Effects of gemcitabine on cis-platinum-DNA adduct formation and repair in a panel of gemcitabine and cisplatin-sensitive or -resistant human ovarian cancer cell lines.

Gemcitabine (dFdC) can increase the sensitivity of both cisplatin (CDDP)-sensitive and -resistant cell lines. It has been postulated that both formation and repair of platinum-(Pt)-DNA adducts are related to these effects. Therefore, we investigated the effects of dFdC on the formation and repair of Pt-DNA adducts in the human ovarian cancer cell line, A2780, and its CDDP- or dFdC-resistant variants, ADDP and AG6000, which have a different expression of various repair enzymes. Cells were exposed for 1 h to CDDP alone or combined with dFdC in IC50 concentrations, followed by a 1-h exposure to thiourea and, subsequently, by a drug-free period of 1, 3 or 23 h (i.e. 2, 4 or 24 h after CDPP +/- dFdC removal). Pt-DNA adducts were quantified with 32P-post-labeling. The gene expression of the repair enzymes, XPA and XRCC1, was the same in all 3 cell lines but ERCC1, ERCC3 and XPC were 2-6 times higher in AG6000 compared to A2780 cells. In contrast, both ERCC1 and ERCC3 were 10- and 1.5-fold lower in ADDP cells compared to A2780. The mismatch enzyme, MLH1, was lower in ADDP cells. At equally toxic CDDP concentrations, all cell lines formed comparable peak levels of total Pt-DNA adducts (36-48 fmol/microg DNA). However, the time at which peak levels were reached showed large variation. The repair of the adducts was very efficient in the resistant cell lines whereas, in A2780 cells, plateau levels were retained until 24 h after CDDP exposure. In A2780 cells, dFdC shifted the adduct peaks from 4 h to directly after CDDP exposure and increased peak levels by >3.9-fold. dFdC also enhanced the repair of adducts by >1.7-fold and increased the Pt-GG:Pt-AG ratio compared to CDDP alone by >1.4-fold. Overall, dFdC decreased the area under the Pt-DNA adduct-time curve (AUA0-25 h) in A2780 cells by 2.7-fold. In ADDP cells, dFdC shifted the adduct peaks from 2 to 4 h and increased them by >2.2-fold. dFdC also increased the Pt-GG:Pt-AG ratio during the repair process by 1.4-fold. Overall, dFdC increased the AUA0-25 h in ADDP cells by 1.7-fold. In AG6000 cells, dFdC increased the Pt-GG:Pt-AG ratio by 1.6-fold directly after exposure but did not clearly affect the AUA0-25 h. In conclusion, dFdC can affect both Pt-DNA adduct formation and repair, depending on the initial sensitivity of the cells.

Comparison of the effects of mirtazapine and fluoxetine in severely depressed patients.

INTRODUCTION: Depression is a major global problem associated with large medical, sociological and economic burdens. Mirtazapine (Remeron, Organon NV, The Netherlands) is an antidepressant with a unique mechanism of action that has similar or superior efficacy to TCAs and SSRIs in moderate-to-severe depression. However, this agent has not yet been tested in patients with severe depression alone. OBJECTIVE: To compare the antidepressant efficacy and tolerability of mirtazapine and fluoxetine and their effects on anxiety and quality of life in patients with severe depression (> or = 25 points on the first 17 items of the Hamilton Depression Rating Scale [HDRS-17]). METHODS: In this double-blind study, 297 severely depressed patients were randomised to receive mirtazapine 15-60 mg/day (n = 147) or fluoxetine 20-40 mg/day (n = 152) for 8 weeks. 294 subjects were actually treated and 292 included in the intent-to-treat population. Symptom severity was measured by the HDRS-17, Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impression (CGI) rating scale. Quality of life was self-assessed by patients using the Leeds Sleep Evaluation Questionnaire and the Quality of Life, Enjoyment and Satisfaction Questionnaire. Adverse events were recorded throughout the study. RESULTS: No statistically significant differences were noted between the two groups in change from baseline HDRS-17 score at any time point; both treatments were associated with large (approximately 15 points) decreases by study end. However, more mirtazapine-treated patients tended to exhibit a > or = 50% decrease in HDRS score (significant at day 7; 9.0% vs 0.7%, p = 0.002). Significant differences in favour of mirtazapine were also observed at day 14 for changes in MADRS scores (-10.9 vs -8.5, p = 0.006) and the proportion of patients with > or = 50% decrease in MADRS score (21.4% vs 10.9%, p = 0.031). On the CGI, the proportion of 'much/very much improved' patients tended to be greater with mirtazapine (significant at day 7; 9.7% vs 3.4%, p = 0.032). No significant between-group differences were observed for the majority of quality-of-life measures. However, mirtazapine produced significantly better improvements on 'sleeping assessment 1' (14.9 +/- 5.2 vs 13.7 +/- 5.4, p = 0.028) and 'sleeping assessment 2' (p = 0.013) than fluoxetine. Both agents were generally well tolerated but mirtazapine-treated patients experienced a mean weight gain of 0.8 +/- 2.7 kg compared with a mean decrease in weight of 0.4 +/- 2.1 kg for fluoxetine-treated patients (p < 0.001). CONCLUSIONS: Mirtazapine is as effective and well tolerated as fluoxetine in the treatment of patients with severe depression.