Cytokinetics of human acute leukemia before and after chemotherapy

Abstract

In order to evaluate the relationship of relative and absolute blast size to blast proliferative activity, both in treated and untreated human acute leukemia, blasts from peripheral blood of patients with acute leukemia were labeled in vitro with tritiated thymidine and then separated as to size by the 1 g sucrose gradient technique for subsequent evaluation of thymidine uptake and DNA content. Results suggested: (1) Leukemic lymphoblasts were smaller and less variable in size than leukemic myeloblasts; (2) thymidine uptake was excluded from relatively small cells and concentrated in relatively large cells, with some medium cell uptake; (3) DNA content of blasts increased with cell size; (4) Cytosine arabinoside and 6-thioguanine in AML caused an early increase in thymidine uptake and a shift of the cell size distribution to larger cells followed by a rapid depletion of all blasts with preferential large cell loss. This is consistent with early recruitment of small cells into cycle and S-phase specific cell kill (5) l-asparaginase in ALL caused a rapid depletion of blasts with a preferential loss of both large and medium cells and with decreased thymidine uptake, consistent with cycle nonspecific kill plus a G 1 S block inhibiting recruitment. The data support a cytokinetic model of human acute leukemia in which relative cell size correlates with cell cycle stage. Changes in size distribution may reflect drug effect and may be of value in evaluating response to chemotherapy, both of proliferating and resting cells, and in planning and sequencing multiple drug chemotherapy.