In vitro and in vivo effects of acetyldinaline on murine megakaryocytopoiesis.
OBJECTIVE
Acetyldinaline (CI-994) has shown preclinical efficacy in vitro and in vivo against solid tumor and leukemia cell lines. Since myelosuppression was the dose-limiting toxicity for acetyldinaline in preclinical and clinical studies, experiments were conducted to examine the in vitro and in vivo effects of acetyldinaline on murine megakaryocytic (CFU-meg) progenitor cells.


METHODS
Bone marrow and spleen cells from untreated mice were continuously exposed in vitro to acetyldinaline or dinaline in clonal assays. For the in vivo study, BDF(1) mice were dosed orally with 50 mg/kg acetyldinaline every day for 14 days.


RESULTS
Both acetyldinaline and dinaline induced an in vitro dose-dependent decrease in CFU-meg colonies derived from either the spleen or bone marrow. Splenic CFU-meg were more sensitive in vitro to acetyldinaline and dinaline than their marrow counterparts. In the in vivo experiments, platelet counts decreased throughout the 14-day dosing period and had returned to normal by day 18. Marrow and spleen CFU-meg declined after the first dose but had recovered by days 4 and 7, respectively. Elevated splenic CFU-meg counts were observed through day 20, 6 days after dosing ended. Recovery of platelet counts in treated mice was associated with increases in both marrow and splenic CFU-meg.


CONCLUSIONS
There was differential in vitro toxicity of acetyldinaline to murine CFU-meg derived from the bone marrow versus spleen. The in vitro assay predicted the more severe effect of acetyldinaline on splenic progenitors than on their marrow counterparts that was observed in the in vivo phase. In addition, megakaryocytopoiesis in the marrow showed evidence of recovery from drug toxicity in the face of continuing daily acetyldinaline treatments.
Volpe
Donna A
DA
Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD, USA. volpe@cder.fda.gov
LoRusso
Patricia M
PM
Foster
Brenda J
BJ
Parchment
Ralph E
RE
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides; D001854:Bone Marrow Cells; D018929:Cell Culture Techniques; D003114:Colony-Forming Units Assay; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010655:Phenylenediamines / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology; D034061:Thrombopoiesis / Q000187:drug effects*
D001549:Benzamides; D010655:Phenylenediamines; C081895:tacedinaline