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Biomedical subjects

P Maier

Publications and source records attributed to P Maier.

At least 73 records · Page 4Linked to original sources
PubMed1985

Aristolochic acid induces 6-thioguanine-resistant mutants in an extrahepatic tissue in rats after oral application.

The mutagenic activity of the natural plant product aristolochic acid (AA) was tested in the Granuloma Pouch Assay, which detects gene mutations induced in a subcutaneous granuloma tissue of rats. After direct exposure of the target tissue, AA induced high frequencies of mutants at a relatively low cytostatic/cytotoxic level. AA was more potent that N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) at equimolar doses. After oral application of AA, a dose-dependent mutagenic activity was seen. In contrast a very weak and inconsistent mutagenic effect was seen after systemic application of MNNG. These observations suggest that after oral application AA is not detoxified efficiently and can exert its mutagenic activity in extrahepatic tissues whereas MNNG is detoxified to a large extent at the site of administration.

Administration, Oral↗
PubMed1983

The mutagenic activity of 5-bromo-2'-deoxyuridine (BrdU) in vivo in rats.

BrdU tablets were implanted subcutaneously in rats, and BrdU concentrations were determined in the serum. Within 5 hr peak concentrations of 10 micrograms BrdU/ml blood were reached. The influence of BrdU in vivo on cell cycling, DNA synthesis, spontaneous sister chromatid exchange (SCE) frequencies, and gene-mutation frequencies (6-TGr) was determined in freshly isolated cells from a subcutaneous granulation tissue. The most significant effect of BrdU in vivo was a doubling of the spontaneous 6-TGr frequency. In reconstruction experiments in vitro the mutagenic activity of BrdU applied in concentrations found in vivo was 2.5-6-fold higher. With the use of agar-coated tablets, BrdU concentrations in the blood were reduced by half, and no peak concentration was found. The differential staining of chromatids was still sufficient. Since the mutagenic effect of BrdU in vitro was found to be strongly concentration dependent, the use of agar-coated tablets is recommended in experiments in which the compound is used to demonstrate SCE in vivo.

Animals↗
PubMed1983

G0-G1 transition of rat hepatocytes detected by changes in nuclear chromatin condensation after in vivo treatment with phenobarbital.

The transition of hepatocytes from G0 to late G1-phase was studied in phenobarbital (PB) treated rats using visual and cytofluorometric evaluations of nuclear fluorescence patterns after quinacrine dihydrochloride (QDH) staining. In controls, about 90% of the nuclei showed bright nuclear fluorescence indicating G0-phase. After 10 days there was a reduction in fluorescence intensity which became more marked with continued PB treatment, indicating a shift from a resting G0 state to a later G1 phase of the cell cycle. The relevance of these findings for the understanding of tumor promoting properties of PB is discussed.

Animals↗
PubMed1983

Single dose carcinogenicity of procarbazine in rats.

Rats carrying a 2-day-old subcutaneous air pouch were treated with single doses of procarbazine. Local fibrosarcomas developed in the pouch after oral, intraperitoneal and local administration of 300 mg/kg, but no tumours were induced if the drug was injected into unstimulated subcutaneous tissue. Tumours only appeared in those animals in which growth of the granuloma tissue was stimulated with a dose of croton oil. The high dose of procarbazine (300 mg/kg) also induced an increase in total tumour incidence at other sites.

Adenoma↗
PubMed1982

Granuloma pouch assay. IV. Induction of sister-chromatid exchanges in vivo.

SCEs were induced, in vivo, in cells of a rapidly proliferating subcutaneous granulation tissue, initiated by the formation of a subcutaneous air pouch, on the backs of adult male rats (Granuloma Pouch Assay). 2 days after pouch formation the test compounds were applied, and 24 h later the granulation tissue was excised and dissociated into single cells. Isolated cells were cultured in vitro in media containing BrdU, and SCEs were determined within 24-48 h. The spontaneous frequency was 14.4 +/- 1.1 per metaphase. Mitomycin C (MMC) and cyclophosphamide (CP) induced a significant and dose-dependent increase in SCE frequencies. Results obtained after i.v., i.p. and intra-pouch application routes are compared.

