ERCC1、RRM1基因与非小细胞肺癌治疗预后的关系

化疗耐药是影响非小细胞肺癌化疗疗效的重要因素。ERCC1、RRM1基因作为DNA损伤后修复的代表,其表达的强弱是非小细胞肺癌化疗药物顺铂、吉西他滨的主要影响因素。现就非小细胞肺癌化疗药物顺铂、吉西他滨疗效的分子标志物ERCC1、RRM1基因与预后关系作一综述。     

DNA损伤修复与铂类耐药研究进展

铂类是非小细胞肺癌化疗的基本药物，它的耐药机制复杂，其中 DNA损伤修复能力改变是铂类耐药的重要分子基础。全文综述DNA损伤修复机制——碱基切除修复、恢苷酸切除修复、酶修复及DNA双链断裂修复等研究进展。     

ERCC1、RRM1及BRCA1在非小细胞肺癌中表达及其临床意义

化疗是肺癌治疗的主要手段,耐药是影响化疗疗效的重要因素.近年来的研究表明,肿瘤细胞DNA修复的异常及其相关基因的表达异常使肿瘤对药物产生耐药是影响药效的一个重要因素.以下对肺癌常用化疗药物铂类、吉西他滨、紫杉类药物疗效相关的分子标志如ERCC1、RRM1、BRCA1等近年来的研究进展进行综述.     

ERCC1与顺铂耐药的研究进展

顺铂广泛应用于恶性肿瘤的化疗,但耐药性的产生严重影响其疗效。顺铂耐药的机制尚不十分清楚,目前普遍认为核苷酸切除修复(nucleotide excision repair,NER)是顺铂耐药的重要机制之一。NER途径是一个复杂的过程,其中DNA损伤的识别/切除为其限速步骤。ERCC1是一种高度保守的DNA核酸内切酶,是NER途径的限速酶。ERCC1基因的表达产物与DNA修复酶缺乏互补基因F(XPF)形成紧密的异二聚体(ERCC1-XPF),该二聚体具有识别损伤和5′端切除的双重作用,在NER中起到限速或调节的重要作用。对卵巢癌、宫颈癌、睾丸癌、膀胱癌及非小细胞肺癌等的研究表明ERCC1的表达与顺铂耐受性相关。抑制ERCC1的表达可克服顺铂耐药性,提高治疗效果。     

核苷酸切除修复与铂类耐药研究进展

目前肿瘤化疗仍以肿瘤发生部位和病理类型为基础选择药物,由于肿瘤本身以及个体之间存在异质性,相同部位和相同病理类型的肿瘤对化疗敏感性存在差异。长期以来,人们追求根据肿瘤自身药物敏感性开展个体化治疗。近年来,药物敏感相关基因检测获得快速发展,使个体化化疗成为可能。在相关基因与化疗药物研究领域中,核苷酸切除修复基因与铂类药物研究是最受瞩目的内容之一。1铂类药物耐药机制铂类药物(顺铂、卡铂、草酸铂)是临床上最常用的一类化疗药物。铂类药物进入肿瘤细胞后与DNA结合,形成Pt-DNA加合物,导致DNA的链间或链内交链,引起DNA复制障碍,从而抑制肿瘤细胞分裂。铂类药物的耐药机制主要有减少药物摄取积聚、通过共扼结合去除药物毒性、提高对铂类药物诱导产生的DNA加合物的耐受性及提高DNA修复能力等。研究证实,临床缓解率与循环中Pt-DNA加合物的水平相关,如果肿瘤细胞DNA修复能力减低,就会导致Pt-DNA加合物清除减少,使患者对铂类药物的疗效提高,反之疗效则差。因此,DNA修复能力是影响铂类药物疗效的主要原因。DNA切除修复途径主要有碱基切除修复(base-exc ision repair,BER)、DNA双链断裂修复(DN...     

