Adenosine 3',5'-monophosphate phosphodiesterase activity in experimental animal tumours which are either sensitive or resistant to bifunctional alkylating agents.
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Biomedical subjects
Publications and source records attributed to B J Phillips.
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Thirty drug taking and thirty non-drug taking delinquent adolescent girls were assessed using a psychiatric interview technique. Differences were observed between the groups on an aggressive-passive-withdrawn dimension. Drug takers were found to be passive and withdrawn whilst control group subjects were found to be more aggressive. These factors were identified within the modal personality of the delinquent girl. The results supported M.M.P.I. studies of the drug taking personality and were seen as an indication of aetiology and its implications for assessment and treatment.
The initial metabolic products of cyclophosphamide (4-hydroxy-cyclophosphamide and aldophosphamide) were prepared biologically in unpurified form. Their toxicity to tumor cells were tested by bioassay techniques and in cell culture, and the deactivation abilities of various tissue-soluble fractions were quantitated. Liver and kidney cytosol effectively deactivated the primary metabolites, whereas cytosols from gastrointestinal tract mucosa, Walker ascites tumor, and spleen were less efficient. When [14C]cyclophosphamide was activated and incubated with liver cytosol, 34% of all radioactivity was identified as carboxyphosphamide, by mass spectrometry of the methyl ester. Measurement of alcohol dehydrogenase (EC 1.1.1.1) and aldehyde dehydrogenase (EC 1.2.1.3) activities by reduced nicotinamide adenine dinucleotide production revealed a qualitative correspondence between aldehyde dehydrogenase activity and deactivation ability. Unpurified aldophosphamide and the analogs prepared from 6-methyl- and 5,5-dimethylcyclophosphamides were substrates for nicotinamide adenine dinucleotide-requiring enzymes, whereas incubation of 4-hydroxy-4-methylcyclophosphamide in an unfractionated incubation mixture with liver soluble enzymes did not cause reduced nicotinamide adenine dinucleotide production.
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Cultured Chinese hamster ovary cells (CHO-KI-BH4) were treated for 2 h with 4CMB, 4HMB and BC, in the absence of any exogenous metabolic activation system. The cells were subjected to tests for survival, sister-chromatid exchange, chromosome aberration and mutation to thioguanine resistance. 4HMB had no effect in any test at concentrations up to 100 microgram/ml. 4CMB was slightly more toxic than BC. Both 4CMB and BC induced SCE and chromosome aberrations, but the effects were more marked with BC. With 4CMB, SCE increased with dose only up to about 7 microgram/ml and then levelled off. A weak mutagenic effect was observed with both BC and 4CMB, but in each case, the response reached a peak and was not evident at higher doses.
The widely used plasticizer di(2-ethylhexyl)phthalate (DEHP), its hydrolysis products mono(2-ethylhexyl)phthalate (MEHP) and 2-ethylhexanol, and also phthalic acid have been tested for clastogenic activity in cultured Chinese hamster ovary (CHO) cells. Only MEHP was found to cause chromosome damage. MEHP was without effect in the SCE and HGPRT mutation test in CHO cells. The clastogenicity of MEHP suggests a role for this compound in the observed carcinogenicity of DEHP and its positive effect in the dominant lethal assay.
In response to stimuli such as irritant chemicals, inorganic particles or micro-organisms, phagocytic cells produce a variety of chemical species including superoxide and hydrogen peroxide. These reactive oxygen species are cytotoxic and genotoxic to cultured cells and may be responsible for some of the tissue damage associated with inflammation in vivo. The role of phagocyte-derived oxygen radicals in the effects of irritants, tumour promoters and carcinogenic inorganic materials has been explored using mixed cultures of phagocytes and fibroblasts. Catalase-inhibitable cytotoxicity and genetic damage were demonstrated in fibroblasts exposed to neutrophils stimulated with the irritant and tumour promoter phorbol myristate acetate or with zymosan particles. To investigate this phenomenon further, other cell systems have been developed, using epidermal keratinocytes or mesothelial cells in combination with neutrophils or macrophages.
We have investigated the effects of reactive oxygen species (ROS) in a wide variety of systems, both in vitro and in vivo, with particular attention to their genetic effects. Some of the results of these studies, as they relate to the protective effects of antioxidants, are discussed.