Decrease in prostate specific antigen secretion correlated with docetaxel-induced growth inhibition and apoptosis in human prostate tumor cells.

The antitumor activity of docetaxel in human prostate tumor cells and correlation between cell-growth inhibition and prostate specific antigen (PSA) secretion were investigated. Cultured human prostate tumor cell lines (LNCaP, DU1 45 and PC-3) were treated with test drugs,after which the number of viable cells and PSA levels in the medium were determined. Apoptosis was assessed by changes in chromatin structure, DNA fragmentation, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) and Annexin V assay. Docetaxel inhibited cell proliferation in a dose-dependent fashion in all cell lines,with IC50 levels from 0.90 to 4.2 nM,which were similar to those of paclitaxel,but more potent than mitoxantrone,estramustine,or cisplatin. Docetaxel-treated cells underwent cell-cycle arrest in the G2/M phase and apoptosis as indicated by chromatin condensation and DNA fragmentation. In docetaxel-treated LNCaP cells,there was a linear correlation between growth inhibition and the decline in PSA level in the culture medium. It was demonstrated that docetaxel had potent antitumor activity against human prostate tumor cells,and the decrease in cell growth was associated with a decrease in PSA secretion,suggesting that PSA would be a useful biological marker for monitoring the efficacy of docetaxel in a clinical setting.

Effects of fexofenadine hydrochloride in a guinea pig model of antigen-induced rhinitis.

Allergic rhinitis is an inflammatory disease of the nasal mucosa, induced by histamine, leukotrienes, and other substances released from mast cells. Fexofenadine hydrochloride, the active metabolite of terfenadine, is a novel, nonsedating antiallergic drug having H1 receptor antagonistic activity. Fexofenadine is effective for the treatment of allergic rhinitis. However, its mechanism of action in attenuating nasal congestion has not yet been elucidated. Therefore, we first examined the effects of fexofenadine on a guinea pig model of antigen-induced rhinitis. We also evaluated the effects of mepyramine, zafirlukast and ramatroban in this model; these drugs are an H1 receptor antagonist, a selective leukotriene antagonist and a selective thromboxane antagonist, respectively. Rhinitis was induced by ovalbumin (OVA) instillation into the nasal cavity of animals that had been sensitized by two earlier OVA injections (s.c. and i.p.). The nasal airway resistance was measured for 45 min after the challenge. Fexofenadine hydrochloride (20 mg/kg) and terfenadine (20 mg/kg) administered orally 70 min prior to the challenge significantly inhibited (fexofenadine, p < 0.001, terfenadine, p < 0.05) the increase in nasal airway resistance. Ramatroban (30 mg/kg) administered orally 60 min prior to the challenge also significantly inhibited (p < 0.05) the increase in nasal airway resistance. In contrast, mepyramine (3 mg/kg i.v.) and zafirlukast (3 mg/kg p.o.) failed to reduce the increase in nasal airway resistance. These results suggest that thromboxane may be involved in the increase in the nasal airway resistance in this model. Accordingly, fexofenadine may reduce the increase in nasal airway resistance by inhibiting the release of chemical mediators, including thromboxane, that are involved in the increase in nasal airway resistance in this model.