Jump in the fire--heat shock proteins and their impact on ovarian cancer therapy.

Ovarian cancer (OC) is a major problem in gynecological oncology. Options for diagnosis and treatment of advanced stages and thus for patient prognosis have not been improved substantially over the past decades. Heat shock proteins (HSP) are characterized as stress-induced molecular chaperones performing cell survival factor functions. In cancer cells, various crucial and clinically important cell responses are vitally influenced and modulated by HSPs, e.g., cell growth and treatment resistance. Despite the limited knowledge on HSPs in OC progression, their roles as biomarkers, prognostic factors and their drug target properties appears promising for future clinical applications and therapeutic approaches.

Polymorphism of the IL-8 gene and the risk of ovarian cancer.

Ovarian cancer still represents a challenge in gynecological oncology. Most patients are diagnosed in an advanced tumor stage. No specific screening or prevention strategies for ovarian cancer exist as of yet. Interleukin 8 (IL-8) is a pro-inflammatory chemokine known for its angiogenetic activity, and is supposedly responsible for tumor-associated angiogenesis in several malignant tumors. The aim of the study was to investigate the susceptibility of patients with an IL-8 gene polymorphism to developing ovarian cancer. Four single nucleotide polymorphisms (SNPs) (IL-8 -251, IL-8 +781, IL-8 +1633 and IL-8 +2767) of the IL-8 gene were screened, using the PCR method in 268 patients with ovarian cancer and 426 healthy women as a control group. Significant associations were noted in patients with the IL-8 +781 (T/T) genotype (p=0.0048) with increased frequencies of ovarian cancer, while women with the IL-8 +781 (C/C) allele suffer from ovarian cancer significantly less frequently (p=0.0003). Furthermore, the IL-8 +2767 (T/T) genotype is also associated with a higher risk of ovarian cancer (p=0.0177). Our results indicate, for the first time, that IL-8 polymorphism is associated with ovarian cancer.

Adjuvant sequential chemoradiation therapy in high-risk endometrial cancer: results of a prospective, multicenter phase-II study of the NOGGO (North-Eastern German Society of Gynaecological Oncology).

PURPOSE: The management of high-risk endometrial cancer (HREC) remains controversial. We conducted a prospective multicenter phase-II clinical trial to evaluate an adjuvant chemotherapy (CT) with sequential radiotherapy (RT) in patients with HREC. METHODS: Patients with HREC from 8 institutions in Germany were enrolled. After surgery, patients received four cycles of paclitaxel 175 mg/m² (P) and carboplatin AUC5 (C) (d1, q21d) and subsequent external pelvic radiation therapy (1.8 Gy/d, d1-5) at a total dose of 45 Gy with vaginal brachytherapy (3 × 5 Gy). Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Primary endpoints were tolerability, toxicity and QoL. Progression-free survival (PFS) was defined as secondary endpoint. RESULTS: Thirty-five patients were enrolled from 2004 through 2008. Median follow-up was 24 months (range 3-24 months). All patients received 4 cycles of P and C and completed RT. Overall, grade 3/4 haematological toxicity was 25.6 %. Three cycles were delayed because of leukopenia. Grade 3/4 non-haematologic toxicities were rare (≤3 %). No overall change in QoL occurred during treatment. Two-year median PFS and OS rates were both 75.8 %. CONCLUSIONS: Adjuvant combination CT with P + C and sequential RT is well tolerated and a feasible regimen in patients with HREC. Subsequent phase-III trials are warranted.

[NF-kappaB subunit p65/RelA expression in ovarian carcinoma: prognostic impact and link to COX-2 overexpression]. / Expression der NF-kappaB-Untereinheit p65/RelA im Ovarialkarzinom: Einflubeta auf Prognose und Uberexpression der COX-2.

