Nerve growth factor and its high-affinity receptor trkA participate in the control of vascular endothelial growth factor expression in epithelial ovarian cancer

OBJECTIVES: To compare the expression of nerve growth factor (NGF) and its high-affinity receptor trkA in normal ovaries and in epithelial ovarian carcinomas. Given NGF acts as an angiogenic factor through a vascular endothelial growth factor (VEGF)-mediated mechanism in several types of tissues, we examined whether NGF regulates the expression of VEGF isoforms in epithelial ovarian cancer (EOC). METHODS: The expression and localization of NGF and tyrosine kinase receptor A (trkA) in normal ovarian samples and in ovarian cancer samples were analyzed by RT-PCR and immunohistochemistry. NGF regulates the expression of three VEGF isoforms (VEGF(121), VEGF(165) and VEGF(189)); these were examined using RT-PCR in explants of EOC and ELISA in culture media. RESULTS: TrkA mRNA levels were over-expressed in ovarian cancer compared to normal ovarian samples, whereas NGF mRNA levels remained unchanged. NGF and trkA proteins were absent or found in very low levels in normal ovarian surface epithelium (OSE), whereas they were highly expressed in epithelial cells of EOC. Additionally, NGF stimulated the expression of VEGF isoforms in cancer explants. The effect was dose-dependent and inhibited by a NGF antibody and by K(252a), a trk receptor inhibitor. CONCLUSION: The abundance of NGF and trkA receptors in epithelial cells of EOC, together with the ability of NGF to increase VEGF expression strongly suggests an autocrine role of NGF in EOC. These findings suggest that blocking neurotrophin action could be a therapeutic target in treating ovarian cancer.     

抗血管生成药物联合化疗在复发性卵巢癌治疗中的研究进展

卵巢癌是妇科常见的恶性肿瘤之一,其发生、发展及肿瘤细胞的浸润转移离不开新生血管,因此通过抑制肿瘤新生血管形成,是治疗卵巢癌的有效途径之一。目前主要研究的抗血管生成药物包括血管内皮生长因子抑制剂(如贝伐单抗)、酪氨酸激酶抑制剂(如索拉菲尼、帕唑帕尼、西地尼布等)和血管生成素抑制剂(如Trebananib)。大量的Ⅱ、Ⅲ期临床试验表明抗血管靶向药物联合化疗为复发性铂敏感性或铂耐药性卵巢癌的治疗带来了曙光,明显延长了疾病无进展生存期。综述不同抗血管靶向药物联合化疗治疗复发性卵巢癌的临床研究现状及最新进展。     

卵巢上皮性癌患者术前血清血管内皮生长因子与CA125水平的相关性及其预测预后的价值

目的分析卵巢上皮性癌（卵巢癌）患者术前血清血管内皮生长因子（VEGF）与CA125水平的相关性,探讨术前血清VEGF水平在卵巢癌患者预后判断中的价值。方法采用酶联免疫吸附试验（EHSA）测定41例卵巢癌患者（研究组）库存的术前血清中VEGF的水平,采用化学发光法测定同一份血清的CA125水平;以同期20例盆腔检查正常的妇女作为对照组。结合随诊资料,分析卵巢癌患者术前血清VEGF水平与CA125水平的相关性,并分析术前血清VEGF水平与患者复发和生存时间的关系。结果（1）研究组术前血清VEGF和CA125水平均明显高于对照组（VEGF中位数分别为415和165ng／L,CA125分别为611和16kU／L）,差异均有统计学意义（P〈0．01）;（2）Spearman等级相关分析显示,卵巢癌患者术前血清VEGF水平与血清CA125水平间无明显相关性（P=0．989）;（3）卵巢癌患者术前血清VEGF水平与其复发相关,复发者术前VEGF水平明显高于无复发者（中位数分别为490和315ng／L,P=0．035）;（4）单因素Kaplan-Meier法分析显示,卵巢癌患者术前血清VEGF水平与其生存时间呈负相关,高血清VEGF水平者的生存时间明显短于低血清VEGF水平者（中位数生存时间分别为18个月和〉35个月,P=0．010）;（5）多因素Cox回归模型分析显示,卵巢癌患者术前血清VEGF水平是与其生存时间有关的独立预后因素（P=0．042）。结论卵巢癌患者术前血清VEGF水平与CA125水平无明显相关性,VEGF水平变化是影响患者预后的独立因素。     

Tyrosine kinase A receptor (trkA): a potential marker in epithelial ovarian cancer

Objectives

To evaluate the role of trkA receptor as a potential tumor marker in serous epithelial ovarian cancer and its relationship with the angiogenic factors expression as vascular endothelial growth factor (VEGF) and nerve growth factor (NGF). Additionally, to examine whether NGF and VEGF secreted by epithelial ovarian cancer (EOC) explants and from epithelial ovarian cancer cell line (A2780) are involved in the process of angiogenesis, such as cellular proliferation, migration and differentiation of the human endothelial cell line (EA.hy926).