口腔鳞状细胞癌铂类药物耐药分子机制研究进展

口腔鳞状细胞癌是头颈部常见的恶性肿瘤,化疗是其常规治疗手段之一,铂类化疗药物作为一线化疗药物应用于口腔鳞状细胞癌的治疗中。然而化疗耐药极大地限制了铂类化疗药物的临床应用,因此阐明口腔鳞状细胞癌铂类化疗耐药的分子机制具有十分重要的临床意义。本文从药物转运蛋白、DNA损伤修复、细胞凋亡、自噬、上皮间质转化和miRNA等方面综述了口腔鳞状细胞癌铂类化疗耐药的分子机制,以期为逆转铂类耐药及相关肿瘤的生物治疗靶点的开发提供新的思路。     

联合铂类的化疗方案在晚期食管癌中的临床评价及Polι对铂类化疗药物敏感性的影响

近年来,食管癌的诊治水平日益提高,然而晚期食管癌患者中位生存期仍偏短,多药联合化疗是其最主要的治疗手段。本文综合大量临床前期和临床早期的试验数据表明,联合顺铂治疗晚期食管癌疗效较好。但第一代铂类顺铂出现原发及继发性肿瘤耐药,以及较重的化疗不良反应,故铂类金属抗肿瘤药物研究开发一直较为活跃,不断有新的顺铂类配合物被合成并应用于临床试验。本文描述了3代铂类抗肿瘤药物中的代表药物,以探究如何发挥铂类抗食管癌最大效果同时又把不良反应降到最低,需更深层次研究铂类耐药的机制,不仅是对铂类本身结构进行改造,更要深入到基因层次。目前一种参与DNA损伤修复的基因Polι受到了越来越多的关注,已有研究证实其参与了肿瘤的发生、发展以及化疗药物的耐药。其表达量高可能提示对顺铂反应性不佳,可作为食管癌生物学特征、预后判断以及是否可行顺铂化疗的参考指标。     

DNA修复基因在鼻咽癌的表达及铂类化疗耐药的研究现状

正顺铂为基础的联合化疗是鼻咽癌(nasopharyn-geal carcinoma,NPC)化疗常用的化疗方案,在综合治疗中占有重要的地位,然而肿瘤细胞对化疗耐药的产生,严重影响了化疗疗效,导致鼻咽癌生存率一直偏低。肿瘤细胞对化疗药物的耐受是多方面的,包括细胞内药物蓄积减少,药物灭活增强(如谷胱甘肽和金属硫蛋白),对DNA损伤的耐受性增加或损伤后的修复功能增强(DRC),肿瘤细胞对DDP作用DNA后形成的Pt-DNA的耐受性增加,其     

ERCC1基因在食管癌中的研究进展

顺铂的细胞毒性主要在于与DNA特定碱基结合形成共价的顺铂-DNA加合物,导致DNA致命的损伤。顺铂-DNA加合物主要靠核苷酸切除修复（NER）系统来修复,ERCCI基因作为NER系统关键的修复基因,在铂类耐药过程中发挥重要作用。研究发现ERCC1的表达情况与恶性肿瘤的发病以及含铂方案的疗效相关。文章着重综述ERCC1基因在食管癌中的研究进展．包括与食管癌发生发展的关系、与含铂化疗方案有效率及预后的关系、基因多态性等。     

卵巢癌化疗耐药及逆转耐药基因水平研究进展

卵巢癌细胞对化疗产生耐药的机制主要有肿瘤细胞内有效药物浓度降低、DNA损伤修复功能异常和细胞凋亡调控异常3个方面.逆转卵巢癌细胞耐药主要包括反义基因治疗、RNA干预、化疗药物的联合应用等.     

Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents

DNA repair competency is one determinant of sensitivity to certain chemotherapy drugs, such as cisplatin. Cancer cells with intact DNA repair can avoid the accumulation of genome damage during growth and also can repair platinum-induced DNA damage. We sought genomic signatures indicative of defective DNA repair in cell lines and tumors and correlated these signatures to platinum sensitivity. The number of subchromosomal regions with allelic imbalance extending to the telomere (N(tAI)) predicted cisplatin sensitivity in vitro and pathologic response to preoperative cisplatin treatment in patients with triple-negative breast cancer (TNBC). In serous ovarian cancer treated with platinum-based chemotherapy, higher levels of N(tAI) forecast a better initial response. We found an inverse relationship between BRCA1 expression and N(tAI) in sporadic TNBC and serous ovarian cancers without BRCA1 or BRCA2 mutation. Thus, accumulation of telomeric allelic imbalance is a marker of platinum sensitivity and suggests impaired DNA repair. SIGNIFICANCE: Mutations in BRCA genes cause defects in DNA repair that predict sensitivity to DNA damaging agents, including platinum; however, some patients without BRCA mutations also benefit from these agents. NtAI, a genomic measure of unfaithfully repaired DNA, may identify cancer patients likely to benefit from treatments targeting defective DNA repair.     

