Adjuvant intravesical BCG is the treatment of choice for superficial bladder cancer. BCG therapy involves the instillation into the bladder through a catheter of a suspension of viable bacteria (BCG). Retention of the bacteria is dependent on the attachment of BCG to fibronectin present in the bladder. The fibronectin/BCG interaction is mediated by bacterial receptor(s) which bind to fibronectin in an essentially irreversible manner. Modulation of the BCG/ fibronectin interaction has been shown to directly affect the antitumor activity of BCG. A better understanding of the nature of the BCG receptor(s), and the biochemical interaction between the receptor(s) and fibronectin may provide a basis for improving BCG therapy and also may provide the tools necessary to develop new treatments for superficial bladder cancer that do not require the use of viable bacteria. To this end the following experiments are proposed. The BCG receptor for fibronectin will be purified, cloned and the cloned gene will be expressed in a vector suitable for production of large quantities of the protein. The biochemical interaction between fibronectin and the BCG receptor will be characterized and the knowledge gained will be applied to an animal model to test the influence of modulating attachment on therapy. Attachment of BCG to integrin receptors expressed on normal and transformed transitional epithelial cells, which is currently thought to occur after BCG/fibronectin attachment, will be characterized and where applicable, proteins involved will be purified, cloned and studied as outlined for the BCG fibronectin binding protein. We also will perform experiments to test the potential of the fibronectin binding protein and others, if warranted, as carrier molecules for the development of new treatments for superficial bladder cancer. Experiments are outlined that will use the BCG fibronectin binding protein incorporated into liposomes as a means of delivering liposome encapsulated drugs or adjuvants. The antitumor activity of the liposome/BCG fibronectin binding protein system will be evaluated in an animal model.
