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2-Dimethylaminomethyl-1-phenyl-2-propen-1-one hydrochloride (3) is a novel cytotoxic and anticancer agent. The objective of this study was to obtain information pertaining to possible toxic symptoms detected by in vivo evaluations in mice and an in vitro test for mutagenicity. The data obtained revealed that 3 had no effect on alanine transaminase, aspartate transaminase, HDL cholesterol and protein concentrations in sera nor were variations in the numbers of red and white blood cells detected. Furthermore autopsies of treated mice revealed no pathological symptoms in the heart, kidney, brain, spleen and testes. However elevation of the concentrations of total cholesterol, triglycerides, creatinine and urea were noted in treated mice as well as inflammation of the liver and lungs. Chromosomal aberrations were detected in a micronuclei test. In the Ames test, compound 3 was converted into one or more mutagens in the presence (but not the absence) of a murine liver homogenate. Thus future molecular modifications of 3 should bear in mind approaches to reduce or minimize unwanted side effects.

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)