SGLT2抑制剂抗恶性肿瘤研究进展

越来越多的证据显示, 糖尿病与肿瘤发生、发展密切关联, 降糖药物与肿瘤的相关性, 尤其是降糖药物是否同时具备抗肿瘤作用逐渐成为内分泌和肿瘤研究的新热点。近来, 一种新型口服降糖药钠-葡萄糖转运体(SGLT2)抑制剂被发现同时具备抑制肿瘤发生、发展的作用, 该文对SGLT2抑制剂与肿瘤的相关性, 尤其是SGLT2抑制剂抗肿瘤作用机制进行归纳综述, 以期为降糖药物SGLT2抑制剂的抗肿瘤相关机制研究提供线索。     

VISTA作为免疫治疗新靶点的研究进展

T细胞活化V结构域Ig抑制因子（VISTA）作为一种新型的免疫检查点分子，在肿瘤微环境中通过结合其伴侣及介导免疫抑制的信号通路来削弱固有免疫和适应性免疫应答，进而促进肿瘤进展。VISTA在不同瘤种中的预后价值仍存在争议，然而，大多数研究更倾向于其作为负性预后指标。在临床前动物模型中，阻断VISTA可重新激活抗肿瘤免疫和增强程序性死亡受体1/程序性死亡配体1抑制剂的抗肿瘤活性，从而抑制小鼠肿瘤生长，这为探索新的免疫治疗靶点和克服免疫耐药提供了新的思路。当前已有多个VISTA抑制剂进入临床研究阶段，并取得阳性结果。因此VISTA是颇具潜力的免疫治疗新靶点。     

蛋白酶体抑制剂药理基础与临床应用进展

蛋白酶体抑制剂是一类通过对泛素化通路阻断的一类新抗肿瘤药物，对肿瘤治疗具有良好的应用前景。蛋白酶体是广泛分布于真核细胞质和细胞核中，具有多种功能的蛋白酶复合物，而泛素—蛋白酶体系统是生物体内进行蛋白质选择性降解的重要途径之一，这些蛋白包括转录因子、肿瘤抑制蛋白、原癌基因等。体外试验和动物模型实验中已显示蛋白酶体抑制剂具有广泛抗肿瘤作用，早期临床试验也为蛋白酶体抑制剂进一步临床应用提供了依据。     

肿瘤相关高血压的血压管理的研究进展

近年来众多研究证实长期使用抗高血压药治疗及高血压本身会导致肿瘤发病风险增加,同时在应用抗肿瘤药过程中也会导致高血压的发生。然而,目前仍缺乏有关肿瘤患者合并高血压的最佳血压管理方法。现强调高血压与肿瘤之间的关系,并讨论接受抗肿瘤药治疗的肿瘤患者的血压控制目标以及评估和管理策略。肿瘤患者的血压达标对于降低抗肿瘤治疗引起的心脏毒性和心血管疾病的风险至关重要。     

炎症性肠病治疗的新进展

炎症性肠病(inflammatory bowel disease,IBD)主要包括溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn’s disease,CD),其病因尚不明确,迄今也无有效的治愈方法.目前临床上的药物治疗包括传统药物治疗及新型生物制剂.传统药物主要有氨基水杨酸类、肾上腺糖皮质激素和免疫抑制剂;用于临床的新型生物制剂主要为肿瘤坏死因子(tumor necrosis factor-α,TNF-α)的单克隆抗体.随着研究的深入及制药的进步,IBD的治疗有了新的进展,如传统药物新剂型的出现及新的给药方式,新型治疗药物的问世.本文就IBD治疗新进展作一综述.     

