Quantitative analysis of the cytokinetic response of KHT tumors in vivo to 1-beta-D-arabinofuranosylcytosine.

Quantitative estimates of cytokinetic perturbations induced over a 30-hr interval in KHT tumor cells in vivo by a single dose of 1-beta-D-arabinofuranosylcytosine (ara-C) were inferred from measurements of DNA distribution sequences, tritiated thymidine incorporation into tumor cell DNA, and radioactivity of cells labeled with tritiated thymidine prior to treatment with ara-C. These data were analyzed collectively to produce a mathematical model describing the effects of ara-C on tumor cell cycle kinetics. During analysis, we postulated that ara-C produced a transient block at the a G1-S-phase boundary, that ara-C killed all cells in S phase, and that the cells killed by ara-C did not cycle after treatment. The analysis showed that the duration of the G1-S-boundary block was 5.5 hr, that cells were recruited from G0 into cycle beginning 5.5 hr posttreatment, and that the G1, S, and G2M phase durations of the clonogenic cells which were initially 2, 11.5, and 2 hr, respectively, changed to 0.8, 4.6, and 0.8 hr at 14 hr posttreatment. Cells killed by ara-C were removed from the tumor beginning 10 hr posttreatment. We then used the mathematical model to predict clonogenic tumor cell survival following a second dose of ara-C administered at time intervals ranging from 1 to 30 hr after the first treatment. Clonogenic tumor cell survival following the second dose of ara-C was then experimentally determined and agreed well with the model predictions.