Comparison of cytarabine, mitoxantrone, and CNDAC in vitro treatment of AML bone marrow and peripheral blood cells.

Abstract

6588 Background: A major challenge in developing treatment regimens for AML is identifying strategies to prevent disease relapse. Advances in understanding the biology of AML leukemogenesis have revealed that schedule and combination strategies for treatment influence outcome. This study examines the in vitro effect of current chemotherapeutic drugs cytarabine, mitoxantrone (synthetic anthracynedione) and the active form of oral drug sapacitabine, 2’-C-Cyano-2’-deoxy-1-β-d-arabino-pentofuranosylcytosine (CNDAC) on leukemic cells from 5 AML patients. Methods: Untreated AML bone marrow (BM) and peripheral blood (PB) mononuclear cells (MNC) from 5 patients were treated with Ara-C (1-100μM), CNDAC (1-100μM) and Mitoxantrone (0.005 – 0.5μM) for 4 days. Total WBC counts ranged from 27.06 – 93.05 K/µL with 58 – 99% CD34+ cells. BM MNC’s were exposed to drugs in a co-culture system using the mouse stromal cell line, M2-10B4. PB MNC’s were drug treated in suspension. Post treatment, both BM and PB cells were replated on M2-10B4 stromal layers. Non-adherent cells were assessed for overall viability post-treatment and at 3, 7 and 31 days of culture following drug treatment. Results: In the PB, after 3 days post drug removal, the total cell survival was significantly lower for cells treated with 1µM CNDAC or 0.005µM Mitoxantrone compared to 1µM cytarabine (p<0.05, n=5). Although a similar trend was seen with BM cells, it did not reach significance. In both the BM and PB, survival of cells treated with 1µM CNDAC or 0.005µM mitoxantrone over the 35 day culture period was significantly less than untreated cells (p<0.05, n=5). The survival of 1µM cytarabine treated cells was not significantly lower. Conclusions: CNDAC and mitoxantrone have a longer in vitro impact on the survival of PB cells than cytarabine. A subset of similar cells in the BM was most likely protected by the stroma in the BM co-culture system, thus lessening the impact. However, as seen by the similar profiles in PB and BM, both CNDAC and mitoxantrone appear to have a greater overall effect on cell survival than cytarabine. Due to the effectiveness and ease of administration of CNDAC, it may complement cytarabine and mitoxantrone and influence optimal scheduling in treatment of AML.