Methods

The mRNA levels of VEGF, NGF and trkA receptors were measured using PCR in 60 ovarian samples. Cellular localization and semi-quantitative estimation of VEGF, NGF, total trkA and p-trkA was performed using IHC in epithelial cells. NGF, total trkA and p-trkA protein were also evaluated in endothelial cells from the same tissues. Human endothelial cell line EA.hy926 was cultured with conditioned media obtained from both EOC explants and from the A2780 cell line, with or without NGF stimulus.

Results

Significantly higher levels of NGF, total trkA and p-trkA protein expressions were observed in epithelial and endothelial cells in poorly differentiated EOC versus normal ovary. Interestingly, the p-trkA receptor expression level showed the most significant difference and its presence was only found in borderline tumor and EOC samples indicating the importance of trkA receptor in EOC as a potential tumor marker.A significant increase in proliferation, migration and differentiation of EA.hy926 cells was observed with NGF, and this effect was significantly reverted when NGF was immuno-blocked and when a trkA inhibitor was used, showing that NGF is an important angiogenic factor in EOC by activating its trkA receptor.

Conclusion

These results indicate that p-trkA may be considered as a new potential tumor marker in EOC, and that NGF may also act as a direct angiogenic factor in EOC.     

Overview of anti-angiogenic agents in development for ovarian cancer

Objective

To review the rationale for targeting the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) pathways for anti-angiogenic therapy in patients with ovarian cancer and to summarize the currently available data with agents that block these pathways.

Methods

Relevant papers and studies were identified by searches conducted on Medline using the terms angiogenesis, ovarian cancer, VEGF, PDGF, FGF, receptor, kinase, and inhibitor alone or in combination as well as by searches by drug name and by review of abstracts presented at recent oncology meetings.

Results

The VEGF pathway is considered to be the key driver of angiogenesis, but the PDGF and FGF pathways also play important roles and may contribute to resistance to VEGF-specific blockade. Each pathway may also promote tumorigenesis; tumor cell overexpression of these growth factors and their receptors have been detected in ovarian tumor specimens, suggesting that autocrine loops may lead to tumor growth and progression. Selective inhibitors of the VEGF pathway (e.g., bevacizumab and VEGF Trap) as well as VEGF/PDGF pathway inhibitors (e.g., sorafenib and sunitinib) and VEGF/PDGF/FGF pathway inhibitors (e.g., cediranib, pazopanib, and BIBF 1120) have shown single-agent activity in women with ovarian cancer in phase II trials. Response rates of up to 21% have been reported with several agents in patients with recurrent ovarian cancer. Phase III trials with many anti-angiogenic agents in the treatment of ovarian cancer are currently ongoing.

Conclusions

Anti-angiogenic agents may provide an improvement in the treatment of patients with recurrent ovarian cancer and may be useful when incorporated into first-line platinum/taxane therapy. It remains to be determined whether multitargeted agents will offer greater clinical benefit than specific VEGF pathway inhibitors.     

Estrogens and epithelial ovarian cancer

OBJECTIVE: Molecular mechanisms involved in ovarian carcinogenesis are still unclear, but there is growing evidence that estrogens promote tumor progression in an epithelial ovarian cancer (EOC) subgroup. METHODS: We reviewed current knowledge on the effects of estrogens in ovarian carcinogenesis and new potential research focuses concerning hormonal therapy of EOC. RESULTS: Experimentally, estrogen stimulates the growth of ovarian tumor cell lines expressing estrogen receptors (ER). We and other authors have demonstrated differential expression of ERalpha or beta during ovarian carcinogenesis, with overexpression of ERalpha as compared to ERbeta in cancer. This differential expression in ER suggests that estrogen-induced proteins may act as ovarian tumor-promoting agents. Among these proteins, c-myc, fibulin-1, cathepsin-D, or several kallikreins may play a role, since high expression levels have been found in EOC. Consistently, recent prospective epidemiological studies have indicated that estrogen replacement therapy in postmenopausal women may increase ovarian cancer incidence and mortality. CONCLUSION: Questions on the estrogen-sensitivity and potential benefits of new hormone therapies in an EOC subgroup should be readdressed in the light of recent experimental and clinical data.     

