Basic fibroblast growth factor (FGF) is an autocrine growth factor for numerous tumor cells. FGF-SAP (a chemical conjugate of FGF and saporin, an enzyme that inhibits protein synthesis) inhibits melanoma and Kaposi's sarcoma cell growth in culture and is also active in tumor animal models. In its current form, the chemical conjugate of FGF-SAP is a highly heterogeneous mixture at the molecular level. Thus, it does not lend itself to the rigorous chemical characterization required for clinical evaluation of its potential application in the treatment of FGF receptor- dependent, proliferative disease. For this reason, we propose to apply recombinant DNA technology to generate a homogeneous product.
The specific aims are to: l) design and synthesize forms of FGF that retain all of the growth factor's mitogenic activity, but have only one reactive site for its conjugation to SAP, 2) prepare a homogeneous preparation of derivatized SAP, giving it only one reactive site for its conjugation to FGF, and 3) produce a homogeneous chemical conjugate FGF-SAP by using these new starting materials. This proposal presents major improvements in an innovative technology for tumOr treatment: direct tumor targeting by growth factors through their receptors.