Molecular basis of cellular response to cisplatin chemotherapy in non-small cell lung cancer (Review)

Cisplatin is one of the most potent anticancer agents, displaying significant clinical activity against a variety of solid tumors. For more than two decades, the most effective systemic chemotherapy for non-small cell lung cancer (NSCLC), the leading cause of cancer morbidity and mortality among men and women in the western world, was cisplatin-based combination treatment. Unfortunately, the outcome of cisplatin therapy on NSCLC seems to have reached a plateau. Therefore, the biological mechanisms of cisplatin action need to be understood in order to overcome the treatment plateau on NSCLC. Moreover, the development of resistance is a hurdle in the use of this drug. The molecular mechanisms that underlie this chemoresistance are largely unknown. Possible mechanisms of acquired resistance to cisplatin include reduced intracellular accumulation of cisplatin, enhanced drug inactivation by metallothionine and glutathione, increased repair activity of DNA damage, and altered expression of oncogenes and regulatory proteins. In addition, it is generally accepted that cytotoxicity of cisplatin is mediated through induction of apoptosis and arrest of cell cycle resulting from its interaction with DNA, such as the formation of cisplatin-DNA adducts, which activates multiple signaling pathways, including those involving p53, Bcl-2 family, caspases, cyclins, CDKs, pRb, PKC, MAPK and PI3K/Akt. Increased expression of anti-apoptotic genes and mutations in the intrinsic apoptotic pathway may contribute to the inability of cells to detect DNA damage or to induce apoptosis. Towards an understanding of the molecular basis of the cellular response to cisplatin-based chemotherapy in NSCLC, in this review we provide some insights into the pathways involved in cisplatin damage from entering the cells to execution of apoptosis or survival of NSCLC cells. We believe that as more and more molecular mechanisms of response to cisplatin-based therapy are unraveled, this knowledge should provide a basis for further studies to improve our understanding of molecular events associated with lung NSCLC as well as to devise novel and effective therapeutic approaches to overcome the treatment plateau or reverse drug resistance in this disease.     

The role of DNA repair pathways in cisplatin resistant lung cancer

Platinum chemotherapeutic agents such as cisplatin are currently used in the treatment of various malignancies such as lung cancer. However, their efficacy is significantly hindered by the development of resistance during treatment. While a number of factors have been reported that contribute to the onset of this resistance phenotype, alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating this phenomenon. The mode of action of cisplatin has been linked to its ability to crosslink purine bases on the DNA, thereby interfering with DNA repair mechanisms and inducing DNA damage. Following DNA damage, cells respond by activating a DNA-damage response that either leads to repair of the lesion by the cell thereby promoting resistance to the drug, or cell death via activation of the apoptotic response. Therefore, DNA repair is a vital target to improving cancer therapy and reduce the resistance of tumour cells to DNA damaging agents currently used in the treatment of cancer patients. To date, despite the numerous findings that differential expression of components of the various DNA repair pathways correlate with response to cisplatin, translation of such findings in the clinical setting are still warranted. The identification of alterations in specific proteins and pathways that contribute to these unique DNA repair pathways in cisplatin resistant cancer cells may potentially lead to a renewed interest in the development of rational novel therapies for cisplatin resistant cancers, in particular, lung cancer.     

Drug resistant mechanisms of platinum derivatives in a human cisplatin resistant ovarian cancer cell line

We investigated cisplatin resistant mechanisms in a cisplatin resistant ovarian cancer cell line (KFr) by means of flow cytometric analysis for damage of cisplatin to DNA base and DNA synthetic cells. Cisplatin showed cycle delay at 0.5 microgram/ml and then cycle arrest at 1 microgram/ml in G2 + M phase. KFr cells showed relatively rapid inhibition of DNA synthesis based with G-C base damage by cisplatin however, KFr cells had a capacity to repair DNA damage by cisplatin as showing cycle progression from G2 + M phase to G1-early S phase. Of the cisplatin derivatives tested which are of current clinical interest, Carboplatin and DWA 2114 R showed cross resistance to cisplatin in KFr cells.     

