and other tissues with a high demand for polyamines to ensure their polyamine requirement. Consequently, combined treatment of tumor-bearing animals with an inhibitor of ornithine decarboxylase (e.g. alpha-difluoromethylornithine) and polyamine oxidase (e.g. N,N'- bis-allenylputrescine) has an antitumoral effect superior to that of either drug alone. In the present work, it was demonstrated that the alimentary tract is a third important source of polyamines which maintains tumor growth. Gastrointestinal polyamines are of alimentary origin, and are also formed by aerobic and anaerobic microorganisms. They can be reduced by feeding a polyamine deficient diet together with antibiotics that are suitable for decontaminating the gastrointestinal tract. This treatment combined with the administration of the mentioned inhibitors of ornithine decarboxylase and polyamine oxidase completely prevents Lewis lung carcinoma from growing, and prolongs considerably the average life span of L1210 leukemia mice. The results of the polyamine analyses of tumors, leukemia cells and tissues are compatible with the notion that the effective blocking of the three main putrescine sources (intracellular decarboxylation of ornithine, formation of putrescine from N1-acetylspermidine, and the gastrointestinal tract) produces a very strong cytostatic effect. It is expected that the clinical efficacy of polyamine antimetabolites can be considerably improved by measures analogous to those applied in this pilot study.

Animals↗

PubMedDate not supplied

3,4,5-Trimethoxybenzoic acid, a new mescaline metabolite in humans.

After ingestion of 400 mg of mescaline sulfate by human volunteers, 3,4,5-trimethoxybenzoic acid was isolated from urine and identified by gas chromatography-mass spectrometry. The amount of this anionic mescaline metabolite was found to be very low as compared with that of the well-konwn 3,4,5-trimethoxyphenylacetic acid. The significance of this finding is discussed.

Adult↗

PubMedDate not supplied

Inhibition of polyamine oxidase improves the antitumoral effect of ornithine decarboxylase inhibitors.

Specific inhibition of ornithine decarboxylase activity prevents the formation of putrescine from ornithine and decreases spermidine levels of slow-growing organs by about 20%. However, spermidine levels of rapidly growing tissues, such as tumors, may under the same conditions be decreased by as much as 60%. Inactivation of polyamine oxidase prevents oxidative splitting of N1-acetylspermidine and N1-acetylspermine and therefore the reutilization of putrescine for de novo polyamine biosynthesis. Prolonged inhibition of ornithine decarboxylase and polyamine oxidase activities leads in all normal tissues studied so far to a decrease of the spermidine concentration by 50% or more, demonstrating the general physiological significance of polyamine reutilization. In this work the role of polyamine reutilization in tumors was studied. Combined treatment with the inhibitors of ornithine decarboxylase, alpha-difluoromethylornithine or (2R, 5R)-6-heptyne-2,5-diamine, and N1, N4-bis-allenylputrescine, an inhibitor of polyamine oxidase, produced a more marked depletion of the polyamine contents of L1210 ascitic cells and of Lewis lung carcinoma, than treatment with either compound alone. Concomitantly, the proliferative activity of these tumors decreased significantly below the value that was observed after treatment with an ornithine decarboxylase inhibitor alone. Our results demonstrate that polyamines which are produced by the interconversion pathway are used by the tumors in order to cover their polyamine requirement.

Alkynes↗

PubMedDate not supplied

Polyamine metabolism and polyamine excretion in normal and tumor bearing rodents.

Aminoguanidine sulfate (AG) inhibits in vivo oxidative deaminations of the polyamines and their derivatives. This compound was used to study urinary polyamine excretion by normal, and tumor bearing rodents. Of the total expendable polyamines, 64 percent were catabolized by AG-sensitive oxidases and escaped observation. Tumor bearing animals did not excrete enhanced amounts of polyamines at any stage of tumoral growth. However, treatment with adriamycin caused an increased polyamine excretion. Prolonged administration of a 2% solution of a-difluoromethylornithine (DFMO), reduced urinary polyamine excretion to the same level of about 27%, irrespective whether the animals carried a large tumor or not. Cadaverine excretion was not affected by treatment with DFMO. Based on these animal data, it appears that urinary polyamines are of restricted value in the diagnosis of tumors.

9,10-Dimethyl-1,2-benzanthracene↗

PubMedDate not supplied

Accumulation of hydroxyspermidine in red blood cells, a potential index of tumor proliferation rate.

It has previously been demonstrated that during Lewis Lung carcinoma growth, red blood cell spermidine levels increase concomitantly with tumor volume. If [14C] putrescine or 2-methylputrescine are administered, [14C] spermidine and methylspermidine, respectively, accumulate in red blood cells in proportion with the tumor volume. In the present work the metabolic transformation of 2-hydroxyputrescine, a natural derivative of putrescine, to hydroxyspermidine, was studied in tumor bearing mice. After a single i.p. injection of 2-hydroxyputrescine, higher concentrations of hydroxyspermidine were found in the tumor than in liver. In the red blood cells of Lewis lung carcinoma-bearing mice, hydroxyspermidine was detected between 24 hours and 96 hours after i.p. injection of 2-hydroxyputrescine. The concentration of hydroxyspermidine found in red blood cells was proportional to the tumor volume. Hydroxyspermidine has potential as a marker of malignant cell proliferation in human oncology.

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