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© 1990 Oxford University Press

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Toxicologic Studies on a Novel Antineoplastic Bis-Mannich Base, Derived from a Conjugated Styryl Ketone

C. G. ROUSSEAUX*, H. G. TOWNSEND{dagger}, O. A. PHILLIPS{ddagger} and J. R. DIMMOCK{ddagger}

*Departments of Veterinary Pathology Saskatoon, Saskatchewan, Canada S7N OWO {dagger}Veterinary Internal Medicine, Western College of Veterinary Medicine, University of Saskatchewan Saskatoon, Saskatchewan, Canada S7N OWO {ddagger}College of Pharmacy, University of Saskatchewan Saskatoon, Saskatchewan, Canada S7N OWO

Received April 20, 1989; accepted September 11, 1989

Toxicologic Studies on a Novel Antineoplastic Bis-Mannich Base, Derived from a Conjugated Styryl Ketone. ROUSSEAUX, C. G., TOWNSEND, H. G., PHILLIPS, O. A., AND DIMMOCK, J. R. (1990). Fundam. Appl. Toxicol. 14,318–326. A new bis-Mannich base (NC758) derived from a conjugated styryl ketone has demonstrated activities against human and animal tumors, both in vitro and as xenografts in athymic mice. The present study examined the toxicity of this candidate anticancer drug, when administered intraperitoneally by undertaking LD50, acute dose-response and time-response toxicity studies using CD-1 mice following OECD guidelines. An LD50 of 46.9 ± 1.4 mg/kg (males) and 65.2 ± 1.5 mg/kg (females) was calculated using the moving averages method. Signs of toxicity included diarrhea, piloerection, and coma. Gross pathologic findings consisted of an acute fibrinous peritonitis in animals surviving 24 hr or more before death. The acute dose-response study revealed anorexia in mice 24 hr after receiving 25 mg/kg NC758 or more, lasting up to 72 hr in the 50 mg/kg treated group. Neutrophils were significantly elevated in the 25 and 50 mg/kg groups in conjunction with the observed acute peritonitis. Treatment (p = 0.0001), sex (p = 0.0008), and treatment/sex interaction (p = 0.0001) effects were seen in the myeloid-erythroid ratio (MER) of bone marrow. Pathologic changes included thymic necrosis (in all treated mice) and intestinal villous atrophy (in mice treated with 25 and 50 mg/kg). In time-response studies, pathological changes disappeared after 14 days, except for the MER which remained abnormal in males. It was concluded that NC758 was corrosive; hence future studies should utilize the intravenous route, or be given intraperitoneally as divided doses. Its corrosive action may account for the hematological and myelopoietic changes; however, this compound has the potential for irreversible bone marrow changes in CD-1 male mice when given at levels greater than those used for its antineoplastic activity.


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