Mwang'ombe, Nimrod J.; (1990) Induction of tumour differentiation as a tool in chemotherapy of gliomas. Doctoral thesis (Ph.D.), University College London.

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Abstract

During in-vitro cultivation murine astrocytoma cells derived from a spontaneous murine astrocytoma undergo de-differentiation as evidenced by a fall in the markers of astrocytic differentiation glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS). Growth in culture was accompanied by a rise in the polyamine marker enzyme, ornithine decarboxylase (ODC), cell proliferation and increase in protein. Exposure of VMDk P497 cells to dexamethasone-containing growth medium after plating on day 0 produced a decrease in proliferation with a concomitant induction in GS activity by sixfold. This functional differentiation was independent of the age of the cultures. The effect of dexamethasone was mediated at the transcriptional level through cytosolic glucocorticoid receptors, the presence of which was confirmed during all phases of culture in vitro. Inhibition of ODC activity with difluoromethylornithine (DFMO) resulted in a decrease in cell proliferation and elevation of GS activity. A time-course experiment showed that inhibition of ODC resulted in a rise in GS activity within 24 hours of treatment and this biochemical differentiation lasted for more than 48 hours. When VMDk P497 cells were subcutaneously implanted into syngeneic VM mice, tumours of short latency with a Gompertzian growth pattern were obtained. DFMO administered in drinking water alone did not arrest growth of these tumours. BCNU alone, administered as a single intraperitoneal dose of 30 mg/kg, produced a short but statistically significant growth delay. However, when DFMO pretreatment was combined with single dose BCNU, it potentiated the cytotoxic effect of BCNU. Analysis of changes taking place at the molecular level showed a greater inhibition of ODC in tumours treated with combined therapy than in those which were treated with either BCNU or DFMO alone. Tumour samples from mice treated with combined therapy had less deoxyribonucleic acid (DNA) than samples of tumours from mice treated with either BCNU or DFMO alone.

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