Peritoneal VEGF burden as a predictor of cytoreductive surgery outcome in women with epithelial ovarian cancer

Objective

To determine whether peripheral plasma concentration, peritoneal fluid concentration, and/or peritoneal vascular endothelial growth factor (VEGF) burden can predict the possibility of optimal cytoreduction in women with epithelial ovarian carcinoma (EOC); and if so, to determine cutoff values below which optimal cytoreduction is likely to occur.

Methods

We measured plasma VEGF concentration, peritoneal VEGF concentration, and VEGF burden in 46 women undergoing cytoreductive surgery. Univariate analysis, bivariate analysis, correlation tests, and stepwise regression were performed with cytoreduction as the outcome.

Results

The VEGF burden best predicted the outcome. The area under the curve was 0.84 and the log-transformed cutoff value was 15.52 log pg. Overall, the chance of optimal cytoreduction was 11 times greater when the VEGF burden was less than 15.52 log pg. For women with advanced disease, the chance was 6 times greater below this value.

Conclusion

The VEGF burden may quantify tumor activity, and it could be used when selecting patients likely to benefit from induction chemotherapy before undergoing cytoreductive surgery.     

Gene expression and prognostic significance in ovarian cancer

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancies in the United States. Most patients with EOC will respond to surgical debulking followed by platinum and paclitaxel based chemotherapy. Unfortunately, the relapse rate within 2 years is more than 70%. The molecular events leading to the development of EOC and the molecular factors that may predict response to treatment are not well established. Such knowledge would not only improve the understanding of the biology of EOC, but may help in the identification of new tumor markers and the design of molecular therapies for EOC. A literature review was conducted using MEDLINE to delineate studies that investigated gene expression in ovarian cancer correlated with outcome. A review is presented of the expression and role of the BRCA1 and 2 genes, p53, amplification of Her2/neu, PIK3CA, AKT2, K-ras, c-myc, BRCA1, p53, p16, and p27 in ovarian cancer. Additionally, a review of the use of microarray technology is presented and its use in determining expression patterns in ovarian cancer. The accumulation of data derived from new technologies, as well as that obtained from well-established methods, has provided new insights into gene expression profiles in EOC. The utilization of novel technologies that allow high throughput analysis of thousands of genes may lead to the development of new biomarkers or novel therapies that are urgently needed in this deadly disease.     

卵巢上皮性癌组织中肿瘤浸润性树突状细胞的状态及其与血管内皮生长因子表达的相关性

目的研究卵巢上皮性癌组织中肿瘤浸润性树突状细胞(TIDC)的状态及其与血管内皮生长因子(VEGF)表达的关系。方法采用免疫组化链霉菌抗生物素蛋白-过氧化酶连接法和Picture二步法,检测57例卵巢上皮性癌(恶性组)、30例良性卵巢上皮性肿瘤(良性组)及16例正常卵巢(正常组)组织中S-100蛋白、CD83标记的TIDC状态及其VEGF的表达。结果(1)恶性组TIDC光镜下形态基本可分成两种,其分布有异质性。恶性组S-100^ TIDC中位数为4．3个／400高倍视野(HPF),分别与良性组(中位数为1．8个／HPF)和正常组(中位数为2．0个／HPF)比较,差异有显著性(P值分别为0．000和0．015)。恶性组中,早期(Ⅰ～Ⅱ期)肿瘤组织中S-100^ TIDC数量明显多于晚期(Ⅲ～Ⅳ期,中位数分别为6．0个和3．8个／HPF,P=0．026)。恶性组中,CD83^ TIDC浸润肿瘤间质者极少,中位数为0个／HPF。(2)恶性组细胞中VEGF高表达(5．0分),分别与良性组(3．8分)和正常组(2,4分)比较,差异均有极显著性(P=0.000)。(3)恶性组中,S-100^ TIDC数量与VEGF表达呈明显负相关(P=0．001)。结论(1)卵巢上皮性癌细胞可刺激TIDC的募集,但同时受VEGF的抑制。(2)卵巢上皮性癌中TIDC成熟严重受抑。     

Co-expression of angiogenic markers and associations with prognosis in advanced epithelial ovarian cancer: a Gynecologic Oncology Group study

