Thesis (M.S.)--Marshall University, 2003. / Title from document title page. Document formatted into pages; contains vi, 74 p. including illustrations. Includes bibliographical references (p. 71-74).

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.

The most exciting area in current cancer research is immuno-oncology, which aims to develop immunotherapy that activates the human immune system to attack cancers. However, we still lack broadly effective drugs and drug targets for this promising new cancer treatment modality. In an attempt to seek new immuno-oncology drugs that particularly target the antitumor innate immunity, our lab had previously screened traditional Chinese herbal medicine and found that water extract from a medicinal plant, Alocasia Cucullata (AC), has strong anticancer activity in mouse solid tumor models and acts partly by promoting antitumor, proinflammatory macrophages. However, the active components responsible for this exciting immuno-oncology activity and the corresponding immune targets are unknown. Therefore, the aim of my PhD study is to develop chemical biology strategies to isolate and purify the active components of AC from the crude water extract and identify the corresponding cellular targets and mechanisms. Results from my study identified two separable activities and active components, one smaller than 3K and the other larger than 100K, which work synergistically to simulate antitumor macrophages. Further analysis revealed the >100K active component is a large polysaccharide that binds to multiple Toll-like Receptors (TLRs) critical for activating proinflammatory M1-type macrophages. Identity of the Nonetheless, I was able to clean up this fraction by 50 fold and perform RNAseq to examine the innate immune targets of this intriguing drug lead and found it acts to differentiate monocytes to macrophages. Overall my PhD thesis has explored new chemical biology strategies to purify and characterize active components from traditional Chinese medicine towards new drug development and developed a variety of cell-based immune activity assays for identifying and characterizing novel innate immune drug targets and mechanisms

Thesis (Ph.D) -- McMaster University, 1997 / Includes bibliographical references Also available via World Wide Web.

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