AIMS: NF-kappaB has been demonstrated to activate proliferative, inflammatory, and angiogenic processes in ovarian cancer cells in vitro. To add translational information on the situation in vivo, we determined the expression pattern of p65, an important subunit of the classic NF-kappaB pathway, in ovarian carcinoma tissue, and investigated in vivo and in vitro whether this pathway is implicated in the known overexpression of cyclooxygenase-2 (COX-2). METHODS: p65 siRNA, chemiluminescent NF-kappaB transcription factor assay, Taqman PCR, as well as immunoblotting were performed with OVCAR-3 ovarian cancer cells. 83 primary ovarian cancinomas as well as 17 cases of benign ovarian tissue were analyzed by p65 and COX-2 immunohistochemistry using a tissue microarray. RESULTS: DNA-binding avtivity as well as COX-2 mRNA and protein expression were strongly inducible by IL-1beta treatment in OVCAR-3 cells, while p65 siRNA inhibited IL-1beta-dependent p65 activity (p = 0.037) as well as COX-2 expression on the mRNA (p < 0.03) and on the protein level. In human tumor tissue, p65 protein expression was significantly associated with COX-2 expression (p = 0.002) as well as tumor grading (p = 0.005). Furthermore, p65 expression was a significant prognostic indicator of a reduced patient survival both in univariate (p = 0.038) and in multivariate analysis (p = 0.014). CONCLUSION: Our study indicates a deregulation of the classical NF-kappaB pathway in ovarian cancer, which results in the overexpression of the NF-kappaB target gene COX-2. Components of this pathway might constitute novel attractive targets for a specific therapy of advanced ovarian cancer.

Overexpression of the plasminogen activator inhibitor type-1 in epithelial ovarian cancer.

BACKGROUND: The plasminogen activator-plasmin cascade plays a central role in the progression of solid tumors. The type-1 plasminogen activator inhibitor (PAI-1) is the major physiological regulator of plasminogen activation. PAI-1 is suggested to play a crucial role in tumor cell invasion and metastasis of various solid tumors. The aim of this study was to analyze the clinical and prognostic roles of PAI-1 in epithelial ovarian cancer (OC). MATERIALS AND METHODS: Expression analysis was conducted by immunohistochemistry and ELISA. Tissue sections of paraffin-embedded tumor specimens and fresh-frozen tumor samples from patients with benign and malignant ovarian tumors (OT), who had undergone surgical intervention in the Department of Gynaecology and Obstetrics, Charité, Germany, from 02/01 to 06/02, were used. Correlation analysis with conventional clinical factors, univariate and multivariate analyses were performed using SPSS (SPSS Inc., V.11.0). RESULTS: Sixty-five patients (31 primary OC, 20 recurrent OC, 4 low-malignant potential OT, 6 benign OT, 4 normal ovary) were allocated to this trial. The median age was 57 years (range, 34-86) and the median follow-up was 20 months (range, 0-64). The distributions of (FIGO) tumor stage of all primary OC were: I = 16.1%, II = 3.2%, III = 45.2% and IV = 35.5%. PAI-1 was significantly overexpressed in the tumor epithelium of OC in comparison to the ovarian epithelium of benign OT and normal ovary (p < 0.001). The median PAI-1 level was 1.92-fold higher in malignant OT than in benign OT. Statistical analyses showed no significant correlation between the expression of PAI-1 and clinical parameters. The expression of PAI-1 and the PAI-1 level, according to 3 different cut-off values, showed no prognostic impact in univariate analysis. In multivariate analysis, only tumor stage (FIGO) (p = 0.003) and residual tumor (p = 0.009) remained independent prognostic factors for post-operative survival. CONCLUSION: PAI-1 is significantly overexpressed in OC.

Interleukin-1 receptor antagonist gene polymorphism is associated with increased risk of epithelial ovarian cancer.

BACKGROUND: Different studies indicate that immunological components play a key role in the development of cancer. Interleukin-1 (IL-1) is known to be critically involved in ovarian carcinogenesis and in other solid tumors. Therefore, we investigated the possible influence of the polymorphism of the IL-1 receptor antagonist (IL-1 RA) genes on the development of ovarian cancer. PATIENTS AND METHODS: In a prospective study we analyzed the polymorphism of the IL-1 RA gene in 108 women with ovarian cancer compared with 112 patients with benign gynecological diseases. Genomic DNA fragments were amplified by PCR. RESULTS: The distribution of genotype frequencies was significantly different between the study and control group with respect to allele 1/2 heterozygotes (32.4% versus 15.2%; P = 0.004). Patients who were heterozygous at allele 2 for IL-1 RA (IL-RA 1/2) had a significantly higher risk of ovarian cancer with a calculated odds ratio of 2.7 (95% confidence interval 1.4-5.2). There were no differences between IL-1 RA 1/2 polymorphism and all other alleles in tumor stage (International Federation of Gynecology and Obstetrics), histological type, grading, postoperative tumor volume, volume of ascites, recurrence status or age. CONCLUSIONS: The allele 2 polymorphism of the IL-1 RA gene seems to play a role in the occurrence of ovarian cancer and should be investigated for screening and risk evaluation.