卵巢癌铂类药物耐药分子机制研究进展

上皮性卵巢癌是妇科常见的恶性肿瘤,晚期患者5年生存率不足30%。化疗结合肿瘤细胞减灭术是治疗卵巢癌的重要方式。化疗耐药是导致卵巢癌患者预后差的主要原因。卵巢癌化疗耐药是由多基因、多因素共同导致的结果。克服铂类耐药,寻找导致化疗耐药的分子机制是提高患者生存率亟待解决的问题。本文就卵巢癌化疗靶前、靶标、靶后及靶外耐药的分子机制研究进展作一综述。     

卵巢癌细胞耐药机制及其对策研究进展

克服化疗耐药是提高晚期卵巢癌远期疗效的关键.卵巢癌细胞耐药的可能分子机制有:P糖蛋白(P-gp)、谷胱甘肽S转移酶(GST)使细胞内有效药物浓度降低,β微管蛋白亚型改变及基因突变,MLH1、BRCA1等DNA损伤修复功能异常,p53失活、BCL2过表达及其他细胞凋亡信号途径异常.已开展试图克服耐药的临床试验包括:铂类类似物ZD-0473和BBR-3464,紫杉醇类似物埃坡霉素;ET-743和喹唑啉等新的细胞毒药物;PSC-83和地西他滨等耐药逆转剂;Ad-p53、ZD-1839及蛋白酶体抑制剂等.     

卵巢癌细胞耐药机制及其对策研究进展

克服化疗耐药是提高晚期卵巢癌远期疗效的关键。卵巢癌细胞耐药的可能分子机制有：P糖蛋白（P-gp）、谷胱甘肽S转移酶（GST）使细胞内有效药物浓度降低，β微管蛋白亚型改变及基因突变，MLH1、BRCA1等DNA损伤修复功能异常，p53失活、BCL2过表达及其他细胞凋亡信号途径异常。已开展试图克服耐药的临床试验包括：铂类类似物ZD-0473和BBR-3464，紫杉醇类似物埃坡霉素；ET-743和喹唑啉等新的细胞毒药物；PSC-83和地西他滨等耐药逆转剂；Ad-p53、ZD-1839及蛋白酶体抑制剂等。     

交叉反应物质197在卵巢癌耐药中的研究进展

卵巢癌起病隐匿,多数晚期卵巢癌患者会出现复发及对常规化疗耐药现象,严重威胁女性的生命健康。因此,化疗耐药已成为治愈卵巢癌的关键制约因素。肝素结合表皮生长因子(HB-EGF)作为表皮生长因子家族成员,已经被证实是一种有前景的卵巢癌化疗靶点。交叉反应物质197(cross-reacting material 197,CRM197)是一种无毒的白喉毒素变异体,特异性结合并抑制HB-EGF,从而抑制卵巢癌化疗耐药。研究表明,CRM197在多种肿瘤治疗及卵巢癌耐药方面均有显著作用,但是关于CRM197参与卵巢癌耐药的具体机制仍有待进一步研究。本文系统性描述CRM197的特性,并讨论CRM197在肿瘤治疗中的应用及CRM197与顺铂、紫杉醇联合应用在卵巢癌耐药中的研究进展。     

拓扑特肯治疗晚期上皮性卵巢癌的疗效和毒性

自1989年,紫杉醇即为公认的晚期卵巢癌的二线化疗药物。最近妇科肿瘤组(GOG)对Ⅲ、Ⅳ期减瘤术后的卵巢癌病例随机分组,比较顺铂+环磷酰胺及顺铂+紫杉醇联合化疗。在216例可评估病例中,有效率(RR)后者高于前者,病情稳定期及生存期后者均长于前者。因此紫杉醇、顺铂联合化疗渐成为治疗晚期卵巢癌的一线治疗方案。尽管如此,经这种联合方案治疗者,在随访至48个月时已有53%死亡。为此应积极寻找无交叉耐药的二线药物。拓扑特肯(Topotecan)是极有潜力的药物,它是喜树碱半合成衍生物,与顺铂、紫杉醇无交叉耐药,并具备新的作用机制,它通过与细胞核内的DNA——拓扑异构体酶Ⅰ复合物的结合,阻碍DNA双链裂解及复制,最终导致细胞死亡。     