OBJECTIVES: The aim of this study was to explore the co-expression and prognostic relevance of thrombospondin-1 (THBS-1), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and VEGF receptor 1 (VEGFR-1) in epithelial ovarian cancer (EOC). METHODS: Frozen tumor specimens with defined p53 status were obtained from 67 patients with previously untreated advanced-stage EOC who participated in a Gynecologic Oncology Group specimen-banking protocol and a phase III treatment protocol. Relative expression of the angiogenic markers was quantified by immunoblot analysis and categorized at the median angiogenic marker/actin ratio. p-values are provided as an indication of confidence in the results and to prioritize further testing. RESULTS: An association was observed between categorized VEGF and p53 overexpression (p=0.022), and between VEGFR-1 and race (p=0.027) or histologic subtype (p=0.007). Unadjusted Cox regression analyses indicated that high compared with low THBS-1, but not VEGF or VEGFR-1, was associated with an increased risk of disease progression (hazard ratio [HR]=2.19; 95% confidence interval [CI]=1.29-3.71; p=0.004) and death (HR=1.93; 95% CI=1.12-3.32; p=0.018) whereas bFGF was associated with a reduced risk of disease progression (HR=0.60; 95% CI=0.36-0.99; p=0.046) and death (HR=0.54; 95% CI=0.32-0.93; p=0.026). After adjusting for prognostic factors including clinical characteristics and p53 overexpression, THBS-1 but not bFGF, VEGF or VEGFR-1 was associated with progression-free and overall survival. CONCLUSIONS: These data suggest that high THBS-1 is an independent predictor of worse progression-free and overall survival in women with advanced-stage EOC. A larger prospective study is warranted for validation of these findings.     

The special role of ultrasound for screening,staging and surveillance of malignant ovarian tumors: distinction from other methods of diagnostic imaging

Ovarian cancer is the most aggressive gynecologic malignancy, with a 5-year survival rate ranging around 40 %. A crucial factor influencing the prognosis is early detection of a suspicious mass and referral to a gynecologic oncology center for further diagnosis, staging and debulking surgery. Here, we present the different imaging methods ultrasound (US), magnetic resonance imaging, computer tomography (CT) and 18F-fluoro-deoxyglucose positron emission tomography (PET)/CT that are used for the characterization, diagnosis, staging and surveillance of ovarian cancer. In this review, we focus on US and discuss in detail the advantages and the limitations, as well as the appropriate indications for each of the individual imaging techniques.     

Survival of women diagnosed with malignant, mixed mullerian tumors of the ovary (OMMMT)

OBJECTIVE: To analyze the survival of women with malignant, mixed mullerian tumors of the ovary (OMMMT) compared to women with epithelial ovarian cancer (EOC). METHODS: Data from the Surveillance, Epidemiology and End Results (SEER) Program on 14025 women diagnosed with primary invasive ovarian cancer between 1988 and 1997 were used for this analysis (382 had OMMMT). Differences in distribution of prognostic variables by histological type were compared using a chi-square test. Multivariable survival models were fit using Cox proportional hazards regression analysis to compare risk of death for OMMMT compared to EOC. Analyses were also performed using cases with OMMMT compared to high-grade EOC only. RESULTS: Women with OMMMT were older at diagnosis and were more likely to have primary surgery compared to women with EOC. The majority of women in either histological group had advanced-stage disease at diagnosis. Women with OMMMT had a significant increased risk of death from any cause whether being compared to all women with EOC (HR = 1.69, 95% CI = 1.50,1.90) or to women with high-grade EOC only (HR = 1.58, 95% CI = 1.40,1.79). Women with advanced-stage OMMMT were at a 60% increased risk of death compared to women with advanced-stage, high-grade EOC, after adjustment for other variables of interest (adjusted HR = 1.60, 95% CI = 1.40,1.84). There was no difference in risk of death for these two groups of women with early-stage disease. CONCLUSION: OMMMT is a rare malignancy compared to EOC and had a significantly worse prognosis compared to EOC.     

