The objective of this application is to develop antisense oligodeoxynucleotide therapies in SCID mice carrying Philadelphia leukemias targeting BCR-ABL and its downstream effectors, or by combining bcr-abl oliogodeoxynucleotides with conventional anti-cancer agents. Recent evidence suggest that p210bcr-abl activates p21ras, cRAF-1, PI-3 kinases, and c-myc, which in turn are required for Philadelphia cell proliferation. Initial data indicate that bcr-abl antisense oligodeoxynucleotides temporarily halt the leukemic disease process in SCID mice. To improve the efficacy of bcr-abl-targeted therapy the applicant will treat leukemic SCID mice with a combination of: 1) bcr-abl and c-myc antisense oligodeoxynucleotides because of the ability of c-myc to cooperate with bcr-abl in transformation of hematopoietic cells; and 2) bcr-abl antisense obligodeoxynucleotides and a single injection of cyclophosphamide. Furthermore, the in vivo anti-leukemia effects of phosphoramidates and phosphorothioate derivatives will be compared to determine whether the therapeutic potential of oncogene-targeted ODNs can be improved by use of more potent oligonucleotide derivatives.
