INCREASING 1-BETA-D-ARABINOFURANOSYLCYTOSINE EFFICACY BY SCHEDULED DOSING INTERVALS BASED ON DIRECT MEASUREMENTS OF BONE-MARROW CELL-KINETICS

The therapeutic efficacy of cell cycle phase-specific drugs can be imp roved by repeated administrations, the dosing interval being related t o the cell cycle time of the susceptible normal host tissue, Kinetic m easurements of bone marrow cell proliferation, with bromodeoxyuridine labeling and now cytometry analysis, were used to determine the optima l dosing intervals of 1-beta-D-arabinofuranosylcytosine for minimizing bone marrow cell damage in mice, The results showed that cells surviv ing a single dose 1-beta-D-arabinofuranosylcytosine treatment remained temporarily blocked at the G(1)-S boundary, and upon release from the block the cells crossed through S phase in a nearly synchronized way, The optimal spacing of repeated treatments, evaluated by measurements of the drug-induced transit times through the different cell cycle ph ases, equaled the bone marrow cell cycle time following treatment, Rep eated 1-beta-D-arabinofuranosylcytosine injections according to this p rotocol markedly diminished drug toxicity in C3H mice, as compared to protocols of other time intervals, A therapeutic schedule based on the se measurements was highly effective in lymphoma-bearing mice: the des igned protocol of dosing intervals significantly delayed tumor growth whereas other intervals were highly toxic.