Costs of treatment and outcomes associated with second-line therapy and greater for relapsed ovarian cancer

OBJECTIVES: Most women with epithelial ovarian cancer (EOC) will develop disease progression or recurrence with resistance to platinum therapy. We report overall costs and treatment outcomes associated with topotecan or gemcitabine administration in platinum- and paclitaxel-resistant EOC patients. METHODS: Patients who received topotecan (n = 51) or gemcitabine (n = 56) as second-line therapy or greater for platinum- and paclitaxel-resistant EOC were retrospectively identified. Per patient costs for each regimen were determined and compared. RESULTS: The mean total direct cost per cycle per patient of gemcitabine was $2732.28, with a median total direct cost per cycle of $1382.73. The mean total direct cost per cycle per patient of topotecan was $7832.07, with a median total direct cost per cycle of $4219.02. By comparison of the means, total direct cost per cycle per patient was significantly more expensive for topotecan (P = 0.001). Fifty-six patients received a total of 415 cycles of gemcitabine, median 5 cycles per patient (range, 1-59). Thirteen (23.2%; 95% CI, 11.9-34.5%) of 56 patients displayed clinical benefit, with median PFS of 1.8 months and median overall survival (OS) of 8.2 months. Fifty-one patients received topotecan, for a total of 264 cycles, median 4 cycles per patient (range, 1-42). Twenty-eight (56%; 95% CI, 42.0-70.0%) of 50 patients achieved clinical benefit, with PFS and OS medians of 3.6 and 16.8 months, respectively. CONCLUSIONS: Gemcitabine and topotecan are active agents in heavily pretreated, platinum- and paclitaxel-resistant EOC patients. Topotecan was more costly to deliver. Although a larger percentage of patients received clinical benefit with topotecan use, this likely reflects physician selection for use of topotecan earlier in the course of disease.     

New modalities in detection of recurrent ovarian cancer

PURPOSE OF REVIEW: The vast majority of women diagnosed with ovarian cancer and subsequently treated with debulking surgery and adjuvant chemotherapy will ultimately relapse. As is the case with primary diagnosis, detection of recurrent ovarian cancer is limited due to lack of sensitivity and specificity. Specific guidelines for surveillance of this disease are controversial, partly because evidence to support such guidelines is scant and partly because the management of identified recurrences continues to be of minimal success. Subsequently, whether early detection actually can make a difference is not necessarily made clear in the literature. However, there are advances in radiological and molecular biology technology that may offer new possibilities in cancer surveillance. This review will outline the latest evidence to address their use in ovarian cancer. RECENT FINDINGS: Most of the recent literature involving detection of recurrent ovarian cancer addresses the use of positron emission tomography. There are also some data addressing the use of magnetic resonance imaging and computed tomography in this arena. Data pertaining to other modalities such as biological markers are limited. Ca-125 is the accepted assay used for ovarian cancer surveillance, but other options are introduced that may hold promise for the future. SUMMARY: A review of the recent literature concerning ovarian cancer surveillance techniques offers few new definitive avenues. While radiological technology and discoveries in detection assays are noteworthy, their potential impact on surveillance appears to be minimal at this time. Low sensitivity and specificity, along with expense, continue to be limiting factors.     

Serum vascular endothelial growth factor in epithelial ovarian neoplasms: correlation with patient survival.

OBJECTIVE: To investigate the relationship between serum vascular endothelial growth factor (VEGF) and clinicopathological factors and to determine whether VEGF is an independent prognostic factor of ovarian cancer patients. METHODS: Fifty-six women with International Federation of Gynecology and Obstetrics stages I to IV epithelial ovarian cancer undergoing surgery were enrolled. Clinical and pathologic items were recorded. Pretreatment VEGF serum samples of the 56 women were measured by an enzyme-linked immunosorbent assay. The results were correlated to clinical data. The histopathologic items and serum VEGF influencing clinical outcome were evaluated comparatively. RESULTS: The median VEGF serum level in ovarian cancer patients was 458.7 pg/mL. The 75% quatile was defined as the cutoff level. Elevated vascular endothelial growth factor serum levels before therapy correlated significantly with poorer disease-free survival (DFS) (log rank test, P = 0.001) and overall survival (OS) (log rank test, P < 0.001) on all of the 56 patients. Besides, significantly reduced DFS (log rank test, P = 0.001) and OR (log rank test, P = 0.006) were also observed on 40 patients with residual disease less than 2 cm. High histologic grade (RR = 2.24 for DFS; RR = 2.38 for OS) and elevated serum VEGF levels (RR = 3.34 for DFS; RR = 4.47 for OS) are the prognostic factors on the 56 ovarian carcinoma patients by multivariate analyses. The advanced surgical staging (RR = 3.28 for DFS; RR = 3.84 for OS), high histologic grade (RR = 2.55 for DFS; RR = 2.44 for OS), and elevated serum VEGF levels (RR = 5.62 for DFS; RR = 5.37 for OS) are the prognostic factors for 40 ovarian carcinoma patients with residual disease less than 2 cm by multivariate analyses. CONCLUSIONS: Pretreatment VEGF serum levels might be regarded as an additional factor in predicting the outcome of ovarian cancer patients. It also could provide prognostic information in clinically relevant subsets, such as those of residual disease less than 2 cm. Anti-angiogenic therapy, if is available, might be a new treatment modality for ovarian cancer patients with poor prognosis predicted by VEGF and other clinical parameters.     

