In vitro evidence for dose-dependent cytotoxicity as the predominant effect of low dose Ara-C on human leukemic and normal marrow cells

To determine whether cytosine arabinoside (Ara-C) has a differentiating effect in vitro, marrow cells from nine patients with acute non-lymphocytic leukemia or myelodysplastic syndrome and eight non-leukemic controls were exposed to drug concentrations comparable to those achieved in vivo with low-dose Ara-C therapy. In soft agar cultures, the predominant effect of Ara-C at concentrations between 10-8M and 10-6M was cytotoxicity with a dose-dependent decrement in Colony Forming Unit of the granulocyte and monocyte lineage (CFUg/m) at 14 days. Growth in liquid cultures containing Giant Cell Tumor(GCT)-conditioned media without Ara-C resulted in a significant increment in the recovery of mature cells at day 10 from the non-leukemic cultures (P=0.03), while only a minor increase was found in the leukemic cultures (P=0.09). All liquid cultures exposed to ≽10-9M Ara-C showed a marked reduction in the immature proliferating cell pool, with a concomitant increase in the percentage of mature non-dividing cells at 10 days. However, the absolute number of differentiated cells recovered remained constant or decreased in all non-leukemic and eight of nine leukemic cultures, compared with cultures without Ara-C. Enhanced recovery of differentiated cells was also never observed in any culture exposed to the relatively non-toxic 10-9M Ara-C. These in vitro findings support clinical observations suggesting that cytotoxicity rather than differentiation is the major mechanism involved in the therapeutic effect of low-dose Ara-C in acute leukemia and myelodysplasia.