吉西他滨在妇科肿瘤中的应用

吉西他滨(gemcitabine)商品名为健择(gemar),是一种阿糖胞苷类似物,属于嘧啶类抗代谢药物,于1989年进入Ⅰ期临床研究,1991年进入Ⅱ期临床研究,国内外已报道了单药或联合用药治疗NSCLC(非小细胞肺癌)、胰腺癌、乳腺癌、结肠癌、膀胱癌及前列腺癌等实体瘤,取得了较好的疗效。国外对吉西他滨治疗卵巢癌的研究已有80余篇的文献报道,国内各大医院也开始将其作为晚期卵巢癌的第二或三线化疗药物。     

2016年12月FDA批准新药概况

2016年12月，FDA批出3个新分子实体药品（表1），为治疗湿疹新药Eucrisa（crisaborole）、治疗卵巢癌新药Rubraca（rucaparib）和治疗脊髓性肌萎缩症药物Spinraza（nusinersen）。     

抗肿瘤新药——培美曲塞

培美曲塞是一种作用于叶酸代谢过程中 多种靶点的抗肿瘤新药。临床前研究及临床研究证 实该药对多种实体肿瘤有明确的抗瘤活性,包括肺 癌、乳腺癌、胰腺癌、卵巢癌等,特别是对恶性胸膜间 皮瘤的治疗。药物的不良反应主要包括骨髓抑制和 皮疹,在补充叶酸和维生素B12的情况下,不良反应 明显减轻,病人耐受性良好。本文就近年来该药的 研究进展作一简要的介绍。     

治疗卵巢癌新药——多腺苷二磷酸核糖聚合酶抑制剂rucaparib

多腺苷二磷酸核糖聚合酶(PARP)在单链DNA断裂修复过程中起着重要作用。rucaparib为一口服PARP抑制剂,由克洛维斯肿瘤公司开发,于2016年12月19日获美国食品和药物管理局批准单独用于携生殖或体细胞乳腺癌易感基因突变且曾接受过两次以上化疗的卵巢癌患者的治疗。本文从药效学、药动学、临床疗效及不良反应等方面对rucaparib进行介绍。     

蒽环类药物的心脏毒性及预防

蒽环类药物是活性很强的一类抗肿瘤药物,单用或与其它化疗药物联用对白血病、淋巴瘤、多发性骨髓瘤等血液系统肿瘤以及乳腺癌、卵巢癌、胃癌、肉瘤等多种实体瘤均具有很好的抗肿瘤作用。蒽环类药物虽为临床广泛使用,但骨髓和心脏毒性也使其应用受到限制.     

三氧化二砷联合用药治疗乳腺癌的研究进展

乳腺癌是女性发病率最高的恶性肿瘤之一。药物治疗和放射疗法是乳腺癌临床治疗的主要手段,但仍存在副作用大,肿瘤易耐药等问题。三氧化二砷是治疗急性早幼粒细胞白血病的一线用药,其也可联合多种药物对乳腺癌等实体瘤产生良好疗效,并在一定程度上缓解临床治疗弊端。本文综述三氧化二砷联合化疗药、激素类药、营养补充剂类药、中药等多种药物或放射疗法对乳腺癌的研究进展,为乳腺癌联合用药研究提供新思路。     

抗肿瘤新药黄酮醋酸

黄酮醋酸(Flavone Acetic Acid,LM975,1以下简称FAA)是一种化学合成的黄酮类化合物。临床前研究表明FAA对于许多移植性肿瘤,特别是实体瘤,具有明显的抑制活性。与一般细胞毒药物比较,FAA化学结构新颖、表现出不同的抗瘤谱与毒副作用。目前FAA已在美国和欧洲进入Ⅰ期和Ⅱ期临床研究。一、FAA的合成路线 FAA的合成路线如下图。二、FAA的抑瘤活性动物试验表明,FAA抗瘤谱异常,抑制实体瘤的活性显著,对于移植性结肠腺癌38、07/A、51、10A、结肠癌26、黑色素瘤B16、胰腺管癌02、03、乳腺癌16/C/adr、M 5076卵     