卵巢癌化疗诱导周围神经病变的作用机制与临床研究进展

紫杉醇联合铂类化疗是晚期卵巢癌的一线标准化疗方案。化疗对提高临床有效率,延长患者无进展生存期及总体生存率有积极的意义,但可诱导周围神经病变(PN)发生,导致化疗延迟或停止,从而影响化疗药物的疗效。化疗诱导的周围神经病变(CIPN)症状持续存在影响卵巢癌患者的生存质量,因此了解化疗诱导CIPN的作用机制及危险因素尤为重要。本文就紫杉醇及铂类药物导致CIPN的发病机制及卵巢癌CIPN的发病率、危险因素、不良影响及防治研究进展进行综述。     

腹腔温热化疗在晚期卵巢癌中的临床应用

多数卵巢癌患者确诊时已属临床晚期,虽然经过理想的肿瘤细胞减灭术及以顺铂为基础的联合化疗,仍有部分患者出现复发、耐药。因此,晚期卵巢癌仍是当前女性生殖系统恶性肿瘤中引起死亡的主要原因。腹腔温热化疗（IPHC）是一项很有希望的治疗措施,为提高晚期、复发和耐药患者的生活质量,改善患者预后提供了一种方法。对IPHC的药物代谢动力学及其在晚期及复发与耐药卵巢癌中的可行性、有效性、安全性进行综述。     

卵巢癌靶向药物治疗的研究进展

卵巢癌是妇科常见的恶性肿瘤之一。卵巢癌早期诊断困难,一旦确诊卵巢癌,75%的患者已是中晚期。目前国际上比较公认的卵巢癌化疗为紫杉醇联合铂类,但原发耐药和在治疗中产生的多药耐药导致晚期卵巢癌患者5年生存率仅为20%～30%。靶向药物治疗对卵巢癌个体化治疗提供可能,给卵巢癌患者提供了更大的治疗空间。     

腹腔温热化疗在晚期卵巢癌中的临床应用

多数卵巢癌患者确诊时已属临床晚期,虽然经过理想的肿瘤细胞减灭术及以顺铂为基础的联合化疗,仍有部分患者出现复发、耐药.因此,晚期卵巢癌仍是当前女性生殖系统恶性肿瘤中引起死亡的主要原因.腹腔温热化疗(IPHC)是一项很有希望的治疗措施,为提高晚期、复发和耐药患者的生活质量,改善患者预后提供了一种方法.对IPHC的药物代谢动力学及其在晚期及复发与耐药卵巢癌中的可行性、有效性、安全性进行综述.     

长链非编码RNA在卵巢癌化疗耐药过程中的调控作用

卵巢癌是女性生殖系统三大恶性肿瘤之一,也是导致女性妇科恶性肿瘤相关死亡的主要原因之一。虽然包括手术和化疗在内的治疗方案取得一定疗效,但卵巢癌患者5年总体生存率仍不令人满意。一是由于多数卵巢癌早期无明显症状,诊断时已是晚期;二是归因于卵巢癌复发率及化疗耐药性的提升。降低卵巢癌患者死亡率的关键是早期诊断和治疗以及对化疗耐药的有效预测。研究与卵巢癌相关的基因和蛋白的表达模式对促进诊断相关生物标志物的产生至关重要,并为药物设计、治疗和耐药性提供新的研究靶点。近年来,长链非编码RNA(long non-coding RNA,lncRNA)的作用日益凸显。已在包括癌症在内的许多疾病中发现lncRNA的异常表达,但其在疾病病因学和生物学的确切作用尚不清楚。随着对卵巢癌发病机制的深入研究,已有报道lncRNA的异常表达与铂类/紫杉醇耐药有关。综述近年来lncRNA在卵巢癌化疗耐药方面的研究进展。     

Repeated chemosensitivity testing in patients with epithelial ovarian carcinoma

Epithelial ovarian carcinoma (EOC) is a highly chemosensitive tumor, but most patients with advanced EOC initially responding to first-line chemotherapy will eventually relapse. Chemosensitivity testing may offer an opportunity for the optimal selection of chemotherapeutic agents for individual patients. In the present retrospective analysis we have examined the changes in chemosensitivity profiles during the course of the disease. Chemosensitivity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test. Two or more samples at least 14 days apart were obtained from 34 patients with ovarian cancer. Chemoresistance increased significantly at the second measurement only for paclitaxel and carboplatin, the most frequently used cytotoxic drugs. No significant difference compared to baseline was observed at subsequent measurements for any other cytotoxic agent studied, although a non-significant trend for increased chemoresistance was observed. In conclusion, in the present cohort only paclitaxel and carboplatin chemosensitivity changed significantly, although to a limited extent, during the course of the disease. In contrast to a limited increase of paclitaxel and carboplatin chemoresistance, no significant changes were observed for other cytotoxic agents examined. The present data indicate that chemoresistance increases, to a modest extent, against the drug most frequently used, but remains relatively stable during the course of disease, especially for agents that are not used in the therapeutic regimen.     