环氧化酶-2抑制剂对非小细胞肺癌抗肿瘤作用机制的研究进展

肺癌目前位于全世界癌症死因的首位,约占全部恶性肿瘤的19％。每年约有超过100万人死于肺癌,严重威胁着人类的健康和生命。其中,非小细胞肺癌约占80％～85％。研究显示环氧化酶-2（cycl00xygenase-2,COX-2）在非小细胞肺癌组织中表达上调,并且与肿瘤细胞的增殖、侵袭和远处转移有关。近年来COX-2抑制剂在非小细胞肺癌治疗中的作用日益受到关注。特异性COX～2抑制剂（尼美舒利、塞来昔布、罗非昔布、NS398等）和非特异性COX-2抑制剂（吲哚美辛、布洛芬等）对非小细胞肺癌均有抗肿瘤作用,可增加非小细胞肺癌化疗及放疗的敏感性。实验研究表明COX-2抑制剂可抑制非小细胞肺癌细胞的增殖,诱导细胞的凋亡,抑制肿瘤新生血管的生成,抑制肿瘤远处转移等。国外临床研究表明COX-2抑制剂可提高化疗药物的临床疗效,并减弱化疗不良反应。COX-2抑制剂显著的抗肿瘤作用为非小细胞肺癌的治疗带来了新的曙光。     

免疫检查点抑制剂在晚期非小细胞肺癌治疗中的应用进展

随着程序性死亡受体1(PD-1)、程序性死亡配体1(PD-L1)以及细胞毒性T淋巴细胞抗原4(CTLA-4)等免疫检查点的发现，免疫检查点抑制剂（ICI）逐渐成为肿瘤治疗领域中最有前景的方法之一，已被证实可以提高晚期非小细胞肺癌（NSCLC）患者的生存率。与化疗相比，对于肿瘤细胞表面PD-L1高表达的晚期NSCLC患者，抗PD-1/PD-L1治疗后生存期显著延长且不良反应较少。抗CTLA-4药物单药治疗效果有限，通常与PD-1/PD-L1药物联合可进一步提高抗肿瘤效果。另外一些新型免疫检查点抑制剂，如依吉利单抗、替拉戈鲁单抗等在临床试验中也表现出一定的抗肿瘤作用，未来在晚期NSCLC患者的治疗中或许能提供帮助。对ICI在NSCLC治疗中的临床应用进行总结，同时对未来免疫治疗的发展和预测性生物标志物进行展望，可以为晚期NSCLC患者的治疗提供新的靶点和思路。     

蛋白酶体抑制剂的发现和临床应用给我们带来了什么?

医学的发展和进步经常要依赖和借助其他科学技术的创新和发展。例如,计算机技术的发展,出现了CT和磁共振技术在医学领域的应用,进一步提高了医学影像学的诊断治疗水平。泛素-蛋白酶体系统及其功能的发现与应用,使一类全新的抗肿瘤药物的研究及发展成为可能。第1个蛋白酶体抑制剂药物Bortezomib的出现,更加激发了人们对此类新型抗肿瘤药物的研究兴趣。在有关Bortezomib的报道出现5年来,Bortezomib不仅在治疗多发性骨髓瘤取得了令人瞩目的成绩,而且也在治疗其他血液系统恶性肿瘤方面初露锋芒。蛋白酶体抑制剂的发现和临床应用给我们医务工作…     

分子靶向药物治疗晚期胆道肿瘤的研究进展

随着胆道肿瘤基础研究的深入,分子靶向治疗成为新的热点。旨在对分子靶向治疗晚期胆道肿瘤的Ⅱ、Ⅲ临床试验作一综述,为临床实践提供新的思路。Ⅱ临床试验中,血管生长因子受体阻滞剂、有丝分裂原活化蛋白激酶阻滞剂没有体现良好的抗肿瘤活性,而表皮生长因子受体抑制剂对晚期胆道肿瘤显示出良好的安全性和有效性。唯一的一项Ⅲ期随机、开放、多中心对照研究表明尼洛替尼联合吉西他滨、奥沙利铂作为晚期胆道肿瘤一线治疗手段未能显著改善患者的总体生存。亚组分析胆管癌能从标准化疗联合尼洛替尼获得显著的无疾病进展生存时间。通过分析认为表皮生长因子受体抑制剂有效地控制胆道肿瘤进展,有望成为靶向治疗的新方向。     

依维莫司相关性肺损伤一例

随着肿瘤发病率的升高及新型抗肿瘤药物的出现,肺损伤越来越常见.文献报道约10%[1].而抗肿瘤药物的肺损伤是引起抗肿瘤药物停用的重要原因.哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂,主要用于实体器官移植后的免疫抑制作用.     