抗体-药物偶联物在实体瘤治疗中的临床研究进展

目的:为进一步研究抗体-药物偶联物(ADCs)在实体瘤中的应用提供参考。方法:以"抗体-药物偶联物""实体瘤""Antibody-drug conjugates""Solid tumor"等为关键词,组合查询Pub Med、EMbase、中国期刊全文数据库、中国生物医学文献数据库和万方数据库中1999-2014年ADCs在实体瘤中的应用相关文献,对其研究现状及在实体瘤中的应用情况进行总结归纳。结果与结论:共获得文献1 059条,其中有效文献30条。ADCs是一类高效且特异性强的肿瘤靶向药物,由特异性抗体、细胞毒性药物通过链分子连接而成,既可提高肿瘤治疗的选择性、降低药品不良反应,又可应对单抗和化疗的耐药性问题。已有3种ADCs药物上市,其中Mylotarg和Adcetris应用于急性髓性白血病、淋巴瘤等血液系统肿瘤,2013年上市的Kadcyla是第一个治疗实体瘤的ADCs;目前有AMG595、SGN-75、IMGN901、PSMA-ADC、MEDI-547等多种ADCs处于~期临床试验阶段,应用于乳腺癌、肺癌、前列腺癌、黑色素瘤等实体瘤,并取得了显著的临床效果,成为未来实体瘤治疗的新趋势。     

吉西他滨联合铂类治疗卵巢癌的研究进展

吉西他滨(gemcitabine,GEM)是嘧啶类抗肿瘤药物,已广泛用于实体瘤的治疗,在卵巢癌治疗中,吉西他滨单药或铂类联合方案,是晚期复发转移卵巢癌的标准方案之一.另有临床研究显示,吉西他滨与铂类联用可作为卵巢癌的一线治疗方案.本文简要介绍了吉西他滨联合铂类治疗卵巢癌的相关信息.     

预防长春瑞滨致静脉炎的临床分析

长春瑞滨是第三代长春碱类抗肿瘤药物,其抗瘤谱广,临床常用于治疗非小细胞肺癌、转移性乳腺癌、晚期卵巢癌、恶性淋巴瘤等。该药局部刺激性大,静脉注药外渗可引起严重     

复方苦参注射液联合醋酸甲地孕酮治疗子宫内膜癌的疗效观察

目的探讨复方苦参注射液联合醋酸甲地孕酮治疗子宫内膜癌的临床疗效。方法选取2013年4月—2015年8月在临高县人民医院妇产科接受治疗的子宫内膜癌患者88例,根据治疗方案的差别分为对照组和治疗组,每组各44例。两组患者均给予必要的基础治疗。对照组口服醋酸甲地孕酮片,160 mg/次,1次/d。治疗组在对照组基础上静脉滴注复方苦参注射液,20 mL加入0.9%生理盐水250 mL中,1次/d。两组患者均连续治疗4周。治疗后比较两组患者近期疗效,观察生存质量的改善和不良反应发生情况。结果治疗后,对照组客观缓解率(ORR)为43.18%,临床获益率(CBR)为70.45%,治疗组ORR为65.91%,CBR为88.64%,两组ORR、CBR比较差异有统计学意义(P0.05)。治疗后,对照组和治疗组生存质量改善率分别为75.00%和90.91%,差异具有统计学意义(P0.05)。治疗过程中,对照组不良反应例数明显高于治疗组,差异具有统计学意义(P0.05)。结论复方苦参注射液联合醋酸甲地孕酮治疗子宫内膜癌效果显著,可显著改善患者生活质量,具有一定的临床推广应用价值。     

Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) Restrict Oral Availability and Brain Accumulation of the PARP Inhibitor Rucaparib (AG-014699)

Background

Rucaparib is a potent, orally available, small-molecule inhibitor of poly ADP-ribose polymerase (PARP) 1 and 2. Ongoing clinical trials are assessing the efficacy of rucaparib alone or in combination with other cytotoxic drugs, mainly in breast and ovarian cancer patients with mutations in the breast cancer associated (BRCA) genes.

Purpose

We aimed to establish whether the multidrug efflux transporters ABCG2 (BCRP) and ABCB1 (P-gp, MDR1) affect the oral availability and brain penetration of rucaparib in mice.

Results

In vitro, rucaparib was efficiently transported by both human ABCB1 and ABCG2, and very efficiently by mouse Abcg2. Transport could be inhibited by the small-molecule ABCB1 and ABCG2 inhibitors zosuquidar and Ko143, respectively. In vivo, oral availability (plasma AUC_0–1 and AUC_0–24) and brain levels of rucaparib at 1 and 24 h were increased by the absence of both Abcg2 and Abcb1a/1b after oral administration of rucaparib at 10 mg/kg.