Molecular/genetic therapies in ovarian cancer: future opportunities and challenges

Ovarian cancer is the most lethal gynecologic cancer. Traditional therapies have included surgical management and cytotoxic chemotherapy; however, treatment paradigms continue to shift from empiric cytotoxic chemotherapy to more individualized treatment. Recent research efforts have focused on determining and targeting the molecular biological mechanisms of ovarian cancer in an attempt to develop novel therapeutic modalities with the ultimate goal of improving outcome while limiting toxicity. This chapter reviews progress in the development of novel therapies directed at major pathways implicated in ovarian tumorigenesis including angiogenesis, PARP inhibition, signal transduction, antifolate therapies, death receptor-mediated therapies, histone deacetylase inhibition, immunotherapeutics, and oncolytics.     

Diagnostik und Therapie des Ovarialkarzinoms

Ovarian cancer carries the worst prognosis among all gynecological cancers, mainly due to resistance to chemotherapy and the lack of effective screening methods for early stage detection of the disease. Early detection is necessary to reduce the mortality of ovarian cancer. Imaging techniques including transvaginal ultrasound evaluation have not reached this aim and, therefore, novel biomarkers in addition to the well established CA-125 may serve as early detection markers. Over the past years molecular screening methods and challenging biostatistical algorithms have been developed which have identified many novel biomarkers. Thus it is becoming possible to analyze the relevance of combinations of markers for identification of early stages and therapy resistance. Furthermore overcoming chemoresistance of ovarian cancer seems to be achievable by the development of targeted therapies based on the identification of certain drugs for specific targets. With molecular methods disseminated tumor cells with the potential to metastasize can also be detected in blood and bone marrow. This review gives a summary of molecular screening methods which have led to identification of novel molecular markers or are already the basis of clinical diagnostics and therapy of ovarian cancer.     

Breast cancer treatment and ovarian function

The aim of this study was to provide an update on ovarian function and the mechanisms of gonadal damage after exposure to chemotherapy in breast cancer survivors. The alkylating agents are toxic to both primordial and growing follicles. However, anti-metabolite drugs are more likely to destroy preantral and antral follicles. Younger patients are more likely to have a higher ovarian reserve, and therefore, more likely to retain some residual ovarian function after exposure to gonadotoxic regimens. However, there can be significant variability in ovarian reserve among patients of the same age. Furthermore, patients with critically diminished ovarian reserve may continue to menstruate regularly. Therefore age and menstrual status are not reliable indicators of good ovarian reserve and might give a false sense of security and result in an adverse outcome if the patient is consulted without considering more reliable quantitative markers of ovarian reserve (antral follicle count and anti-Müllerian hormone) and fertility preservation is not pursued. In contrast to well-documented ovarian toxicity of older chemotherapy regimens, data for newer taxane-containing protocols have only accumulated in the last decade and data are still very limited regarding the impact of targeted therapies on ovarian function.     

Diagnosis and management of epithelial ovarian cancer

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States. Although there has been a statistically significant improvement in 5-year survival, in 2005 more than 16,000 women were expected to die of this disease. To date, there is no reliable method to screen for ovarian cancer; therefore, the majority of cases are diagnosed with advanced disease. For early ovarian cancer, appropriate surgical staging and adjuvant chemotherapy for selected cases will result in survival rates of 90-95%. For advanced ovarian cancer, survival depends primarily on the success of the initial surgical procedure. Patients with complete cytoreduction to microscopic disease are often cured with adjuvant chemotherapy. There is growing evidence that these patients with microscopic residual disease are excellent candidates for intraperitoneal chemotherapy, and this mode of chemotherapy delivery may be their best opportunity for cure. Patients with optimal cytoreduction also may benefit from intraperitoneal chemotherapy, but cure is less likely. For patients with suboptimal cytoreduction, intravenous chemotherapy with a combination of carboplatin and paclitaxel is the current standard therapy. Most of these patients will experience recurrence of the cancer, with small chance of cure. Salvage chemotherapy is important in ovarian cancer because many patients respond to several salvage regimens. Because of the high response rate of ovarian cancer, even after relapse, it is probably better to consider 10-year survival as the ideal end point. Finally, new biologic agents, in combination with traditional surgery and chemotherapy, may result in further improvement in survival for patients with ovarian cancer.     