Which novel agents will have a clinically meaningful impact in AML at diagnosis?

New drug approvals now afford AML physicians a wider choice of initial treatment options than ever before. Although chemotherapy for AML is by no means ready to be replaced entirely by novel agents, the role of traditional cytotoxics in AML therapy is rapidly changing. In particular, biologically targeted agents such as the BCL2 inhibitor venetoclax and inhibitors of FLT3 and IDH mutations stand out as drugs likely to take AML therapy in important new directions. Maximum response and survival benefits likely require combinations of novel agents and chemotherapy or multiple novel agents together. The recently-published phase 3 VIALE-A study demonstrates a very successful example of a new combination approach, which led to venetoclax plus azacitidine establishing itself as the new standard of care for patients unfit for intensive chemotherapy. One could reasonably expect other subsets of AML to benefit from this regimen or other applications of venetoclax combinations. Building on this experience, venetoclax-based regimens also have the potential to replace standard intensive cytarabine/anthracycline “7&3” induction approach for some if not many patients who are fit for induction. This review will describe novel agents with the greatest potential for impactful frontline applications that will change the AML treatment paradigm.     

Oral chemotherapy in colorectal cancer treatment: review of the literature

Recent advances in anticancer treatment have focused on the development of oral anticancer agents with the intention of improving the patients' quality of life as well as providing therapeutic alternatives to intravenous chemotherapy. Until agents such as oxaliplatin and irinotecan became available, the treatment of colorectal cancer, one the most common cancers diagnosed in industralized countries, was mainly based on 5-fluorouracil modulation. The overwhelming majority of these new drugs are pyrimidine analogues intended to replace intravenous treatment or to make the therapy more acceptable to the patients. In this article, the use of oral chemotherapy, alone or in combination with radiotherapy, in colorectal cancer is reviewed and updated. The rationale for using oral compounds is discussed and newer agents, such as oral camptothecin analogues and antiangiogenic agents, are presented with the results of their clinical and preclinical developments.     

Intensive chemotherapy for patients with high-risk myelodysplastic syndrome

Standard antileukemic chemotherapy induces complete remission in approximately half of patients with high-risk (HR) myelodysplastic syndrome (MDS). Intensification of induction therapy by the use of intermediate- or high-dose cytosine arabinoside in combination with fludarabine, idarubicin, or topotecan seemingly improved complete response (CR) rates, particularly in patients with poor prognosis karyotypes. The various high-intensity regimens appear to be comparable in inducing CR, although some are better tolerated with low mortality even in advanced-age populations with MDS. The encouraging early results with new agents, eg, topoisomerase inhibitors (topotecan) and hypomethylating agents (5-azacytidine), have been disappointing because long-term follow-up has shown continuous relapses. Regardless of the intensity of chemotherapy, remissions are short, even with continuation of intensive postremission therapy. Long-term disease-free survival remains dismal. In a large population with HR MDS treated with high-dose chemotherapy, only 5% of patients were alive at 3 years, and a majority of survivors were the younger patients with diploid karyotype refractory anemia with excess blasts in transformation. Further intensification of either induction chemotherapy or postremission therapy is unlikely to improve results with current drug combinations. With these results at hand, the role of intensive chemotherapy in the management of MDS remains controversial. Because CR status is associated with clinical benefits and possibly better survival, induction of CR should remain an important aim for HR MDS. The intensive combination chemotherapy may be integrated as an initial part of the management of HR MDS, as an alternative for patients not eligible for allogeneic bone marrow transplantation (BMT). Regimens with low early mortality, eg, topotecan plus intermediate dose Ara-C, could also be used to reduce tumor load prior to allogeneic BMT. Induction of CR should be attempted with the most effective and best tolerated regimens, particularly, but not only, in younger patients with good performance status regardless of karyotype. Postremission therapy remains a major challenge. It should involve either allogeneic BMT or investigational approaches to eliminate or control the minimal residual disease with different mechanisms In elderly patients, allogeneic "minitransplant" is an investigational alternative seeking to exploit graft-versus-tumor reaction. New agents, such as farnesyl transferase inhibitors (ras inhibitors), drug-antibody conjugates (Myelotarg), thalidomide, arsenic trioxide, maintenance chemotherapy with hypomethylating agents, or oral topoisomerase inhibitors along with agents modulating factors affecting growth and differentiation, should be explored to maintain remission with minimal compromise of quality of life. Although prognostic scoring systems such as the new International Prognostic Scoring System (IPSS) do not predict for initial response, IPSS continues to predict survival in patients treated with high-dose chemotherapy. Although activity of new agents could be rapidly assessed in single-arm pilot studies, the final merit of high-dose chemotherapy could be assessed only in well-designed randomized trials with patients assigned according to risk-based classification and evaluated for response by generally accepted and standardized criteria.     

