Preclinical toxicity of a new oral anticancer drug, CI-994 (acetyldinaline), in rats and dogs.
CI-994 (acetyldinaline) is an orally active anticancer drug currently in Phase 1 clinical trials. To assess its preclinical toxicity, CI-994 was administered orally as suspensions to Wistar rats (10/sex/dose) and in capsules to beagle dogs (3/sex/dose) once daily for two weeks. Doses were 1.5, 5, and 15 mg/kg for rats (9, 30, and 90 mg/m2, respectively), and 0.5, 2, and 5 mg/kg for dogs (10, 40, and 100 mg/m2, respectively). Systemic exposure was dose-proportional based on toxicokinetic analysis in dogs. Severe clinical signs and mortality occurred at the highest dose in both species beginning on Day 10. Neutropenia, lymphocytopenia, thrombocytopenia, lymphoid depletion, bone marrow hypocellularity, and testicular degeneration were observed in both species, primarily at the mid- and high-doses. Despite continued treatment, neutrophil counts in dogs returned to control levels in Week 2. Other microscopic findings in rats included splenic hematopoietic depletion at all doses and epithelial cell necrosis in various tissues at 15 mg/kg. Additional bone marrow changes in dogs involved myeloid and megakaryocyte hyperplasia at 2 mg/kg and abnormal myeloid and megakaryocyte maturation at 2 and 5 mg/kg. Except for the testicular effects in both species, all changes were reversible within a 4-week (rat) or 9-week (dog) recovery period. The results of these studies show that target organ effects of CI-994 principally involve tissues with rapidly dividing cell populations and that bone marrow suppression is the dose-limiting toxicity. CI-994 also seems to interfere with the release and/or maturation of cells in the bone marrow.
Graziano
M J
MJ
Department of Pathology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA.
Pilcher
G D
GD
Walsh
K M
KM
Kasali
O B
OB
Radulovic
L
L
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D001549:Benzamides; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000473:pathology; D004285:Dogs; D004435:Eating / Q000187:drug effects; D005260:Female; D007700:Kinetics; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010655:Phenylenediamines / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D013737:Testis / Q000473:pathology
D000970:Antineoplastic Agents; D001549:Benzamides; D010655:Phenylenediamines; C081895:tacedinaline