Medikamentöse Therapie des Ovarialkarzinomrezidivs

The majority of patients with advanced ovarian cancer relapses after primary operation and chemotherapy. The selection of agents for second line chemotherapy depends on the treatment-free interval after primary therapy. In patients with platinum-resistant ovarian cancer, a combined chemotherapy with its high toxicity has not shown any significant benefit for the relapse-free interval or overall survival. Therefore, monotherapy is still the treatment of choice in this patient collective. Contrarily, the situation for platinum-sensitive ovarian cancer has changed due to the data of two large randomized phase III studies, the ICON-4/AGO-OVAR-2.2 and the OVAR-2.5. It was shown that patients with platinum-sensitive ovarian cancer profit from a combined chemotherapy, especially those who had a treatment-free interval of more than 12 months.     

From gene therapy to virotherapy for ovarian cancer

Ovarian cancer has the highest mortality of all cancers of the female reproductive system. Although progress in conventional therapies (surgery, chemotherapy and irradiation) has been achieved, the 5-year survival rate for patients with advanced stage ovarian cancer is still low. On this basis it is clear that there is a need for novel therapeutic paradigms. Targeted approaches are based on the increasing knowledge of the molecular basics of ovarian cancer. In this regard, gene therapy is a novel targeted approach for the treatment of ovarian cancer. However, current gene therapy delivery systems (viral and non-viral vectors) have to address the issues of inefficient transduction of target ovarian cancer cells and/or ectopic non-target delivery with attendant toxicity. Of note, the limited tumor transduction associated with current gene therapy interventions is due, in large part, to the fact that the employed vectors have been replication-incompetent. In this regard, human clinical trials have shown that the approach of replication-incompetent vectors has yet to succeed in ovarian cancer patients. In contrast, replication-competent viruses offer a method to achieve efficient tumor cell oncolysis (virotherapy) in ovarian cancer. Thus, in this very promising approach of virotherapy the replicating virus itself is the anti-cancer agent. This review discusses the concepts of gene therapy and virotherapy as novel targeted therapeutic approaches for the treatment of ovarian cancer.     

Clinical trials in gynecologic oncology: Past,present, and future

The Gynecologic Oncology Group has historically performed ground-breaking, practice-changing clinical trials in women's cancers. The current standard of care for initial treatment of ovarian, endometrial, cervical, and trophoblastic cancers was determined by clinical trials completed within this cooperative group structure. For example, trial GOG-0111 set the standard for combining platinum and taxane chemotherapy in ovarian cancer, and more recently GOG-0240 provided evidence for adding bevacizumab to chemotherapy for women with advanced cervical cancer. The landscape of clinical trial design has markedly changed in recent decades, with a clear emphasis on streamlining drug development towards specific patient populations and indications for investigational agents. Translational science in gynecologic cancers can set the stage for rapid and efficient introduction of new therapies for our patients. The gynecologic oncology community of researchers and clinicians is well positioned to enter into the new era of drug development, with breakthrough discoveries increasing each year. It is clear that we must incorporate smarter clinical trial design to get the right drugs to the right patients expeditiously, so we can continue to improve outcome for women with gynecologic cancers.     

伏隔核因子1在卵巢癌化疗耐药中的研究进展

化疗耐药是制约卵巢癌治疗效果的主要原因之一,寻找逆转卵巢癌耐药的有效方法是当前国内外研究的热点。近年来研究表明,伏隔核因子1（nucleus accumbens-1,NAC-1）在卵巢癌中的过度表达不仅在其发生发展、转移复发中起重要作用,而且与化疗耐药密切相关。NAC-1通过调节药物耐药相关的多种信号通路,导致卵巢癌细胞对抗肿瘤药物的敏感性降低。因此以NAC-1为靶点逆转卵巢癌耐药可能为治疗开辟新的思路,NAC-1特异性抑制剂联合其他化疗药物有望成为卵巢癌新的治疗策略。现就NAC-1在卵巢癌化疗耐药中的研究进展进行综述。