Nutlin-3 cooperates with doxorubicin to induce apoptosis of human hepatocellular carcinoma cells through p53 or p73 signaling pathways

Purpose  

Despite recent advances in chemotherapeutic agents for Hepatocellular carcinoma (HCC) treatment, the results of chemotherapy remain unsatisfactory. Doxorubicin (DOX) still represents the cornerstone in HCC chemotherapy, but resistance and toxicity to normal cells are major obstacles to successful chemotherapy. Therefore, new active agents in HCC chemotherapy and agents that increase the chemosensitivity of HCC cells to DOX are still urgently required. Nutlin-3 is a small-molecule inhibitor that acts to inhibit murine double minute-2 (MDM2) binding to p53 or p73, and subsequently activates p53- or p73-dependent apoptosis signaling pathway. This study was designed to investigate whether Nutlin-3 alters cell toxicity to HCC cells following DNA damage and to assess the suitability of DOX/Nutlin-3 as a chemotherapeutic combination in HCC chemotherapy.     

Advances in the management of nausea and vomiting induced by non-cisplatin containing chemotherapeutic regimens

Nausea and vomiting are the most feared toxicities of chemotherapy. Afferent impulses from the chemoreceptor trigger zone, peripheral sites, the cerebral cortex, or the vestibular center can initiate the emetic reflex. Antiemetic protection therefore requires interruption of appropriate emetogenic pathways. Since the chemoreceptor trigger zone contains numerous dopaminergic neurons, antidopaminergic agents including phenothiazines and metoclopramide have gained importance as antiemetics. However standard dose phenothiazines have limited efficacy while high dose metoclopramide may have excessive toxicity in the non-cisplatin setting. Recent advances have therefore centered on development of new classes of antiemetics. Corticosteroids have excellent activity alone or in combination with other antiemetic agents. Cannabinoids have recently been introduced into commercial use as antiemetics with particular activity against non-cisplatin chemotherapy. Benzodiazepines are active against anticipatory nausea and vomiting and are also used in combination antiemetic regimens. Although the vestibular center seems to have a lesser influence on chemotherapy-induced nausea and vomiting, vestibular blocking agents such as scopolamine may have a potential role as adjunctive antiemetics. Finally, appreciation of the role of serotonin (5-HT3) receptors in both peripheral and central emetic pathways may lead to a new class of antiserotonergic antiemetic agents.     

The role of high-dose chemotherapy in the treatment of non-small cell lung cancer

The literature on high-dose chemotherapy in non-small cell lung cancer (NSCLC) with autologous bone marrow or peripheral blood stem cell transplantation does not - as of yet - provide evidence of relevant benefits. At the same time, the significant risks of treatment-related morbidity and mortality associated with dose-intensified chemotherapy in this vulnerable patient population are increasingly recognized. Whether the advent of new cytotoxic agents such as the Taxans or newer Topoisomerase inhibitors will help to improve the hitherto unsatisfying results of high-dose chemotherapy in NSCLC, remains to be determined. The few ongoing studies in the area strive to examine such newer drug-combinations in a multimodality treatment concept combining neo-adjuvant chemotherapy or chemoradiation with surgery and adjuvant thoracic radiation therapy.     

