Summary Epidermal growth factor receptor (EGFR) content was determined by a radioligand receptor assay in 140 primary laryngeal squamous cell carcinomas (median value of 8.4 fmol mg-1 protein, range 0-169.9 fmol mg-protein). Cox univariate regression analysis using EGFR as a continuous variable showed that EGFR levels are directly associated with the risk of death (X2 = 14.56, P-value = 0.0001) and relapse (x2 = 7.77, P-value = 0.0053). A significant relationship between EGFR status and survival was observed at the different arbitrary cut-off values chosen (8, 16 and 20 fmol mg-1 protein). The cut-off value of 20 fmol mg-' protein was the best prognostic discriminator. In fact, the 5 year survival was 81% for patients with EGFRtumours compared with 25% for patients with EGFR+ tumours (P<0.0001). The 5 year relapse-free survival was 77% for patients with EGFR-tumours compared with 24% for patients with EGFR+ tumours (P <0.010). When clinicopathological parameters and EGFR status were examined in the multivariate analysis, T classification and EGFR status retained an independent prognostic value. In this study we demonstrated that high EGFR levels single out patients with poor prognosis in laryngeal cancer.

Taxanes act by inhibiting microtubule dynamics; in this study, we have investigated mitochondria as an additional target of taxanes. We incubated isolated mitochondria in the presence of taxanes with or without stimulation of the mitochondrial respiratory state. Results showed that they rapidly induced the loss of ⌬ m after stimulation of the respiratory state. CPM values after Bcl-2 immunoprecipitation was 62.8-fold higher than those of the control antibody, thereby indicating the involvement of Bcl-2 in paclitaxel binding. Then, we established a panel of A2780 cell lines resistant to increasing doses of paclitaxel alone or to high doses of paclitaxel/cyclosporin A (A2780 TC cells). In both cases, Bcl-2 expression was consistently down-regulated, whereas levels of other members of the Bcl-2 family, such as Bax and Bcl-x, did not change in paclitaxel-resistant cell lines. When A2780TC cells were stably transfected with a Bcl-2 construct, paclitaxel sensitivity was partially restored, thereby supporting a direct role of Bcl-2 down-regulation in the maintenance of drug-resistance. Finally, we examined Bcl-2 by immunohistochemistry in a small subset of ovarian cancer paclitaxel-resistant patients and we noticed that the protein is down-regulated in this clinical setting with respect to the expression levels found in drug-sensitive tumors. These findings demonstrate that Bcl-2 is an additional intracellular target of taxanes and that its down-regulation is involved in taxane resistance.Taxanes are natural products derived from trees of the genus Taxoidaceae. The first taxane introduced in cancer therapy was paclitaxel, firstly isolated from Taxus brevifolia (Schiff et al., 1979). The clinical success of taxanes is dependent on the excellent response rate in second-line treatment of relapsing/resistant cancers and on the efficacy of taxanes in the multichemotherapeutic approach of ovarian and breast cancer (Verweij et al., 1994).In earlier studies, the microtubule network appeared as the main target of paclitaxel (Schiff et al., 1979;Manfredi et al., 1982). In fact, taxanes bind to ␤-tubulin subunits, thereby disrupting normal turnover of the microtubules. The final consequence is the arrest of the cell cycle in M phase with formation of aberrant mitosis and the activation of cell death pathways (Jordan et al., 1993). Along with arrest in M phase of the cell cycle, taxanes have also been reported to induce post-translational serine phosphorylation of the Bcl-2 protein (Haldar et al., 1995). The BCL2 gene is the homologous of the nematode CED-9 gene product (Hengartner and Horvitz, 1994) and is capable of prolonging cell survival by inhibiting apoptotic cell death. Overexpression of Bcl-2 has been observed in follicular lymphoma, where this protein is deregulated by chromosomal translocation, and in a large number of human tumors, including breast, lung, and prostate cancer.Disagreement exists on the levels of Bcl-2 and resistance to taxanes. A strong suggestion for a direct role of Bcl-2 in mediating paclitax...

Optimal management of recurrent ovarian cancer (ROC) remains an area of uncertainty. An estimated 85% of patients with epithelial ovarian cancer who achieve a full remission following first-line therapy will develop recurrent disease and median survival for these patients' ranges from 12 months to 24 months. Many patients receive several lines of treatment following recurrence and, although each subsequent line of therapy is characterized by shorter disease-free intervals, decisions about the most appropriate treatment is complex. Areas covered: This review focuses on chemotherapy, surgery and emerging biologic agents that present a therapeutic option for patients with ROC. Expert commentary: Recurrent ovarian cancer is not curable. The goals of therapy should focus on palliation of cancer-related symptoms, extension of life, and maintenance of quality of life. Patients with platinum-sensitive ovarian cancer should have their recurrence treated with a platinum-based agent. For patients whose cancer progresses after platinum retreatment and for those with platinum-resistant disease, numerous other non-platinum combination and targeted therapies have been shown to be effective in palliating cancer-related symptoms and extending life.

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Summary Recent data have demonstrated that the anti-oestrogen tamoxifen (TAM) is able to facilitate apoptosis in cancer cells not expressing oestrogen receptor (ER). In an attempt to identify the biochemical pathway for this phenomenon, we investigated the role of TAM as an oxidative stress agent. In two ER-negative human cancer cell lines, namely T-leukaemic Jurkat and ovarian A2780 cancer cells, we have demonstrated that TAM is able to generate oxidative stress, thereby causing thiol depletion and activation of the transcriptional factor NF-κB. As described for other oxidative agents, TAM was able to induce either cell proliferation or apoptosis depending on the dose. When used at the lowest dose tested (0.1 µM), a slight proliferative effect of TAM was noticed in terms of cell counts and DNA synthesis rate, whereas at higher doses (10 µM) a consistent occurrence of apoptosis was detected. Importantly, the induction of apoptosis by TAM is not linked to down-regulation or functional inactivation by phosphorylation of the antiapoptotic bcl-2 protein.