Bone Marrow Cell Kinetics Scheduled Dosing Intervals Based on Direct Measurements of - d - Arabinofuranosylcytosine Efficacy by β Increasing 1 - Updated

The therapeutic efficacy of cell cycle phase-specific drugs can be im proved by repeated administrations, the dosing interval being related to the cell cycle time of the susceptible normal host tissue. Kinetic measure ments of bone marrow cell proliferation, with bromodeoxyuridine labeling and flow cytometry analysis, were used to determine the optimal dosing intervals of 1-@3-D-arablnofuranosylcytosine for minimizing bone marrow cell damage in mice. The results showed that cells surviving a single dose 143-D-arabinofuranosylcytosbe treatment remained temporarily blocked at the G1-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 phases, equaled the bone marrow cell cycle time following treatmenL Repeated l-I3-D-arabino furanosylcytosine injections according to this protocol markedly dimin ished drug toxicity in C3H mice, as compared to protocols of other time intervals. A therapeutic schedule based on these measurements was highly effective in lymphoma-bearing mice: the designed protocol of dosing intervals significantly delayed tumor growth whereas other intervals were highly toxic.