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Biomedical subjects

A M Rauth

Publications and source records attributed to A M Rauth.

At least 91 records · Page 5Linked to original sources
PubMed1979

Isolation and characterization of revertants of the mammalian temperature sensitive leucyl-tRNA synthetase mutant tsHl.

Nine spontaneous and seven ethyl methanesulfonate induced revertants of the Chinese hamster ovary cell line mutant (tsHl), which possesses a temperature sensitive leucyl-tRNA synthetase, were isolated and characterized with respect to growth rate, leucyl-tRNA synthetase activity and thermolability, intracellular leucine pool size, and rRNA content. Although most revertants had increased leucyl-tRNA synthetase activity, and of those tested, all but one had increased thermostability, each appears to be unique. One revertant may be an intergenic suppressor since it appears to contain an elevated level of tsHl-like synthetase. There was no evidence for any of the revertants having increased rRNA and tRNA contents, however, many showed leucine pools two to three times larger than wild type cells. Since similar increases have been observed in tsHl cells they are believed to result from regulation of leucine pool size by the leucyl-tRNA synthetase and are of a magnitude sufficient to affect significantly the growth of revertants at 38.5 degrees C.

Amino Acyl-tRNA Synthetases↗
PubMed1978

Testing of hypoxic cell radiosensitizers in vivo.

Use has been made of the transplantable KHT sarcoma in C3H mice to test the in vivo effectiveness of some 2-, 4-, and 5-nitroimidazoles as hypoxic cell radiosensitizers. A comparison of the in vivo versus the in vitro sensitizing ability of misonidazole and metronidazole indicates some differences, probably due to drug delivery problems in vivo. The relative sensitizing abilities of eight 2-nitroimidazoles, two 4-nigroimidazoles and two 5-nitroimidazoles are compared on the basis of the amount of drug injected and the plasma levels obtained.

Animals↗
PubMed1978

Nitropyrrole radiosensitizers: structure function relationships.

Nitropyrrole derivatives have been tested as hypoxic cell radiosensitizers in vitro and in vivo. Radiosensitizing potential generally increases with nitropyrrole electron affinity. N-hydroxyethyl substitution decreases toxicity relative to N--CH3, N--CH2 CH3 and N--CH2 CH2 CH3 substitution. The most effective nitropyrrole tested in vivo is N-hydroxyethyl-2-cyano-5-nitropyrrole (NP-1).

Animals↗
PubMed1978

Screening for the mutagenicity of nitro-group containing hypoxic cell radiosensitizers using Salmonella typhimurium strains TA 100 and TA98.

A series of sixteen 2-, 4- and 5-nitroimidazoles, four nitrobenzenes, five nitrofurans, and a nitropyrrole, most of which have been studied previously as hypoxic cell specific radiosensitizers, have been screened for their mutagenicity using the Salmonella typhimurium strains TA 100 and TA 98 developed by Ames and co-workers. Most of these compounds were mutagenic and had a one to two order of magnitude greater mutagenicity towards TA 100 (base-pair substitution sensitive) than TA 98 (frame-shift sensitive). The spectrum of mutagenic efficiencies for the drugs which was observed could be correlated to some extent with the electron affinity of these compounds. Exceptions to this correlation may indicate drugs of interest for further studies both as mutagens and hypoxic cell radiosensitizers.

Drug Evaluation, Preclinical↗
PubMed1976

An investigation into the potential of a mammalian temperature sensitive leucyl-tRNA synthetase mutant for mutagenesis studies.

Reversion of the mammalian temperature sensitive leucyl-tRNA synthetase mutant CHO tsH1 [33] has been investigated to determine its potential for mutagenesis studies. The protocol for a mutation assay using the new class of temperature sensitive conditional lethal mutants of somatic cells is presented. While it requires careful control of temperature during revertent selection it promises to provide a system complementary to the existing mutation assays. UV and EMS mutagenesis of tsH1 has confirmed that approx. 3TD of expression time are sufficient for complete expression of induced mutants at low mutagen doses (80% survival following UV and 40-50% with EMS). At a higher UV dose resulting in only 10% survival much longer expression times were required which cannot be explained by growth delays alone. While the reason for this is unknown it suggests that care must be taken in studies which require high mutagen doses. Representative revertants which were isolated show a range of phenotypes between those of tsH1 and WT. They appear to be a promising source of extragenic suppressor mutants [33] with alterations in functions affecting protein synthesis.

Amino Acyl-tRNA Synthetases↗
PubMed1976

Increased cell killing by metronidazole and nitrofurazone of hypoxic compared to aerobic mammalian cells.

