Immunotoxicity of the anticancer drug CI-994 in rats: effects on lymphoid tissue.
CI-994 (acetyldinaline) is an investigative oral anticancer drug currently in clinical trials. To characterize the effects of CI-994 on lymphoid tissue, male rats were administered single oral doses at 0 (vehicle control), 10, 23, and 45 mg/kg and killed up to 7 days after dosing for evaluation of white blood cell differentials, bone marrow differentials, lymphoid tissue weights, and selected histopathology of lymphoid tissue. Statistically significant dose-related reductions in blood lymphocytes (CD-3+, CD-4+, CD-8+, CD-20+), monocytes, neutrophils, and bone marrow lymphoid cells were observed in all drug-treated groups on days 1 and/or 3. Statistically significant reductions in bone marrow myeloid cells were also observed on days 1 and 3 at 23 and 45 mg/kg. Complete or partial reversal of most parameters was evident on day 7. Spleen and/or thymus weights were significantly decreased in the groups administered 23 and 45 mg/kg on days 1, 3, and/or 7. Minor reductions in lymphoid organ weights were noted at 10 mg/kg. Minimal to moderate lymphoid depletion of the spleen and thymus was noted on day 3 in animals dosed at 23 mg/kg. In vitro, CI-994 inhibited mitogen-stimulated blood lymphocyte proliferation with a 50% inhibitory concentration (IC50) value of 3 microM. The results demonstrate that CI-994 can effect lymphoid tissue in rats within 1 day of a single oral dose, that effects are generally reversible within 7 days, and that inhibition of lymphocyte proliferation is a sensitive indicator of CI-994 immunotoxicity in vitro.
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA. michael.graziano@wl.com
M J
MJ
Graziano
A J
AJ
Galati
K M
KM
Walsh
D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000633:toxicity*; D001549:Benzamides; D015415:Biomarkers; D001772:Blood Cell Count / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects; D008221:Lymphoid Tissue / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects*; D010655:Phenylenediamines / Q000276:immunology / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
D000970:Antineoplastic Agents; D001549:Benzamides; D015415:Biomarkers; D010655:Phenylenediamines; D003208:Concanavalin A; C081895:tacedinaline