PD176067 is a reversible and selective inhibitor of fibroblast growth factor receptor tyrosine kinase, and was in preclinical development as an angiogenesis inhibitor for the treatment of solid tumors. A 14-day oral toxicity study of PD176067 in young female rats (7 weeks old) was conducted at doses of 2.5, 5, and 10 mg/kg/day (15, 30, and 60 mg/m 2 , respectively). Skeletal changes, and vascular and soft tissue mineralization were observed as primary drug-related toxicities. To determine if these changes are specific to young, rapidly growing animals with increased vascular and osseous development, PD176067 was administered to mature (11 months old) rats. Female rats received PD176067 by gavage for 14 days at doses of 2.5, 5, and 10 mg/kg/day and necropsied on day 15. Clinical signs of toxicity were seen at ≥5 mg/kg and one death occurred at 10 mg/kg. Physeal dysplasia (distal femur, proximal tibia, sternum) occurred in all drug-treated animals and was characterized by dose-related increased thickness of the zones of chondrocyte proliferation and hypertrophy, and marked thickening of the zone of ossification. Cartilage hyperplasia was characterized by proliferation of chondrocytes along margins of the synchondrosis and subperiosteum of sternebrae. Serum phosphorus levels increased 47% and 166% at 5 and 10 mg/kg, respectively. Mineralization of cardiac myocytes, aorta, various arteries, renal tubules, and gastric mucosa and muscularis was seen at 10 mg/kg, and consistent with the presence of calcium-phosphorus deposition. Physeal changes occurred at similar plasma PD176067 exposures in young and mature rats (AUC ≥ 4.83 µg · hr/mL). PD176067 produced morphologically similar lesions in young and adult rats.

A selective non-peptide endothelin A (ET A ) receptor antagonist, CI-1020, was administered to cynomolgus monkeys intravenously (iv) for 2 or 4 wk and orally for 4 wk. Groups consisting of 3 animals of each sex received CI-1020 at 1, 5, and 10 mg/kg/hr (iv) or orally at 250, 500, and 750 mg/kg body weight for 4 wk. Control animals received the vehicle only. In a separate experiment, 1 male was infused with 10 mg/kg/hr for 2 wk, and Monastral blue dye was administered iv to facilitate localization of lesions to the vascular walls. One female was administered saline and the dye and served as a control. One female at 1 mg/kg/hr was found dead at week 2, and 1 female at 5 mg/kg/hr was euthanatized during week 4 as a result of severe thigh swelling at the catheter site. Macroscopically, extramural coronary arteries appeared thickened and nodular in the 4-wk iv study in the female found dead at 1 mg/kg/hr, in 1 male and 1 female at 5 mg/kg/hr, and in 2 females at 10 mg/kg/hr. Histologically, Monastral blue pigment trapped in the walls of coronary arteries with arteriopathy was observed in the male treated with CI-1020 at 10 mg/kg/hr for 2 wk. Extramural coronary arteriopathy occurred at all doses in the 4-wk iv study, with higher incidence occurring in females than in males (7 of 9 treated females compared with 3 of 9 treated males). In the oral study, 1 female at 500 mg/kg/day and 1 male and 2 females at 750 mg/kg/day had coronary arteriopathy. Histological changes after 2 wk of treatment were characterized by intimal thickening, fragmentation of the internal elastic lamina, necrosis and edema of the media, and mixed inflammatory-cell infiltrates in the intima, media, and adventitia. After 4 wk of iv administration, arteriopathy was characterized by segmental disruption of the elastic lamina and intimal and medial fibrosis with complete replacement of smooth muscle with fibrous tissue. The adventitia was thickened as a result of fibrosis and mixed or mononuclear inflammatory-cell infiltrates. CI-1020 concentrations were higher in males (1.57 to 29 μg/ml) than in females (0.974 to 24.4 μg/ml) in the iv study. Transient systemic exposure with high maximum plasma concentration (Cmax) (120-352 μg/ml) in the oral study was insufficient to provoke arterial changes of the same magnitude as those noted with continuous iv administration. The regeneration of the media by fibrous tissue and the disruption of the elastic lamina may weaken the arterial wall and increase the susceptibility of the artery to the development of aneurysm.

The hepatic tumorigenicity of CI-924 (5,5'-(1,1'-biphenyl)-2,5-diylbis(oxy)(2,2-dimethylpentanoic acid)), a hypolipidemic agent, was evaluated in 50 B6C3F1 mice/sex/dose given drug in the diet at 0, 5, 25, and 75 mg/kg/day for 2 yr. Peroxisomal and drugmetabolizing enzyme determinations, as well as ultrastructural evaluations, were conducted in subsets of these same groups, because drugs of this class cause peroxisome proliferation and hepatic tumors in rodents. CI-924 elicited dose-dependent increases in the incidence of hepatocellular adenomas and carcinomas in both sexes that were statistically significant at 75 mg/kg. Stereologic evaluation revealed significant increases in hepatocellular peroxisome volume ratio, due to increased numbers of peroxisomes, in females at all doses and males at 75 mg/kg. Peroxisomal enzyme activity measurements revealed no change in catalase, but dose-dependent increases in carnitine acetyltransferase and cyanide-insensitive beta-oxidation in both sexes. Peroxisome proliferation, determined biochemically or ultrastructurally, was twice as great in females compared to males. Total cytochrome P-450 was increased in both sexes given 75 mg/kg. There were dose-dependent decreases in glutathione S-transferase in males and increased glutathione peroxidase in both sexes at 25 and 75 mg/kg. In conclusion, this study demonstrated that while CI-924 induced hepatic tumors in male and female B6C3F1 mice the associated peroxisome proliferation, while moderate in females, was only weak in the males after 2 yr of exposure.

The lipid lowering agent 5,5'[[1,1'-biphenyl]-2,5-diylbis(oxy)]bis[2,2-dimethylpentanoic acid] (CI-924) is a peroxisome proliferator in rats and mice, but increased the incidence of hepatic tumors in mice only. Male and female B6C3F1 mice and albino Wistar rats were treated with CI-924 at doses of 0, 25 and 75 mg/kg for 1, 3, 7 and 28 days. Our aim was to identify species differences potentially related to tumorigenicity and to establish the time course of early events related to or associated with peroxisome proliferation. After 24 h of exposure to CI-924 in the diet there were increases in carnitine acyl transferase and CYP4A1 activity in mice at 25 and 75 mg/kg. In rats, carnitine acyl transferase activity was increased after 24 h and CYP4A1 activity increased after 3 days at 75 mg/kg. Acyl CoA oxidase activity was increased at both doses in male and female rats and mice by 3 days. In general the changes in enzyme activity were of greater magnitude in rats. In contrast to the rapid peroxisome proliferation, increases in the amount of PCNA were observed in CI-924 treated rats and mice at later times after administration and only at 75 mg/kg. PCNA was increased to a similar extent in both rats and mice, while apoptosis was decreased at both doses of CI-924 after 3 days in female rats, 7 days in male rats, and was largely unchanged in mice. It was concluded that the sequence of peroxisome proliferation was generally similar in rats and mice. Early changes in cell proliferation and programmed cell death were not directly correlated with subsequent CI-924-induced hepatotumorigenicity.

No abstract