The use of rhIL-2 to augment antitumour immunity was seen as having great potential for the treatment of neoplasia, but the efficacy of immunotherapy has remained poor despite encouraging experimental data. A reason for this could be active immunosuppression by the tumour mediated by the secretion of suppressor factors. Suramin is a polyanionic drug which blocks and inhibits a range of growth factors and cytokines. This project investigates the potential of suramin to act as an adjunct to rhIL-2 based immunotherapy by acting as a blockade to suppressor factors. In vitro studies showed that rhIL-2 generation of LAK cells resulted in an increase in expression of activation associated antigens, a proliferation of cytotoxic T cells and natural killer cells and augmentation of cytolytic activity. These parameters could be suppressed by factors released from the colorectal cell line LoVo, but co-culture with suramin reversed the suppression in cells isolated from normal individuals. A suramin induced fall in the percentage of cells expressing CD4 was shown to be due to CD4 modulation and not the apoptotic death of CD4+ve cells. CD4 modulation could be reversed by the removal of suramin and could be influenced by tyrosine kinase inhibitors, though direct tyrosine phosphorylation of CD4 did not occur. The CBHlCBi Hooded rat was used as an in vivo model to study the potential of suramin and rhIL-2 in controlling induced liver metastasis from the syngeneic HSN sarcoma cell line. A toxicology study showed suramin side effects to include a reduction in total body weight gain and an increase in lymph node and spleen weights. Enlargement of kidneys and reduction in liver size were also seen. Haematologically, a suramin induced basophilia and thrombocytopenia were recorded as well as a rhIL-2 induced eosinophilia. In vivo CD4 modulation was also seen. Finally a combined suramin and rhIL-2 therapy regimen was found to be more effective than either agent alone in reducing both hepatic tumour mass and numbers after the induction of metastases in these animals. It was concluded that suramin can be used as an adjunct to rhIL-2 based immunotherapy.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:309057 |
| Date | January 1996 |
| Creators | Allen, Paul David |
| Publisher | Queen Mary, University of London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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