Epidermal growth factor-responsive laryngeal squamous cancer cell line Hep2 is more sensitive than unresponsive CO-K3 one to quercetin and tamoxifen apoptotic effects

Epidermal growth factor receptor (EGFR) plays a role in laryngeal squamous cell carcinoma (SCC) development and progression. The flavonoid quercetin (Q) and the antiestrogen tamoxifen (TAM) inhibit proliferation of both primary laryngeal SCC and laryngeal carcinoma cell lines, through still uncharacterized mechanisms. We studied Q and TAM inhibitory effect on epidermal growth factor (EGF)-stimulated Hep2 and CO-K3 laryngeal squamous cell lines. Q and TAM (0.1-1.0 microM) induced more apoptosis in EGF growth-stimulated than in unstimulated Hep2 cells. EGF neither stimulated CO-K3 cell growth nor enhanced Q and TAM-induced apoptosis. Mitogen-activated protein kinase (MAPK) analysis revealed that in Hep2 cells, but not in CO-K3 cells, EGF induced a time-dependent phosphorylation of p42, p44, p38, and p46. In Hep2 cells, but not in CO-K3 cells, Q and TAM produced, upon EGF treatment, a twofold increase of p38 and p46 and an enhancement of p42 and p44 dephosphorylation, suggesting a requirement of EGFR. The enhancing effect was due to a p38 and p46 dephosphorylation delayed kinetics. An antiphosphorylated p38 antibody prevented Q and TAM inhibitory effect on p42 and p44 phosphorylations, suggesting that the EGF-dependent increase in Q and TAM apoptotic effect on Hep2 cells could depend on the p38 inhibition of the survival kinases p42 and p44. In SCC, EGFR overexpression is an early event from dysplasia to neoplasia. We conclude that the capacity of Q and TAM to increase apoptosis in EGFR-activated cells makes these compounds possible chemopreventive drugs in subjects at risk of developing laryngeal cancer.     

GLUT-1 expression in ovarian carcinoma: association with survival and response to chemotherapy

BACKGROUND: Cancer cell growth is an energy-related process supported by an increased glucose metabolism. The objective of this study was to investigate the association of GLUT-1 with response to chemotherapy and outcome in patients with ovarian carcinoma. METHODS: Histologic sections of formalin fixed, paraffin embedded specimens from 113 primary ovarian carcinomas were stained for GLUT-1 by using polyclonal GLUT-1 antibody (Dako Co., Carpinteria, CA) and the labeled streptavidin biotin procedure. Intensity of GLUT-1 staining was compared with disease free survival (DFS), chemotherapy response, and other clinicopathologic characteristics. RESULTS: GLUT-1 cytoplasmic membrane staining was observed in 89 of 104 (85.6%) malignant tumors. Poorly differentiated tumors showed a trend to overexpress the GLUT-1 protein compared with the more differentiated counterparts (27.6% vs. 8.7%; P = 0.08). Patients who experienced a complete clinical response to chemotherapy were more frequently GLUT-1 positive than GLUT-1 negative (80% vs. 51.5%; P = 0.036). In multivariate analysis of advanced stage disease, residual tumor (P = 0.0001) and high GLUT-1 expression levels (P = 0.028) were the only independent variables that maintained a significant association with response to chemotherapy (P = 0.0001; chi-square = 38.13). In the subgroup of Stage III-IV (International Federation of Gynecology and Obstetrics patients showing a complete clinical response, GLUT-1 overexpression was associated with a shorter DFS. The median time to progression was 30 months in GLUT-1 strongly positive cases (> 50% of cancer cells positive) versus 60 months in GLUT-1 weakly positive cases (< or = 50% of cancer cells positive; P = 0.024). CONCLUSIONS: GLUT-1 status is an independent prognostic factor of response to chemotherapy in advanced stage ovarian carcinoma. Moreover, patients overexpressing GLUT-1 show a significantly shorter DFS. These results suggest that the assessment of GLUT-1 status may provide clinically useful prognostic information in patients with ovarian carcinoma.     

