QUANTITATIVE-ANALYSIS OF THE CYTOKINETIC RESPONSE OF KHT TUMORS INVIVO TO 1-BETA-D-ARABINOFURANOSYLCYTOSINE

  • 1 January 1982
    • journal article
    • research article
    • Vol. 42  (8) , 3125-3131
Abstract
Quantitative estimates of cytokinetic perturbations induced over a 30-h interval in KHT [mouse sarcoma] tumor cells in vivo by a single dose of 1-.beta.-D-arabinofuranosylcytosine (ara-C) were inferred from measurements of DNA distribution sequences, 3H-thymidine incorporation into tumor cell DNA and radioactivity of cells labeled with 3H-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, the following were postulated: ara-C produced a transient block at the a G1-S phase boundary; ara-C killed all cells in S phase; 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 h, that cells were recruited from G0 into cycle beginning 5.5 h posttreatment, and that the G1, S and G2M phase durations of the clonogenic cells which were initially 2, 11.5 and 2 h, respectively, changed to 0.8, 4.6 and 0.8 h at 14 h posttreatment. Cells killed by ara-C were removed from the tumor beginning 10 h posttreatment. The mathematical model was then used to predict clonogenic tumor cell survival following a 2nd dose of ara-C administered at time intervals ranging from 1-30 h after the 1st treatment. Clonogenic tumor cell survival following the 2nd dose of ara-C was then experimentally determined and agreed well with the model predictions.