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Short stature is one of the most well recorded long term sequelae for adult survivors of childhood malignancies. It has become increasingly apparent that cytotoxic chemotherapy, as well as craniospinal irradiation, has a major impact on growth, but there are virtually no studies which explore the mechanisms by which these cytotoxic drugs affect growth. We have used an in vitro system to investigate the direct effects of a range of chemotherapeutic agents on the proliferative responses of rat tibial growth plate chondrocytes, both in suspension and monolayer culture. The glucocorticoids and purine anti-metabolites reduced chondrocyte proliferation both in monolayer and suspension cultures and this resulted from an increase in cell doubling times with a concomittant reduction in the numbers of S phase cells. DNA damaging agents (e.g. actinomycin-D) were also able to reduce chondrocyte proliferation, both in monolayer and suspension culture. This, however, was the result of a cell cycle arrest and subsequent cell death. In our studies, methotrexate had no significant effect on the proliferative responses of the chondrocytes either in monolayer or suspension culture. These results indicate direct effects of a range of chemotherapeutic agents on the proliferative responses of growth plate chondrocytes. Both cytostatic and cytotoxic effects were observed although the impact of either the potential loss of cells from the proliferative pool during chondrocyte differentiation, or the reduction in the rate of chondrocyte turnover on long bone growth remains to be elucidated.
Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Department of Pharmacology, Göteborg University, Göteborg, Sweden
Department of Psychology, Göteborg University, Göteborg, Sweden
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Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Department of Pharmacology, Göteborg University, Göteborg, Sweden
Department of Psychology, Göteborg University, Göteborg, Sweden
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Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Department of Pharmacology, Göteborg University, Göteborg, Sweden
Department of Psychology, Göteborg University, Göteborg, Sweden
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Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Department of Pharmacology, Göteborg University, Göteborg, Sweden
Department of Psychology, Göteborg University, Göteborg, Sweden
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Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Department of Pharmacology, Göteborg University, Göteborg, Sweden
Department of Psychology, Göteborg University, Göteborg, Sweden
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Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Department of Pharmacology, Göteborg University, Göteborg, Sweden
Department of Psychology, Göteborg University, Göteborg, Sweden
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Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Department of Pharmacology, Göteborg University, Göteborg, Sweden
Department of Psychology, Göteborg University, Göteborg, Sweden
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Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Department of Pharmacology, Göteborg University, Göteborg, Sweden
Department of Psychology, Göteborg University, Göteborg, Sweden
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Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Department of Pharmacology, Göteborg University, Göteborg, Sweden
Department of Psychology, Göteborg University, Göteborg, Sweden
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Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Department of Pharmacology, Göteborg University, Göteborg, Sweden
Department of Psychology, Göteborg University, Göteborg, Sweden
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IGF-I is a neuroprotective hormone, and neurodegenerative disorders, including Alzheimer’s disease, have been associated with decreased serum IGF-I concentration. In this study, IGF-I production was inactivated in the liver of adult mice (LI-IGF-I−/−), resulting in an approximately 80–85% reduction of circulating IGF-I concentrations. In young (6-month-old) mice there was no difference between the LI-IGF-I−/− and the control mice in spatial learning and memory as measured using the Morris water maze test. In old (aged 15 and 18 months) LI-IGF-I−/− mice, however, the acquisition of the spatial task was slower than in the controls. Furthermore, impaired spatial working as well as reference memory was observed in the old LI-IGF−/− mice. Histochemical analyses revealed an increase in dynorphin and enkephalin immunoreactivities but decreased mRNA levels in the hippocampus of old LI-IGF-I−/− mice. These mice also displayed astrocytosis and increased metabotropic glutamate receptor 7a-immunoreactivity. These neurochemical disturbances suggest synaptic dysfunction and early neurodegeneration in old LI-IGF-I−/− mice. The decline in serum IGF-I with increasing age may therefore be important for the age-related decline in memory function.