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 improved by repeated administrations, the dosing interval being related to the cell cycle time of the susceptible normal host tissue. Kinetic measurements of bone marrow cell proliferation, with bromodeoxyuridine labeling and flow cytometry analysis, were used to determine the optimal dosing intervals of 1-beta-D-arabinofuranosylcytosine for minimizing bone marrow cell damage in mice. The results showed that cells surviving a single dose 1-beta-D-arabinofuranosylcytosine 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 treatment. Repeated 1-beta-D-arabinofuranosylcytosine injections according to this protocol markedly diminished 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.
Ubezio
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P
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Tagliabue
G
G
Schechter
B
B
Agur
Z
Z
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology*; D001973:Bromodeoxyuridine / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage* / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008938:Mitosis; D016196:S Phase / Q000187:drug effects; D013997:Time Factors
D004273:DNA, Neoplasm; D003561:Cytarabine; D001973:Bromodeoxyuridine