Animals↗
PubMed1980

Granuloma pouch assay for mutagenicity testing.

The Granuloma Pouch Assay (GPA) is an animal model in which mutagenic and carcinogenic effects of a testcompound can be detected in rapidly dividing fibroblasts of a granulation tissue in adult male rats. Growth of this tissue was initiated with a small amount of croton oil at the inside wall of a subcutaneous air pouch on the back of the animals. The test compound can be injected either into the pouch (local) or administered by systemic routes. Alkali labile DNA-lesions, chromosome aberrations, sister chromatid exchanges, point mutations and tumor development in situ were determined. The comparison of mutation frequencies after local and systemic administration of testcompounds, provide an estimation of the pharmacokinetic characteristics and the mutagenic potency of the chemical. The local application route allows the detection of locally active mutagens and of compounds which require activation by P-448 dependent mono-oxygenases. Liver mediated proximate metabolites are detectable when they are transformed into ultimate carcinogens in extrahepatic cells whereas chemicals with a strong organ specific activity are not.

Animals↗
PubMed1980

Granuloma pouch assay. III. Enhancement of the carcinogenic effect of N-methyl-N'-nitro-N-nitrosoguanidine.

Proliferation of granulation tissue on the inside of a subcutaneous (s.c.) air pocket was induced in rats by administration of 0.5 ml of 0.25% croton oil (granuloma pouch). Two days after induction of the granuloma, i.e., during the period of maximal cell growth, a single dose of 0.6 mg or 0.1 mg N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was administered into the pouch. Fibrosarcomas of various histopathological types developed in 87% of the rats receiving the high dose and in 64% of the low dose animals. The mean latency period was 47.5 and 51.7 weeks respectively. Only one local sarcoma developed in rats treated with 0.6 mg MNNG by the s.c. route, and no tumors were observed in the groups treated with 0.1 mg s.c. The appearance of local sarcomas in the granuloma pouch tissue is correlated with previously reported frequency of point mutations (OUAR and HGPRT-) induced in granuloma fibroblasts with the same doses of MNNG. Possible mechanisms explaining the marked enhancement of the carcinogenic effect of MNNG in the granuloma pouch assay are discussed.

Animals↗
PubMed1980

Granuloma pouch assay. II. Induction of 6-thioguanine resistance by MNNG and benzo[a]pyrene in vivo.

Growth of granulation tissue was initiated with croton oil on the inside of a subcutaneous air pouch, on the back of adult male rats. Two days later, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and benzo[a]pyrene (BP) were applied directly into the pouch in doses ranging from 0.05 to 1.8 mg and from 0.03 to 0.5 mg, resp. The granulation tissue was excised after 48 h. Isolated single cells were checked for their 6-thioguanine resistance in vitro. The influence of cell density during expression time in vitro, of 6-thioguanine concentration and cell density in selective media on the recovery of mutant cells was investigated. The spontaneous mutation frequency was 0.53 x 10(-5). There was a dose-dependent increase in mutation frequencies with both compounds. The frequency was 5 times as high with MNNG as with BP.

Animals↗
PubMed1979

Influence of subcellular fractions of mammalian testes on the mutagenic activity of nitrofurans toward Escherichia coli; presence of a co-mutagen-like factor.

The activation of nitrofurans to mutagenic intermediates by testicular tissue was investigated. AF-2 and nitrofurazone were tested in a microsomal suspension assay with strain E. coli K-12 343/113 as indicator and subcellular fractions from rabbit testes. Different mutation patterns were observed in the presence or absence of testicular homogenate, indicating the presence of different mutagenic intermediates. The frequency of arg+ reversion increased proportionally to the homogenate concentration suggesting that the nitrofurans were activated by testicular components to intermediates that induced base-pair substitutions. Other experiments showed that a component of low molecular weight, present in the soluble fraction of homogenates of testes from rabbits, rats and monkeys, was responsible for the increased mutation frequency. It is concluded that this "co-mutagen-like" factor either alters the metabolism of nitrofurans in E. coli and/or promotes the formation of base-pair substitution-type mutations. This direct interaction between a nonenzymic component of mammalian testes and the mutation induction/expression process in E. coli suggests the role of co-mutagen-like factors in the sensitivity of testes to nitrofurans.

