Most patients with acute myeloid leukemia (AML) relapse and ultimately die as a consequence of refractory or resistant disease. Salvage chemotherapy at conventional doses may induce a short-term remission, but this approach is generally not curative. For those patients who are not candidates for allogeneic BMT the prognosis remains dismal and new therapeutic strategies targeting specific leukemogenic mechanisms are highly needed to improve the current clinical results. In the past few years, we have successfully applied the antisense strategy to down-regulate expression of distinct target genes that contribute to chemoresistance in myeloid blasts. Here we propose to explore the activity of a novel ribonucleotide reductase (RR) antisense, GTI-2040, in combination with high-dose ARA-C (cytarabine arabinoside) in refractory or relapsed AML. RR is an enzyme operative in the synthetic pathway of deoxyribonucleotides and a potential key factor in induction of chemoresistance to ARA-C, a nucleoside analog incorporated in a variety of AML chemotherapy regimens. We seek to understand the relation between plasma and intracellular concentration of GTI-2040 and how this correlates to RR down-regulation, patient toxicity and disease response.
Specific Aim #1 will conduct a phase I study of GTI-2040 in combination with high-dose ARA-C in refractory or relapsed AML. The ultimate goal is to assess the feasibility of this combination and recommend a dose for future phase II studies in this patient population.
Specific Aim #2 will evaluate the plasma pharmacokinetics of GTI-2040 using a sensitive ELISA-based assay that we have developed at OSU. This assay will also allow us to measure intracellular concentrations of GTI-2040 in selected leukemia cells from patients enrolled on this protocol.
Specific Aim #3 will examine the correlation between plasma and intracellular concentrations of GTI-2040 with toxicity, disease response and biological endpoints such as down-regulation of the antisense target (i.e., the R2 subunit of RR) at the mRNA and protein levels, changes in RR enzymatic activity and levels of apoptosis in selected leukemia cells collected from patients enrolled in this protocol. It is expected that the analysis of these data will allow us to elucidate the intrinsic mechanisms of the antitumor activity of the antisense compounds and plan their incorporation in future therapeutic strategies for AML patients. ? ?
