Randomized trial of cisplatin and carboplatin versus cisplatin, vinblastine and bleomycin in ovarian cancer

Between January 1992 and July 1997, 202 cases of epithelial ovarian cancer were registered and assigned randomly to a combination of cisplatin and carboplatin (PP group), or cisplatin, vinblastine and bleomycin (PVB group). We analyzed 189 patients whose clinical records were available. The PP chemotherapeutic regimen was advantageous in terms of overall survival compared to the PVB regimen until 4 years after the initial operation. However, the 5-year survival rates were almost the same in both groups. However, in stage III patients, the mean survival time in the PP group was 51.4 months and that in the PVB group was 23.3 months, and there was a statistically significant difference in the survival curves between the two groups (p = 0.0158). The 5-year survival rates were 31.1 and 20.4% in the PP and PVB groups, respectively, in stage III patients. The PP regimen was also significantly superior in patients with macroscopic residual tumor after the initial operation, and the 5-year survival rates were 25.7 and 10.1% in the PP and PVB groups, respectively (p = 0.0128). However, there was no significant difference between the two regimens in patients without macroscopic residual tumor. Cox's proportional hazards regression analysis showed that tumor stage, presence of macroscopic residual tumor, and the chemotherapeutic regimen used were significant prognostic factors. In conclusion, the PP chemotherapeutic regimen is superior to the PVB regimen especially in the treatment of advanced ovarian cancer.     

Ethanol, but not the anxiolytic drugs buspirone and diazepam, produces a conditioned place preference in rats exposed to conditioned fear stress

The present study was designed to investigate the role of an anxiolytic effect in the development of a drug-associated place preference in rats exposed to conditioned fear stress, using the conditioned place-preference paradigm. The administration of a low dose of ethanol (300 mg/kg, IP) and the anxiolytic drugs, buspirone (1 and 2 mg/kg, IP) and diazepam (1.25 and 2.5 mg/kg, IP), did not produce a place preference in rats that were not exposed to conditioned fear stress. In rats that were exposed to conditioned fear stress, ethanol produced a significant place preference, while buspirone and diazepam failed to produce a place preference. In addition, ethanol, buspirone, and diazepam produced no place preference in rats treated with an anxiogenic dose of pentylenetetrazole (20 mg/kg, IP). A significant decrease in locomotor activity was observed in rats exposed to conditioned fear stress. Ethanol, but not buspirone and diazepam, significantly recovered or increased locomotor activity in rats exposed to conditioned fear stress. Further, the locomotor-stimulating effect of ethanol was markedly enhanced by repeated exposure to conditioned fear stress. These results suggest that the stimulating effect may be strongly related to the development of the rewarding effect of a low dose of ethanol under psychological stress, and that the conditioned place preference paradigm with conditioned fear stress may be useful for studying the rewarding mechanism of ethanol with regard to the interaction between ethanol and psychological stress.     

Analysis of nondegradative protein ubiquitylation with a monoclonal antibody specific for lysine-63-linked polyubiquitin

Modification of proteins by the addition of lysine (K)-63-linked polyubiquitin (polyUb) chains is suggested to play important roles in a variety of cellular events, including DNA repair, signal transduction, and receptor endocytosis. However, identifying such modifications in living cells is complex and cumbersome. We have generated a monoclonal antibody (mAb) that specifically recognizes K63-linked polyUb, but not any other isopeptide-linked (K6, K11, K27, K29, K33, or K48) polyUb or monoubiquitin. We demonstrate the sensitivity and specificity of this K63Ub-specific mAb to detect K63Ub-modified proteins in cell lysates by Western blotting and in cells by immunofluorescence, and K63Ub-modified TRAF6 and MEKK1 in vitro and ex vivo. This unique mAb will facilitate the analysis of K63-linked polyubiquitylation ex vivo and presents a strategy for the generation of similar reagents against other forms of polyUb.