Myb targeted therapeutics for the treatment of human malignancies

For the past several years, we have been engaged in developing a therapeutically effective strategy for disrupting gene function with reverse complementary, or so called 'antisense', oligodeoxynucleotides (ODN). This pursuit has focused on finding appropriate diseases in which to apply this approach, and suitable gene targets. Of the genes that we have targeted for disruption using the antisense ODN strategy (Clevenger et al., 1995; Gewirtz and Calabretta, 1988; Ratajczak et al., 1992c; Small et al., 1994) one that has been of particular interest, and one where therapeutically motivated disruptions are now in clinical trial, is the myb gene (reviewed in Lyon et al., 1994). These trials involve treatment of human leukemias. These diseases are a logical choice for developing oncogene targeted therapies because of easy access to tissues, and the abundance of knowledge about the cell and molecular biology of these diseases. Nevertheless, as will be touched on below, other malignancies have also been examined as models for Myb targeted therapy with some surprisingly encouraging results. Finally, while we have focused our efforts on the ODN strategy, I will allude briefly to other strategies for disrupting Myb function with therapeutic intent.