P-糖蛋白表达与肺癌顺铂耐药的研究进展

顺铂被广泛应用于肺癌的临床化疗,但耐药性的产生严重影响其疗效。顺铂耐药的机制尚不十分清楚。目前普遍认为P-糖蛋白（P-gp）的表达情况与顺铂耐药性相关。抑制p-gP的表达可克服顺铂耐药性,提高治疗疗效。     

Clinical relevance of the homologous recombination machinery in cancer therapy

Cancer chemotherapy and radiotherapy kill cancer cells by inducing DNA damage, unless the lesions are repaired by intrinsic repair pathways. DNA double-strand breaks (DSB) are the most deleterious type of damage caused by cancer therapy. Homologous recombination (HR) is one of the major repair pathways for DSB and is thus a potential target of cancer therapy. Cells with a defect in HR have been shown to be sensitive to a variety of DNA-damaging agents, particularly interstrand crosslink (ICL)-inducing agents such as mitomycin C and cisplatin. These findings have recently been applied to clinical studies of cancer therapy. ERCC1, a structure-specific endonuclease involved in nucleotide excision repair (NER) and HR, confers resistance to cisplatin. Patients with ERCC1-negative non-small-cell lung cancer were shown to benefit from adjuvant cisplatin-based chemotherapy. Imatinib, an inhibitor of the c-Abl kinase, has been investigated as a sensitizer in DNA-damaging therapy, because c-Abl activates Rad51, which plays a key role in HR. Furthermore, proteins involved in HR have been shown to repair DNA damage induced by a variety of other chemotherapeutic agents, including camptothecin and gemcitabine. These findings highlight the importance of HR machinery in cancer therapy. ( Cancer Sci 2008; 99: 187–194)     

Targeting DNA Repair in Ovarian Cancer Treatment Resistance

Most patients with advanced high-grade serous ovarian cancer (HGSOC) develop recurrent disease within 3 years and succumb to the disease within 5 years. Standard treatment for HGSOC is cytoreductive surgery followed by a combination of platinum (carboplatin or cisplatin) and taxol (paclitaxel) chemotherapies. Although initial recurrences are usually platinum-sensitive, patients eventually develop resistance to platinum-based chemotherapy. Accordingly, one of the major problems in the treatment of HGSOC and disease recurrence is the development of chemotherapy resistance. One of the causes of chemoresistance may be redundancies in the repair pathways involved in the response to DNA damage caused by chemotherapy. These pathways may be acting in parallel, where if the repair pathway that is responsible for triggering cell death after platinum chemotherapy therapy is deficient, an alternative repair pathway compensates and drives cancer cells to repair the damage, leading to chemotherapy resistance. In addition, if the repair pathways are epigenetically inactivated by DNA methylation, cell death may not be triggered, resulting in accumulation of mutations and DNA damage. There are novel and existing therapies that can drive DNA repair pathways towards sensitivity to platinum chemotherapy or targeted therapy, thus enabling treatment-resistant ovarian cancer to overcome chemotherapy resistance.     

Phenylbutyrate interferes with the Fanconi anemia and BRCA pathway and sensitizes head and neck cancer cells to cisplatin

Background  

Cisplatin has been widely used to treat head and neck cancer. One of the clinical limitations with this treatment, however, is that tumors that are initially responsive to cisplatin later acquire resistance. We have recently shown that a subset of head and neck cancer cell lines has a defective Fanconi anemia DNA damage response pathway and this defect correlates to cisplatin sensitivity. We have also shown that the histone deacetylase inhibitor phenylbutyrate sensitize human cells to cisplatin. In this study we explored whether phenylbutyrate may sensitize head and neck cancer cells by interfering with the Fanconi anemia pathway.     

Nucleotide excision repair: Why is it not used to predict response to platinum-based chemotherapy?

Platinum based therapy is one of the most effectively used chemotherapeutic treatments for cancer. The mechanism of action of platinum compounds is to damage DNA and drive cells into apoptosis. The most commonly used platinum containing agents are cis-diammine-dichloroplatinum (II)], more commonly known as cisplatin, its analogue carboplatin, and oxaliplatin. Cisplatin is used to treat a wide variety of tumours such as ovarian, testicular, head and neck and non-small cell lung cancers (NSCLCs). In addition, it forms the basis of most combined treatment regimes. Despite this, cisplatin and its analogues are extremely toxic and although some patients benefit substantially from treatment, a large proportion suffer the toxic side effects without any therapeutic benefit. Nucleotide excision repair (NER) is a versatile DNA repair system that recognises DNA damage induced by platinum based therapy. For many years the components of the NER pathway have been studied to determine mRNA and protein expression levels in response or resistance to cisplatin in many forms of cancer; particularly testicular, ovarian and NSCLCs. Despite the consistent finding that over or under expression of subsets of NER proteins and mRNA highly correlate with response to cisplatin, the translation of these findings into the clinical setting has not been forthcoming. This review summarises the results of previous investigations into NER in cisplatin response and clinical trials where the expression of NER proteins were compared to the response to platinum therapies in treatment.