USE OF SYNTHETIC OLIGODEOXYNUCLEOTIDES IN BONE MARROW PURGING

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"DISCONTINUED This project seeks to develop the use of oligodeoxynucleotides (ODNs) in a clinically optimal manner. A prior series of investigations demonstrated that ODNs could be introduced into cells efficiently by electroporation (EP): 100% transfection rates, instantaneous delivery, more optimal intracellular ODN distribution profile, and immediate onset of action. Those studies also demonstrated that, with antisense to c-myc, U937 human lymphoma cells could be selectively purged from normal human bone marrow, with little effect upon normal CFU-GM numbers. Recent investigations have focused on how this potential bone marrow purging approach effects long term culture initiating cells (LTC-IC); LTC-IC assays provide the most accurate in vitro measure of true stem cell activity in humans. To date, no significant effects upon LTC-ICs have been detected after treatment of normal bone marrow with EP and/or c-myc antisense. Other investigations have focused upon the inhibition of p210bcr-abl associated protein-tyrosine kinase (PTK) activity by an ODN-based inhibitor, which we have developed. Increased p210bcr-abl PTK activity is involved in the initiation and propagation of chronic myelogenous leukemia (CML). After introduction by EP, ODN-1 rapidly decreases p210bcr-abl associated tyrosine phosphorylation, and leads to growth inhibition of both established and primary CML cells by CFU-GM assay. Ongoing studies demonstrate negligible effects upon LTC-IC activity. After screening multiple primary patient samples, we have been able to determine that inhibition of p210bcr-abl PTK activity in patients with CML has effects which appear to vary from patient to patient, consistent with a variable role of p210bcr-abl in different patients. These findings have led to ongoing investigations whose aim is to target multiple molecular targets simultaneously in CML."