Quantitative Analysis of the Cytokinetic Response of kht Tumors in Vivo to 1-β-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-β-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.