Investigation into the effects of suramin and interleukin-2 on anti-tumour immunity.
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.