Conclusions

Our data show to our knowledge for the first time that oral availability and brain accumulation of a PARP inhibitor are markedly and additively restricted by Abcg2 and Abcb1a/1b. This may have clinical relevance for improvement of rucaparib therapy in PARP inhibitor-resistant tumors with ABCB1 and/or ABCG2 expression and in patients with brain (micro)metastases positioned behind a functional blood–brain barrier.

     

Bisphosphonates in lung cancer: can they provide benefits beyond prevention of skeletal morbidity?

Bisphosphonates are the current standard of care for patients with bone metastases from advanced solid tumors. Zoledronic acid has demonstrated the broadest activity in this setting, and is approved for the prevention of skeletal-related events from bone metastases from a variety of solid tumors in addition to breast cancer and multiple myeloma. Ongoing studies are evaluating the antiresorptive potentials of investigational agents in these settings. A large body of preclinical evidence and recent clinical developments support the hypothesis that zoledronic acid can exert clinically meaningful anticancer activities in some settings, thereby improving disease outcomes and survival. These data are especially strong in breast cancer and multiple myeloma, and are emerging in other cancer settings. This review article will discuss the emerging data suggesting an anticancer role for bisphosphonates in the context of lung cancer and solid tumors other than breast and genitourinary malignancies.     

Capecitabine: a novel agent for the treatment of solid tumors

Although 5-fluorouracil (5-FU) has been used to treat breast and colorectal cancers for several decades, bolus 5-FU has disappointing efficacy. Prolonged infusion schedules and biomodulation with leucovorin have resulted in improved response rates, but these have not translated into significant improvements in survival in patients with metastatic disease. Furthermore, prolonged infusion is inconvenient for patients and can result in medical complications. New oral fluoropyrimidines, including capecitabine, are promising alternatives to i.v. 5-FU. Capecitabine generates 5-FU preferentially within tumors through exploitation of the high intratumoral activity of thymidine phosphorylase. The tumor selectivity of capecitabine has been confirmed in a clinical study of colorectal cancer patients. Clinical trials have shown that capecitabine is an effective, well-tolerated treatment for breast and colorectal cancer, with response rates of 20-26% in anthracycline- and taxane-pretreated metastatic breast cancer. As first-line monotherapy, capecitabine produces response rates of 25-27% in metastatic colorectal cancer and 30% in metastatic breast cancer. In all studies to date, capecitabine has been well tolerated, with adverse events typical of infusional 5-FU and manageable with treatment interruption/dose modification. Myelosuppression and alopecia are rare. Capecitabine is also being investigated in other solid tumors (including ovarian, pancreatic and gastric cancers) as adjuvant monotherapy in breast and colorectal cancer, and in combination with other cytotoxic agents. Results of ongoing trials are eagerly awaited.     

Eribulin mesilate, a halichondrin B analogue, in the treatment of breast cancer

Eisai is developing eribulin mesilate (E-7389), a synthetic macrocyclic ketone analogue of the tubulin inhibitor halichondrin B, for the treatment of a variety of solid tumors that include but are not limited to breast and lung cancer. In this context, eribulin is in phase III clinical trials in breast cancer; however, it has also progressed to phase II for nonsmall cell lung cancer, soft tissue sarcomas, pancreatic, prostate, head and neck cancer, bladder and ovarian and related gynecological tumors. Eribulin has shown synergistic in vitro antiproliferative activity in combination with the breast cancer drugs gemcitabine, epirubicin, trastuzumab, docetaxel and vinorelbine. Clinical trials have established efficacy, safety and a distinct survival advantage of 2.5 months with eribulin as compared to other treatments of physician's choice in metastatic breast cancer patients with heavy pretreatment and taxane resistance. It has a manageable side effect profile, consisting mostly of neutropenia and fatigue, with distinct tolerance at full doses in renal dysfunction, a lower incidence of peripheral neuropathy, minimal chances of drug-drug interactions and hypersensitivity. It appears to be a suitable candidate for third-line monotherapy and beyond for locally advanced and metastatic breast cancer. This review will focus on published and peer-reviewed data on breast cancer.     

Patupilone in cancer treatment

Importance of the field: Since the introduction of taxane-based chemotherapy for advanced solid tumors in the 1990s, the median overall survival of patients with metastatic breast cancer increased from 2 years to almost 5 years. Similarly, the 5-year overall survival for ovarian cancer has increased from 30% to more than 40%.

