) The long-term goal of the proposed research is the development of novel and highly effective biotherapeutics against leukemias, lymphomas, and breast cancer. Genistein, an isoflavone from fermentation broth of Pseudomonas spp. is a naturally occurring tyrosine kinase inhibitor present in soybeans. The targeted delivery of genistein by regiospecific linkage to carrier molecules has proven to be a very effective strategy for inducing apostolic cell death in human cancer cells (Uckun et al., Science 267: 886-891, 1995; Proc. Natl. Acad Sci. USA 92: 9575-9579, 1995). CD19 receptor is expressed at high levels on leukemia/lymphoma cells and it physically associates with Src protooncogene family tyrosine kinases to form membrane-associated anti-apoptotic complexes. Epidermal growth factor receptors (EGF-R) are expressed at high levels on breast cancer as well as prostate cancer cells and they are also associated with Src family tyrosine kinases to form vital membrane-associated anti-apoptotic complexes. Our preliminary studies strongly support our hypothesis that CD 19 and EGF receptors are suitable targets for a surface membrane directed apoptosis-induction strategy by delivering Genistein to CD19- or EGF-R-associated vital tyrosine kinases. The goal of our Clinical Program is to develop and implement pharmacologically guided clinical Phase IM protocols using B43-genistein as an anti-leukemia agent and EGF-genistein as an anti-breast cancer agent. It is anticipated that (a) several novel genistein conjugates will become available for clinical studies during the projected grant period and (b) successful completion of the proposed studies will constitute a good start towards the application of genistein conjugates for more effective treatment of leukemia/lymphoma and breast cancer patients.
