Durai, R.; (2008) Effect of insulin-like growth factor binding protein-4 gene therapy on adenocarcinoma of the colon. Doctoral thesis , University of London.

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Abstract

Insulin-like growth factors induce the proliferation of transformed cells. IGF binding proteins (IGFBP) are involved in their local tissue regulation. In this project, the effects of early and late administration of IGFBP-4 gene were assessed on colon cancer model in vivo. Nude mice were subcutaneously inoculated with HT-29 colon adenocarcinoma cells. In the early gene transfer model, IGFBP-4 gene was administered along with cancer cells. In the late gene transfer model, cancer was induced first and IGFBP-4 gene was administered when the tumour became visible (one week after inoculation). Animals received either mammalian expression vector containing IGFBP-4 cDNA, or vector alone, or PBS as peritumoral injection. Tumour size was measured at different time periods during the experiment. After three to four weeks of IGFBP-4 induction, the mice were sacrificed and tumour tissues were collected for further examinations. Tumour proliferative activity was determined by counting mitotic cells. Tumour apoptosis was investigated by TUNEL assay and electron microscopy. Results showed that tumour tissues had large necrotic areas, significantly increased numbers of apoptotic cells, and decreased cells undergoing mitosis following treatment with IGFBP-4 gene, in both early and late gene transfer model. Despite increased apoptosis and decreased mitosis in IGFBP-4 treated tumours, tumour volume was not significantly altered, possibly due to cellular debris filling the centre of tumours. There was an increase in Bax protein levels after IGFBP-4 gene therapy in both models. When IGFBP-4 gene was administered late, tumours showed higher expression of IGFBP-4 protein levels as well as IGF-IR levels when compared with controls. However, in the early gene transfer model, when IGFBP-4 gene was administered along with cancer cells, the tumours did not show such an increase in IGFBP-4 levels compared with controls. Although the tumours of the late group showed a reduction in Bcl-2 protein levels, the early gene transfer model did not show a similar reduction. In fact the Bcl-2 was elevated after IGFBP-4 gene therapy.

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