Targeted therapy in colorectal cancer: do we know enough?

The present paper is a critical review about the recent development of new agents that have revolutioned the therapeutical approach of solid tumours with a particular focus on colorectal cancer. Until a few years ago, chemotherapy has been considered the only medical treatment for advanced disease. At the moment, new drugs blocking some cell functions, such as monoclonal antibodies or tyrosin kinase inhibitors are available for many oncologists, but their efficacy should be debated for several reasons. Despite having a strong biological and preclinical rationale, the clinical results of these agents are not comparable to the results obtained by imatinib in gastrointestinal stromal tumour or in chronic myeloid leukaemia even though superior to chemotherapy alone. Moreover, the efficacy does not show any correlation with the molecular expressions of the tumours. In this review, we considered different hypotheses in order to explain these results.     

Management of advanced gastric cancer

The management of advanced gastric cancer has only evolved a little over the last 15 years: platinum and fluoropyrimidine chemotherapy remains the backbone of therapy with ongoing debate as to the benefit of triplet therapy with either an anthracycline or taxane. Recently published trials of biological agents, in particular those targeting the Her2 receptor, have provided some signs of improvement. This article summarizes the relevant literature, discusses the role of these agents, as well as geographical variations in use, and provides recommendations regarding both ‘standard chemotherapy’ and the role of biological agents in advanced gastric cancer. Given the relative lack of progress for gastric cancer over the last 15 years, the focus for the next 5 years should be on an improved understanding of the molecular basis of gastric cancer, thus allowing rational integration of new molecular agents.     

Metastatic Bladder Cancer: Role of Chemotherapy and New Agents

The M-VAC chemotherapy regimen has been widely used in locally advanced as well as in metastatic disease. Since only a proportion of patients with advanced disease will survive, there is a dire need to identify patients who will respond to chemotherapy and to identify new agents, targets and strategies to improve treatment outcome. Approaches to the management of advanced urothelial cancer include: intensifying the dose intensity, doublet and triplet combination chemotherapy, sequential regimens, reducing toxicity in unfit or elderly patients, and the use of biologic targeted therapies and promising new chemotherapeutic agents. These include MTA, the epothilones, topoisomerase inhibitors and vinflunine which act upon folate metabolism or upon different phases of the cell cycle. New agents that are coming into clinical trials include farnesyl transferase inhibitors, several growth factors receptor inhibitors, anti-sense therapy and COX-2 inhibitors. Significant progress has been made in understanding the molecular biology of cancer. Numerous novel agents, many of which are in clinical trials, have been developed to target various processes of tumor progression. The rationale behind application of these molecularly targeted therapies is to overcome resistance to cytotoxic therapies. Bladder cancer represents a unique model for targeted therapy. As our understanding increases, integration of newer biologic agents will condition future trials, and our ability to target bladder and urothelial cancers will be enhanced.     

Antiangiogenic therapy for liver metastasis of gastrointestinal malignancies

In about half of the patients with gastrointestinal carcinomas, surgical excision of the primary tumor is not curative because metastasis has already occurred. Recent investigations of metastasis have shown that angiogenesis plays an important role in this process. In solid tumors angiogenesis occurs continuously to provide a blood supply for the proliferating cancer cells. As a new and potent method to control metastasis, antiangiogenic therapy has attracted considerable interest. This therapy inhibits angiogenesis, inducing a dormant state in which tumors cannot grow; the prognosis may thus be remarkably improved. Antiangiogenic agents show a characteristic antitumor effect which is different from that of chemotherapy. Based on our experimental in-vivo data, we conclude that antiangiogenic agents should not be used only for achieving tumor shrinkage, like chemotherapy. These agents should be used to control micrometastases, as the therapeutic effect on such metastasis is excellent. In addition, antiangiogenic agents may be valuable for long-term administration to maintain tumor dormancy, because drug resistance does not develop and these agents have a sustained effect. Combinations with conventional anti-cancer treatments such as chemotherapy, radiotherapy, immunotherapy, or surgery may also be valuable.