""""""""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.""""""""

National Institute of Health (NIH)
National Cancer Institute (NCI)
Intramural Research (Z01)
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Special Emphasis Panel (M)
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National Cancer Institute Division of Clinical Sciences
United States
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