Nitromidazole and nitrofuran derivatives comprise a large family of compounds, some of which have been shown to be hypoxic cell specific radiosensitizers in vivo and in vitro. The effects of metronidazole (2-methyl-5-nitroimidazole-1-ethanol) and nitrofurazone (5-nitro-2-furaldehyde semicarbazone) were studied on cell viability in vitro in the presence of air or nitrogen in the absence of radiation. Exponential-phase Chinese hamster ovary cells were placed in suspension culture in complete medium in the presence of air, made hypoxic by flowing nitrogen (less then 0.001% oxygen), and exposed to various concentrations of these drugs. As a function of time, aliquots were removed and plated to determine cell viability. After 8 hr of incubation of Chinese hamster ovary cells in 29 mM metronidazole or 500 muM nitrofurazone, the absolute plating efficiency remains relatively constant (80 to 40%) in the presence of air. In contrast, under hypoxic conditions the plating efficiency of the cells dropped to 1% after 6 hr of incubation in 29 mM metronidazole or 500 muM nitrofurazone. This phenomenon of hypoxic cell specific toxicity was found to be dependent upon cell type, concentration of drug, temperature of incubation, and oxygen concentration. The results of these experiments indicate an increased toxicity of these drugs under hypoxic conditions and suggest that further investigation into the mechanism and specificity of these effects is warranted.

Air↗
PubMed1975

Effect of leucine on the temperature sensitive phenotype of a mammalian leucyl-tRNA synthetase mutant.

The concentration of leucine in the growth medium has been found to influence the expression of the temperature sensitive phenotype of a mutant of Chinese hamster ovary cells with an altered leucyl-tRNA synthetase. Plating efficiency and growth studies showed that increasing the leucine concentration allows cells to survive at normally non-permissive high temperatures and conversely decreasing the leucine concentration enhances the adverse effectsof high temperature. A similar but smaller effect was noted with isoleucine. It is suggested that this observation may form the basis of a rapid test, useful in directing the investigation of the lesion in similar mutants to pathways involving specific amino acids.

Amino Acyl-tRNA Synthetases↗
PubMed1975

In vivo testing of hypoxic radiosensitizers using the KHT murine tumour assayed by the lung-colony technique.

The KHT transplantable tumour of C3H mice has been used as a model tumour for the invivo study of hypoxic cell sensitizers. Eleven sensitizers comprising four nitrofuran five nitrobenzene and two nitroimidazole derivatives, which have been shown to be effective on hypoxic mammalian cells in vitro, have been investigated. Two of these compounds, metronidazole (2-methyl-5-nitroimidazole-1 ethanol) and tinidazole (ethyl [2-(2'-methyl-5'-nitro-1'-imidazolyl) ehtyl] sulfone), showed signs of hypoxic cell-sensitization in vivo when given systemically by intraperitoneal injections. In addition, preliminary testing of the nitrobenzene NDPP (P-NITRO-3-DIMETHYL-PROPRIOPHENONE HYDROCHLORIDE) INDICATED THAT WHEN IT WAS INJECTED DIRECTLY INTO THE TUMOUR AND IRRADIATION WAS COMPLETED WITHIN TEN MINUTES AFTER INJECTION, APPRECIABLE SENSITIZATION WAS OBTAINED. More detailed studies indicated that both metronidazole at 1,500 mg/kg and tinidazole at 750 mg/kg given intraperitoneally gave an enhancement ratio of 1-5 for a chronically hyopix cell population in this solid tumour in air-breathing mice. Measures of plasma levels of metronidazole and enhancement ratios obtained in the present in vivo system seem in relative agreement with the in vitro and in vivo results of others.

Animals↗
PubMed1974

Nascent DNA synthesis in ultraviolet light-irradiated mouse, human and Chinese hamster cells.

The technique of alkaline sucrose gradient centrifugation was used to study newly synthesized DNA in control and ultraviolet light-irradiated mouse L, human HeLa, and Chinese hamster ovary cells. Nascent DNA molecular weight distributions did not appear to differ among the three cell lines for unirradiated cells. However, at short times after ultraviolet light irradiation, human HeLa cells appeared to synthesize more low molecular weight DNA than either mouse L or Chinese hamster ovary cells. Since this difference was not related to differences in either the rate of DNA synthesis or amount of ultraviolet damage in the irradiated cells it appeared to be a phenotypic characteristic of the cell lines tested. A parallel was noted for these three cell lines between an increase in the synthesis of low molecular weight DNA, detected on alkaline sucrose gradients, and cell killing as measured by the ability of irradiated cells to form colonies.

Animals↗