TP53 gene expression levels and tumor aggressiveness in canine mammary carcinomas.

The protein p53 is considered to be one of the most important tumor suppressor factors. Despite this importance, a potential association between TP53 messenger (m)RNA levels and tumor aggressiveness has not been well defined in animal cancer. We assessed and correlated TP53 gene expression in 40 canine mammary carcinomas with histologic grade, tumor size, and aggressiveness. The tumors were subjected to histologic analysis and the TP53 mRNA levels determined by RT-rtPCR. Statistical analysis revealed no correlation between levels of TP53 mRNA and tumor aggressiveness ( r = 0.00) or tumor growth ( r = 0.06). Histologic grades ( r = 0.17) and mitosis count ( r = 0.12) showed a weak correlation with TP53 mRNA expression levels. These findings are consistent with molecular studies that revealed heterogeneous expression of TP53 in canine and human mammary tumors. Hence, TP53 gene expression alone cannot be considered a marker for tumor aggressiveness in canine mammary carcinomas.

Treatment effects of bisphosphonates on ovariectomy-induced osteopenia in rats: comparison between clodronate and etidronate.

We studied the effects of clodronate and etidronate on bone loss induced by ovariectomy (OVX) in rats. Drug administration was initiated 8 weeks after the surgery and continued for 12 weeks (twice per week, s.c.). Lumbar (L4-L5) bone mineral density (BMD) and femoral BMD in the sham-operated group were increased to 113% and 114%, respectively, whereas those in OVX group were suppressed to 98.8% and 105%. Clodronate significantly restored the suppressed BMD over the entire dose range used (4-25 mg/kg). Etidronate restored BMD only at 4 mg/kg. In a histomorphometric analysis of lumbar vertebrae, both bisphosphonates depressed the amount of labeled surface, which was increased by OVX, to 11.9%-20.1% of the OVX group value for clodronate and to 0.23%-9.7% of the OVX group value for etidronate. The osteoid area was significantly increased by etidronate treatment over the entire dose range (OS/BS, 175%-295%). On the other hand, the osteoid area in the clodronate group did not increase at any dose tested (OS/BS, 38.1%-49.9%). Urinary excretion of deoxypyridinoline and plasma level of osteocalcin were elevated in the OVX group (162%-182% and 123%, respectively), suggesting that OVX enhanced bone turnover. Both bisphosphonates suppressed the bone turnover accelerated by OVX, and the data indicated that both bisphosphonates recovered BMD by means of inhibition of bone resorption. These data suggested that clodronate and etidronate reversed osteopenia induced by ovariectomy in rats. As judged from the dose response of BMD and histomorphometric findings, clodronate showed a wider safety margin than etidronate.

Effect of cabergoline, a long-acting dopamine D2 agonist, on reserpine-treated rodents.

We studied the characterization of cabergoline, a new ergot alkaloid derivative and a selective dopamine D2 receptor agonist, in comparison to bromocriptine and pergolide in reserpine-treated rodents. Cabergoline (0.25-1.0 mg/kg, s.c.) improved dose-dependently the reserpine-induced akinesia that was assessed on the locomotor activity, and the efficacy lasted longer than those of bromocriptine (1.25-5.0 mg/kg, s.c.) or pergolide (0.0625-0.5 mg/kg s.c.). Cabergoline (ED50 = 1.10 mg/kg, at 4 h after the administration of drugs) also reversed catalepsy, the failure to correct an externally imposed posture, and its efficacy was stronger and longer than bromocriptine (ED50 = 4.65 mg/kg, at 4 h). Further, reserpine-induced rigidity was improved equally by cabergoline (0.125-1.0 mg/kg, i.v) and bromocriptine (1.0 mg/kg, i.v.). When cabergoline was administered together with 3(3,4-dihydroxyphenyl)-L-alanine (L-DOPA), the effects were additive. Our results indicate that the long-lasting effects of cabergoline could be beneficial for treating Parkinson's disease.

Dopamine receptor affinities in vitro and stereotypic activities in vivo of cabergoline in rats.

An ergot alkaloid derivative, cabergoline, and its metabolites were investigated for their affinities for dopamine D1 and D2 receptors in rat striatum in vitro in comparison with those of bromocriptine and pergolide. The affinity for D1 receptors was in the following order: pergolide > des-dimethylaminopropyl cabergoline (FCE21904) > cabergoline > or = bromocriptine > or = des-methyl cabergoline (FCE27395) > or = des-ethylcarbamoyl cabergoline (FCE21590). From the effects of GTP on these affinities for the D1 receptor, cabergoline, some of its metabolites, and pergolide were characterized as agonists in contrast to bromocriptine which was classified as an antagonist. The affinity for D2 receptors was ranked as follows: pergolide > or = cabergoline > or = FCE27395 > or = FCE21904 > bromocriptine > FCE21590 > carboxylic acid-type derivative of cabergoline (FCE21589). The affinity of each compound for the D2 receptor was much higher than that for the D1 receptor. The selectivity of cabergoline for D2 receptor was higher than those of bromocriptine and pergolide. Furthermore, these ergot alkaloids were investigated for eliciting stereotypy after subcutaneous administration to normal rats. Pergolide potently induced stereotypy at doses of 0.5 and 1.0 mg/kg, cabergoline slightly induced it only at a high dose of 2.0 mg/kg, whereas bromocriptine did not induce it at any of the doses tested, 10-40 mg/kg. These results suggest that pharmacological properties of cabergoline for the D1 and D2 receptors differ from those of bromocriptine and pergolide.

[Effect of tranilast ophthalmic solution on allergic conjunctivitis in guinea pigs].

The effect of the ophthalmic solution of tranilast, an anti-allergic agent, on allergic conjunctivitis was studied in passively sensitized guinea pigs. We determined the content of uranine dye and histamine in tears and histopathologically examined palpebral conjunctiva. After instillation of antigen into the conjunctival sac, inflammation of the palpebral conjunctiva, an increase in leaked dye and the release of histamine were found. In the histopathological study, tranilast (1.0%) suppressed the appearance of edema and infiltration of inflammatory cells. Tranilast suppressed the leakage of uranine in a dose-dependent manner. A 0.5% solution of diphenhydramine also showed the inhibitory effect on the leakage of uranine. The inhibitory effect of 0.5% tranilast on antigen-induced dye leakage and histamine release lasted for 6 hr. These results suggest that topically applied tranilast is effective for allergic conjunctivitis.