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.(ABSTRACT TRUNCATED AT 250 WORDS)