Characterization of surgically transposed ovaries in integrated PET/CT scan in patients with cervical cancer

BACKGROUND: The purpose of this study was to determine the ovarian findings on integrated positron emission tomography/computed tomography scans during follow-up in cervical cancer patients with ovarian transposition. METHOD: We retrospectively reviewed the clinical data and integrated 18F-fluorodeoxyglucose positron emission tomography/computed tomography of women with ovarian transposition during radical hysterectomy for cervical cancer between December 2003 and March 2006. RESULTS: Eighty-four premenopausal women had ovarian transposition performed during the study period. Twelve positron emission tomography/computed tomography scans from 11 patients were registered for the current study and three women were diagnosed with metastasis: two in lung and one in pelvis. Two patients complained of menopausal symptoms during follow-up, and the hormonal tests were consistent with it. In the current study, an integrated positron emission tomography/computed tomography scan detected one patient with right lower abdominal mass with increased 18F-fluorodeoxyglucose uptake, which was identified as a transposed right ovary. Clinical information of ovarian transposition was helpful in interpretation of the lesion. In the patient, transposed ovary was associated with increased fluorodeoxyglucose uptake, with standard uptake values ranging from 3.7 to 5.5. Other positron emission tomography/computed tomography scans did not show abnormal uptake of 18F-fluorodeoxyglucose. CONCLUSIONS: Transposed ovary in premenopausal women may appear on integrated positron emission tomography/computed tomography scan as a mass with increased 18F-fluorodeoxyglucose uptake, which may be associated with preserved ovarian function. Clinical information regarding transposition should be noted in order not to interpret these as recurrent or metastatic lesions.     

Impact of new non-cytotoxics in the treatment of ovarian cancer

Abstract. Eisenhauer E, Dancey J. Impact of new non-cytotoxics in the treatment of ovarian cancer.
Over the last decade, a number of new cytotoxic chemotherapy agents have shown evidence of antitumor activity in patients with ovarian carcinoma. These agents are currently being evaluated in large multinational randomized trials to determine whether their addition either concurrently or sequentially to standard paclitaxel and carboplatin regimens will result in improved survival. Whether these new combinations will provide additional benefit may be uncertain; however, it is certain that additional toxicity will limit the continued evaluation of the strategy of adding cytotoxics together. New approaches to improve the systemic therapy of ovarian cancer need to be explored. The next decade will see many trials of non-cytotoxics having a wide range of subcellular and extracellular targets. Many of these targets are abnormally expressed in a variety of solid tumors; thus, it is expected that many of these agents will be appropriate to evaluate in patients with ovarian carcinoma. Based on promising data from preclinical and early clinical studies as well as the presumed applicability of these targets to ovarian carcinoma, the inhibitors of growth factor receptors such as epidermal growth factor receptor and inhibitors of angiogenesis are of particular interest. Despite the interest of the investigators, the rapid evaluation of these target-specific non-cytotoxics is limited by the lack of accurate information on the expression of target in ovarian tumors and the relevance of target expression and its modulation to this tumor type. Early clinical trials are being designed to address these concerns; however, the clinical impact of non-cytotoxic agents in epithelial ovarian carcinoma patients must await the completion of randomized evaluations in combination with standard chemotherapeutic regimens.     

微小RNA在卵巢上皮性肿瘤中诊断及治疗的研究进展

卵巢上皮性肿瘤（EOC）是死亡率最高的妇科恶性肿瘤,也是导致妇女癌症死亡的第五大病因。为了延长晚期EOC患者的生存期,克服化疗耐药是治疗的重要措施。微小RNA（miRNAs）能调控与耐药相关的多种基因,是化疗耐药的研究热点。多种miRNAs在EOC中异常表达,联合检测血浆中miR-205和let-7f可以提高EOCⅠ期的诊断准确性;miR-484,miR-642,miR-217和miR-181a可预测耐药的发生,miR-509-3p,miR-145,miR-181a,miR-34可抑制铂类耐药细胞株的增殖;miR-34c是唯一的可作为无复发的独立预测标志物,miR-519与高级别浆液性癌（HGSOC）的低生存率有关。总结和讨论miRNAs在EOC诊断及治疗上的应用。