Topotecan and gemcitabine in platinum/paclitaxel-resistant ovarian cancer

24 patients were enrolled into a phase I-II study conducted to determine the maximum tolerated doses of topotecan-gemcitabine in sequential combination and the response rate in platinum/paclitaxel resistant ovarian cancer patients. A total of 83 courses are evaluable, with a median number of three cycles administered per patients (range 2-7). Topotecan was administered on days 1-5 by 30 min i.v. infusion immediately after gemcitabine given by 30 min i.v. on days 1 and 3; cycles were repeated every 28 days. The starting doses were topotecan 0.7 mg/m(2) and gemcitabine 200 mg/m(2). Following dose levels were 08/400; 0.9/600; 0.9/800 for topotecan and gemcitabine, respectively. The maximum tolerated dose (MTD) was reached at dose level 3, the dose-limiting toxicity being represented by febrile neutropenia and thrombocytopenia. After the MTD was reached, granulocyte-colony-stimulating factor was administered in 27% of cycles. Mild and manageable was non hematological toxicity. All patients are so far evaluable for response. Among them 2 complete responses (8.3%; 95% CI: 2.6-19), 1 partial response (4.2%; 95% CI: 3.8-12), 9 no change (37.5%; 95% CI: 18-56.8) and 12 progressions (50%; 95% CI: 30-70) have been registered. Based on these data, there is no evidence that combining topotecan and gemcitabine is better than using either of the two drugs used separately.     

hMSH2 and GTBP expression in advanced stage epithelial ovarian cancer.

Defects in DNA mismatch repair have been associated with both hereditary and sporadic forms of human cancer. Most of the attention has been focused on the incidence and genetics of mismatch repair defects, while little is known about the expression levels of the mismatch repair proteins and their significance in cancer cell biology. In this study, both the expression levels of hMSH2 and GTBP proteins were investigated by Western blotting in 20 untreated epithelial ovarian cancers. For these analyses, a commercial anti-hMSH2 monoclonal antibody and a newly generated mouse monoclonal anti-GTBP antibody were used. hMSH2 and GTBP proteins were detected by Western blotting in 19 out of 20 (95%) samples analysed and were found to be directly correlated (r= +0.51, P = 0.025). hMSH2 expression was significantly higher in ovarian cancer cells originating from solid tumours than from ascites (H = 4.5, P = 0.033), whereas GTBP content did not significantly differ according to the origin of cancer cells. No statistically significant differences were found in the distribution of hMSH2 and GTBP levels according to the age of the patients, grade of differentiation, histotype and extent of surgical debulking. The amount of hMSH2 protein was demonstrated to be significantly lower in stage IV than in stage III patients (H = 7.35, P = 0.007). Moreover, significantly lower hMSH2 levels were observed in non-responding patients compared to patients who achieved complete or partial response to cisplatin-based chemotherapy (H = 4.88, P = 0.027). Conversely, GTBP levels were not distributed differently according to stage of disease and chemotherapy response. Our study suggests a possible involvement of hMSH2 in ovarian cancer cell biology and susceptibility to chemotherapy. The possible biological and/or clinical role of GTBP expression in ovarian cancer patients remains to be elucidated.     

Immunoradiometric and immunohistochemical analysis of Cathepsin D in ovarian cancer: lack of association with clinical outcome.

The aim of this study was to analyse the clinical significance of Cathepsin D (Cath D) content as determined by an immunoradiometric assay in a series of primary untreated ovarian cancers from 162 patients. In addition, immunohistochemical analysis of Cath D was also performed on a subset of 86 tumours. Cath D levels were distributed in an asymmetrical way and were skewed towards the lower values (median value 20.8 pmol mg(-1) protein, range 2.0-99.0 pmol mg(-1) protein). No correlation was found between Cath D levels and clinicopathological parameters. However, the percentage of Cath D positivity was significantly higher in oestrogen receptor-positive (57%) compared with oestrogen receptor-negative (36%) cases (P= 0.01). The percentage of Cath D-positive staining was not significantly different for both epithelial (27%) and stromal components (40%). Immunoradiometrically detected Cath D levels were not different according to Cath D stromal immunostaining (P= 0.18), while higher Cath D levels were measured in Cath D-positive than in Cath D-negative tumour epithelial cells (P = 0.027). Survival analysis was conducted on 161 primary untreated ovarian cancer patients. The 5-year overall survival rate was 57% and 55% in Cath D-positive and Cath D-negative patients respectively (P = 0.69). As far as time to progression was concerned, there was no significant difference in the survival rate of patients with either high or low Cath D content (P = 0.56). Similar results have been obtained in the subset of patients in which Cath D was analysed by immunohistochemistry. In conclusion, Cath D measurement in tumour extracts appears to have a limited usefulness in improving the prognostic characterization of ovarian cancer patients.     

