Antitumor activity of zinostatin stimalamer (YM881) in human hepatoma cell lines and VX2 liver tumor-bearing rabbits.

Antitumor activities of zinostatin stimalamer (YM881) were examined in human hepatoma cell lines (SK-Hep1 and HuH2) and VX2 liver tumor-bearing rabbits. YM881 inhibited the growth of human hepatoma cells in a dose-dependent manner. The IC50 values of YM881 causing a 50% inhibition of growth of SK-Hep1 and HuH2 cells were 6.7 and 27 nM, respectively. In VX2 tumor-bearing rabbits, administration of YM881 suspended in Lipiodol, an iodinated fatty acid ethylester of poppyseed oil, (YM881/Lipiodol suspension, 0.2 mg/0.2 ml/body) into the hepatic artery showed significant (p < 0.01, vs. sham-operated and Lipiodol-treated groups) inhibitory effects on tumor growth and histopathological changes at 1 and 2 weeks after administration. In contrast, Lipiodol (0.2 ml/body) tended to inhibit the growth of VX2 tumor (p < 0.1, vs. sham-operated group) at 1 week after administration, but showed only moderate effects at 2 weeks after administration. Minimal necrosis was observed at 1 and 2 weeks after administration of Lipiodol, and histopathological findings were similar to those in the sham-operated group. From the present study, it is suggested that YM881/Lipiodol suspension showed antitumor activity in VX2 tumor-bearing rabbits presumably due to the inhibition of the growth of hepatoma cells by YM881 itself. Lipiodol, on the other hand, is considered to augment the antitumor activity of YM881 by maintaining high YM881 concentrations in tumor tissue.

Mechanism for species-specific induction of Leydig cell tumors in rats by lansoprazole.

Lansoprazole is a substituted benzimidazole which inhibits gastric acid secretion by inhibiting the hydrogen-potassium ATPase (proton pump) in the parietal cell. The finding of Leydig cell hyperplasia and Leydig cell tumors in 2-year oral studies in Sprague-Dawley rats but not in CD-1 mice prompted investigative studies to determine the mechanism for the Leydig cell changes. hCG challenge studies in Sprague-Dawley rats revealed decreased testosterone responsiveness in rats treated orally for 1 or 2 weeks with lansoprazole. After 4 weeks of daily oral treatment increases in serum LH and decreases in serum testosterone were detected within a few hours after dosing. In a study where 9-month-old male F344 rats were given testosterone supplementation via Silastic implants and then treated with lansoprazole for 6 months, a high incidence of Leydig cell tumors was seen in lansoprazole-treated, unsupplemented rats, whereas no Leydig cell tumors were seen in testosterone supplemented rats. This implied that reduction of the normal feedback inhibition at the level of the hypothalamus and/or pituitary due to reduced testosterone levels, thus giving rise to elevated levels of LH, was involved in the induction of Leydig cell tumors by lansoprazole. In vitro studies with Leydig cells from rats using various stimulators and precursors of testosterone biosynthesis demonstrated that the most sensitive site for inhibition of testosterone synthesis by lansoprazole is the transport of cholesterol to the cholesterol side chain cleavage enzyme. The IC50s for inhibition of LH or hCG-stimulated testosterone synthesis in Leydig cells from rats, mice, and monkeys were 11-12, 8, and 24.7 micrograms/ml, respectively. In vitro studies with metabolites of lansoprazole revealed that three metabolites were more potent inhibitors of testosterone synthesis than the parent drug, two of them being at least 10 times more potent. These metabolites are present in rats at substantial levels but are undetectable in humans. The lack of induction of Leydig cell tumors in mice, lower sensitivity of primate Leydig cells, and the absence of testosterone synthesis-inhibiting metabolites in man suggest that Leydig cell tumors found in rats represent a species-specific sensitivity and does not imply a risk for clinical use in man.

[Anti-tumor activity of zinostatin stimalamer (YM 881) examined by human hepatoma cells in vitro and VX2 liver tumor in vivo].

Anti-tumor activities of zinostatin stimalamer (YM 881) were examined using human hepatoma cell lines (SK-Hep1 and HuH 2) and VX2 liver tumor-bearing rabbits. YM881 inhibited the growth of human hepatoma cells in a dose-dependent manner. The IC50 values of YM881 against SK-Hep 1 and HuH 2 cells were 6.7 and 27 mM, respectively. In VX2 tumor-bearing rabbits, administration of YM 881 suspended in iodinated fatty acid ethylesters of poppyseed oil (YM 881/Lipiodol suspension, 0.2 mg/0.2 ml/body) into the hepatic artery showed significant (p < 0.01, vs sham-operated and Lipiodol-treated groups) inhibitory effects on the growth and pathological changes 1 and 2 weeks after administration. On the other hand, Lipiodol (0.2 ml/body) showed a tendency to inhibit the growth of VX2 tumor (p < 0.1, vs sham-operated group) 1 week after administration, but it showed only moderate effects on the VX2 tumor growth 2 weeks after administration. Minimal necrosis was observed 1 and 2 weeks after administration of Lipiodol, and these pathological findings were similar to those in the sham-operated group. From the present study, it is suggested that YM 881/Lipiodol suspension showed the anti-tumor activity against VX2 tumor-bearing rabbits, presumably due to the inhibition of the growth of hepatoma cell by YM 881 per se. On the other hand, Lipiodol is considered to augment the anti-tumor activity by maintaining high YM881 concentrations in tumor tissue.

Hypercholesterolemia in ExHC rats and lipid-lowering drug: a screening method for new hypocholesterolemic agents.

The ExHC rat strain which was selected and bred from the Sprague-Dawley strain, develops severe hypercholesterolemia and is liable to aortic lipid deposition when the rats are fed an atherogenic diet. After only 4 days on the atherogenic diet, hypercholesterolemia was induced in these ExHC rats. Following a study of gel-filtration and SDS-disc electrophoresis, significant increases of broad-LDL (beta-VLDL) and of apo E and apo B were noted. On the other hand, plasma HDL and its major apolipoprotein, apo A-I, showed decreases. All these changes might be responsible for the future induction of aortic lipid deposition. A screening method for new hypocholesterolemic agents which takes advantage of these ExHC rat characteristics has been set up; it involves the evaluation of cholesterol lowering and HDL increasing effects by the determination of plasma cholesterol and by radioimmunoassay of apo A-I, respectively. Although clofibrate (100 mg/kg body weight) reduced plasma cholesterol levels significantly, there was no apo A-I increasing effect.