Animals↗
PubMed1978

Bone marrow and lymphocyte cytogenetics of rhesus monkeys (Macaca mulatta) treated with the clastogen Mitomycin C.

Rhesus monkeys (Macaca mulatta) were used to determine their effectiveness as experimental animals for different cytogenetic tests with mitomycin C (MC). The micronucleus test (MNT and/or chromosome analysis of blood and bone marrow were made before and/or after the treatment with mitomycin C. Thus, the controls data and treated data were obtained from the same animals. With the employed methology, the micronucleus test could not be performed on living animals. Less chromosomal damage was detected in the micronucleus test of post-mortem samples than in the chromosome analysis of bone marrow. No influence by the mutagen could be observed in lymphocyte chromosomes at any of the different times of analysis. In contrast to this, bone-marrow chromosomes seemed to be highly affected by mitomycin C at day 1, 2 and 3 after injection. However, before treatment and at day 14, 16 and 17 after treatment there was no visible increase in chromosomal aberration in bone marrow.

Animals↗
PubMed1978

Granuloma pouch assay. I. Induction of ouabain resistance by MNNG in vivo.

Growth of granulation tissue was induced in rats inside a subcutaneous air pouch by injection of croton oil. Granulation tissue, isolated and cultured in vitro, gave satisfactory and reproducible cloning efficiency of fibroblast-like cells. This experimental model system was used to study the induction of autosomal point mutations in vivo leading to ouabain resistance. For this purpose the mutagen MNNG was administered in the granuloma pouch, and the formation of ouabain-resistant clones was determined in vitro. Various application schedules, expression times in vivo and selective conditions in vitro were evaluated. The highest frequencies of ouabain-resistant clones were found when MNNG was injected into the pouch 24--48 h after induction of granulation tissue, followed by an expression time in vivo of 24--48 h. No ouabain-resistant clones were formed by cells isolated from untreated rats or from animals receiving the highest tolerated doses of MNNG per os or by intraperitoneal injection. The potential usefulness of the granuloma pouch assay for the evaluation of mutagenic and carcinogenic substances in vivo is discussed.

Animals↗
PubMed1976

Ten model mutagens evaluated by the micronucleus test.

The following ten mutagenic compounds were subjected to the micronucleus bone marrow test (MNT) in the mouse: cyclophosphamide (CTX), thiotepa (TT), vincristin (VCR), colcemid (COLC), adriamycin (AM), bleomycin (BM), cytosin arabinoside (ARA C), 6-mercaptopurine (6-MP), methotrexate (MTX) and 5-fluorouracil (5-FU). Dose-effect curves were established for all compounds. With the exception of CTX, COLC and AM, the drugs also were subjected to chromosome analyses on Chinese hamster fibroblasts in vitro. The MNT revealed loss of chromatin due to chromosome breakage and rearrangements by CTX, TT and AM, to breakage by ARA C, 6-MP, MTX and 5-FU, as well as loss of entire chromosomes caused by impairment of the spindle by VCR and COLC. With the exception of BM, the effects were demonstrable in the therapeutic dose range. The MNT, provided it is carried out by the methodology of the authors, not only reveals chromatin loss but permits important conclusions in regard to the proliferative state of the bone marrow and the specific time of action of the mutagens in the cell cycle. If arrest of the cell cycle occurs, as in the case of anti-metabolites MTX and 5-FU particularly, the routine scheme of investigation needs to be modified since micronucleated cells appear only after release of the metabolic block, i.e. after a delay of 24 h. The negative bone marrow results obtained with BM emphasize the importance of combining in vivo and in vitro tests.

Animals↗