The role of growth factor administration and T-cell recovery after peripheral blood progenitor cell transplantation in the treatment of solid tumors: results from a randomized comparison of G–CSF and GM–CSF

BACKGROUND: Peripheral blood progenitor cell (PBPC) transplantation (PBPCT) combined with post-PBPCT administration of myelopoietic growth factors is a valid therapeutic intervention to rapidly restore hematopoiesis after the delivery of intensive, myeloablative cancer chemotherapy. On the other hand, the best growth factor regimen to potentiate PBPC-mediated immunohematopoietic recovery has yet to be determined. STUDY DESIGN AND METHODS: In a randomized evaluation, the effects produced by post-PBPCT G-CSF and GM-CSF on myeloid/lymphoid recovery and transplant outcome in women with chemosensitive cancer were compared. Thirty-seven ovarian cancer patients and 34 breast cancer patients ranging in age from 24 to 60 years were treated with carboplatin, etoposide, and melphalan (CEM) high-dose chemotherapy and then randomly assigned to receive G-CSF (5 microg/kg subcutaneously) or GM-CSF (5 microg/kg subcutaneously) until Day 13 after PBPCT. Patients were compared in regard to hematopoietic recovery, posttransplant clinical management, and immune recovery. Finally, clinical outcome was estimated as time to progression and overall survival. RESULTS: Hematopoietic recovery and posttransplant clinical management were comparable in both the G-CSF and GM-CSF series. Conversely, significantly higher T-cell counts were observed in G-CSF-treated patients during the early and late posttransplant follow-up. Patients who received G-CSF showed a significantly longer median time to progression. A parallel analysis revealed that patients in whom a higher CD3+ count was recovered had a significantly longer overall survival and time to progression. CONCLUSION: The enhancement of post-PBPCT T-cell recovery observed in G-CSF-treated patients encourages the use of G-CSF to ameliorate immune recovery, which seems to play a role in post-PBPCT control of disease in cancer patients. GM-CSF might be administered to prolong immunosuppression after autologous PBPCT for autoimmune diseases or allogeneic PBPCT.     

Successful multimodal treatment of a breast cancer patient with a recurrence invading the chest wall

We describe successful operative management of a solitary breast cancer metastasis in the chest wall after complete response with concomitant non-pegylated liposomal doxorubicin (NPLD) and docetaxel followed by sternal rib resection with prosthetic reconstruction. We report a case of a 41-year-old woman who had a breast cancer recurrence infiltrating neighboring osteo-cartilage of the left sternal body, the cartilaginous portion of the third and fourth ipsilateral ribs and was inseparable from the rear side pectoral reaching deep into contiguity with the pericardium. After 6 cycles of chemotherapy with NPLD plus docetaxel, sternal rib resection with prosthetic reconstruction was performed. Histological examination did not show any evidence of residual tumor. At 9 months of follow-up, the patient appears free of disease. Our case demonstrates that a multimodal approach in patients with chest wall recurrence of breast cancer without distant metastasis, may be safe and effective for maintaining a good quality of life.     

A phase II study of weekly carboplatin and paclitaxel as first-line treatment of elderly patients with advanced ovarian cancer. A Multicentre Italian Trial in Ovarian cancer (MITO-5) study

BACKGROUND: Carboplatin/paclitaxel every 3 weeks is the standard for patients with ovarian cancer, but elderly patients frequently receive modified schedules or single agent chemotherapy to avoid toxicity. A phase II study was conducted to describe tolerability of a weekly schedule of both drugs in elderly patients. METHODS: Patients aged>or=70 years with stage IC-IV ovarian cancer, performance status相似文献   

Growth inhibitory effect of diheptyl diselenide on various human cancer cell lines

We tested the antiproliferative effects of Diheptyl Diselenide (DHDSe) on several different human cancer cell lines. Cells derived from human cancer (CG5), colon cancer (WIDR), laryngeal cancer (Hep-2), ovarian cancer (OV 166, OV 1225) and IM-9 lymphoblastoid cells were used. In all cell lines DHDSe inhibited cell growth in a dose dependent manner. At the highest concentration tested, an inhibition of cell proliferation ranging from 48% to 75% compared with control cells was observed. Our results show that DHDSe exerts a direct antiproliferative effect on human cancer cells in vitro and suggest that it may represent the parent compound of a new group of anticancer agents.