Areas covered in this review: Patupilone is a novel cytotoxic compound, with similar microtubule-binding and apoptotic properties of taxanes and is active in taxane-resistant cell lines. Over 1200 patients have been treated with patupilone in Phase I – III clinical trials and a wealth of knowledge has accumulated about this compound. This review discusses current pharmacology and data from clinical trials with patupilone from the last seven years.

What the reader will gain: We present a comprehensive summary of data from Phase II and III trials, as well as an overview of currently accruing trials.

Take home message: Although patupilone has not demonstrated superiority over pegylated liposomal doxorubicin in a large Phase III trial in relapsed or refractory ovarian cancer, its evaluation is continuing in a range of other malignancies, especially in primary or secondary tumors of the CNS.     

A comprehensive review of denosumab for bone metastasis in patients with solid tumors

Background:

Denosumab is fully human monoclonal antibody that specifically binds and inactivates receptor activator of NF-kB ligand (RANKL), an important ligand that regulates bone remodeling. In this review, we aimed to show the clinical data about denosumab treatment and discuss its advantages for the management of patients with solid tumors and bone metastasis.

Scope:

Denosumab showed positive results in clinical studies of solid tumors with bone metastasis. PubMed database and ASCO Symposium Meeting abstracts were searched until August 2015 by using the terms ‘denosumab’, ‘RANKL inhibitor’ and ‘bone metastasis’. The last search was on 21 August 2015. All resulting studies were retrieved and were also checked for related publications. Clinical trials in this review fulfilled the following criterion: inclusion of sufficient data to allow estimation of the efficacy and safety of denosumab.

Findings:

The effects of denosumab on skeletal-related events (SREs) were investigated in three large randomized trials: one in patients with breast cancer, one in patients with prostate cancer, and one in patients with multiple myeloma or solid tumors other than breast or prostate cancer. In the breast cancer and prostate cancer studies denosumab was non-inferior and also superior to zoledronic acid in terms of the primary outcome time to first on-study SRE. In the third study denosumab was non-inferior to zoledronic acid but was not superior to zoledronic acid in solid tumors excluding breast and prostate cancer with bone metastases. In the three studies median overall survival and disease progression rates were similar between zoledronic acid and denosumab. Denosumab has also been studied in bone loss associated with hormonal therapy in both breast and prostate cancer. Adjuvant denosumab significantly reduced the risk of clinical fracture risk by 50% in breast cancer patients and by 62% in non-metastatic prostate cancer patients treated with adjuvant aromatase inhibitors or androgen deprivation therapy. In addition, biochemical markers of bone turnover and fractures were significantly reduced in patients under denosumab treatment.

Conclusion:

The promising outcomes in the initial trials with denosumab have shown clinical activity and a favorable safety profile in patients with solid tumors and bone metastasis. Denosumab significantly reduced treatment-related osteoporosis associated with breast and prostate cancer and was superior to zoledronic acid in prevention or delaying of SRE.     

西地尼布抗肿瘤作用的临床研究进展

目的 介绍西地尼布的多种抗肿瘤作用临床研究进展。方法 检索近年来国内外相关的文献报道,对西地尼布用于卵巢癌、实体瘤、胆道癌、肾细胞癌、前列腺癌、宫颈癌和结肠癌这七大领域的临床试验进行综述。结果 西地尼布是一种强效的血管内皮生长因子受体抑制剂,大量临床试验资料表明它有潜力用于各种肿瘤。药动学研究显示它口服给药,每日1次,用药方便,且毒性反应与其他血管内皮生长因子受体抑制剂相似。结论 熟悉西地尼布的临床应用,对更好的开发西地尼布具有深远意义。     

表皮生长因子受体酪氨酸激酶抑制剂在肺癌以外的应用进展

表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitor,EGFR-TKIs)主要用于晚期非小细胞肺癌的分子靶向治疗,随着EGFR-TKIs的越来越深入研究,发现EGFR及其配体参与了包括乳腺癌、胰腺癌等在内的不同人类癌症发病过程。因此,EGFR-TKIs的治疗对象也不再局限于晚期非小细胞肺癌,其对乳腺癌、胰腺癌、头颈癌、食管癌和宫颈癌等恶性肿瘤也有较好的抑制作用,并且与EGFR-TKIs联合用药往往比单独用药效果更好。该文讨论了EGFR-TKIs在治疗肺癌以外其他癌症的应用研究,以及EGFR-TKIs与其他药物联合治疗乳腺癌、胰腺癌等恶性肿瘤的潜在应用前景。