齐墩果酸抗人肺癌细胞增殖、侵袭和诱导细胞凋亡的研究

 目的　研究齐墩果酸抗人肺癌细胞增殖、侵袭和诱导细胞凋亡的作用 ,并探讨其抗侵袭作用的机理。方法　用细胞增殖抑制试验、软琼脂集落形成试验、对重建基底膜的侵袭试验、趋化运动试验、对层粘连蛋白的粘附试验以及组织蛋白酶B活性测定观察齐墩果酸对PGCL3细胞侵袭能力的影响 ,用吖啶橙 -溴乙啶荧光双染法和TUNEL法检测细胞凋亡。结果　齐墩果酸可降低PGCL3细胞增殖能力并呈剂量依赖性 ,IC50 为 4 0 .71 μmol/L ;35 μmol/L和 4 5 μmol/L齐墩果酸均能抑制PGCL3细胞的侵袭能力 (P <0 .0 1 )且有剂量依赖性。抗侵袭作用机理的分析结果显示上述浓度的该药物对细胞的运动、粘附及组织蛋白酶B分泌均有明显的抑制作用 (P <0 .0 5和P <0 .0 1 ) ;软琼脂集落形成率也显著降低 ;上述浓度的药物处理 4 8h均使PGCL3细胞凋亡率显著升高 (P <0 .0 1 )。结论　齐墩果酸有抗PGCL3人肺癌细胞增殖和侵袭作用 ,并有诱导PGCL3细胞凋亡的作用。其抗侵袭机理不是对侵袭的某一环节的阻断 ,而是对侵袭各个基本环节都有抑制作用     

烟酸及其衍生物：从传统营养素到肿瘤防治的新认识

烟酸属于B族维生素,是人体必需的维生素之一。过去对烟酸功能的认知主要停留在营养素层面,如参与维持神经功能、促进代谢和发育、保护心脑血管等。随着研究的不断深入,近年来已有多项研究表明,烟酸及其衍生物能起到预防和辅助治疗癌症的作用。烟酸及其衍生物不仅影响肿瘤细胞的生物学功能、参与免疫调节,还能对烟酰胺磷酸核糖转移酶（NAMPT）抑制剂的抗肿瘤疗效起到辅助作用,并以多聚ADP-核糖聚合酶（PARP）依赖方式通过多种分子途径维持基因组的稳定性。本文总结了烟酸及其衍生物在肿瘤中作用的研究脉络和最新进展,并展望其进一步研究和应用方向,对烟酸及其衍生物在肿瘤综合防治中的应用有一定的指导作用。     

结直肠癌患者血清脂肪酸合成酶水平的检测及其临床意义

背景与目的：脂肪酸合成酶(fatty acid synthase, FAS)是唯一有能力在细胞内合成长链脂肪酸的蛋白。由于肿瘤组织对脂肪酸的需求旺盛,包括结直肠癌在内的多种恶性肿瘤组织中常见FAS过表达。本实验研究结直肠癌患者血清FAS水平与肿瘤病理特征的关系。方法：选择2013年3月—2014年3月接受根治性手术治疗的60例结直肠癌患者为研究组,另选20名健康志愿者为对照组。采用酶联免疫吸附法(enzymelinked immunosorbent assay,ELISA)检测血清FAS水平,分析结直肠癌患者血清FAS水平与其临床病理特征的关系。结果：研究组FAS平均为20.77±10.56 mg/L,对照组FAS水平为10.33±5.65 mg/L,差异有统计学意义(P<0.05)。研究组Ⅰ~Ⅱ、Ⅲ及Ⅳ期患者FAS水平分别为13.24±11.43、24.20±11.87和35.44±12.18 mg/L,各组间比较差异均有统计学意义(P<0.05)。研究组高分化、中分化、低分化患者FAS水平分别为16.46±10.58、20.38±11.87和25.84±10.88 mg/L,各组间比较差异无统计学意义(P>0.05)。结论：血清FAS水平可能与结直肠癌的发生、发展有一定关系,可以对其作为评估肿瘤进展情况的标志物的可行性作进一步研究。     

Preclinical analyses of intravesical chemotherapy for prevention of bladder cancer progression

There is a critical need to identify treatment options for patients at high risk for developing muscle invasive bladder cancer that avoid surgical removal of the bladder (cystectomy). In the current study, we have performed preclinical studies to investigate the efficacy of intravesical delivery of chemotherapy for preventing progression of bladder cancer. We evaluated three chemotherapy agents, namely cisplatin, gemcitabine, and docetaxel, which are currently in use clinically for systemic treatment of muscle invasive bladder cancer and/or have been evaluated for intravesical therapy. These preclinical studies were done using a genetically-engineered mouse (GEM) model that progresses from carcinoma in situ (CIS) to invasive, metastatic bladder cancer. We performed intravesical treatment in this GEM model using cisplatin, gemcitabine, and/or docetaxel, alone or by combining two agents, and evaluated whether such treatments inhibited progression to invasive, metastatic bladder cancer. Of the three single agents tested, gemcitabine was most effective for preventing progression to invasive disease, as assessed by several relevant endpoints. However, the combinations of two agents, and particularly those including gemcitabine, were more effective for reducing both tumor and metastatic burden. Our findings suggest combination intravesical chemotherapy may provide a viable bladder-sparing treatment alternative for patients at high risk for developing invasive bladder cancer, which can be evaluated in appropriate clinical trials.     

溶血磷脂酸在结直肠癌发生发展中的机制研究

近年来,自分泌运动因子-溶血磷脂酸(Autotaxin-lysophosphatidic acid,ATX-LPA)信号通路在结直肠癌发生发展中的重要性已逐渐得到了医学界的广泛认可。LPA信号可以通过至少6种G蛋白偶联受体(Gprotein-coupled receptors,GPCRs),即LPA_1-6,诱导各种细胞进程,包括伤口愈合、分化、增殖、迁移和存活等,这些细胞进程对维持肠上皮屏障的功能、促进结直肠癌细胞的存活、增殖及转移都十分重要。因此,本文对近年来发现的ATX-LPA信号通路与结直肠癌相关炎症的关系,及该信号通路对结直肠癌发生发展过程的影响进行综述,同时也对LPA及相关分子在结直肠癌治疗中的价值前景做出预测。     

Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy

Perillyl alcohol (POH) is a naturally occurring dietary monoterpene isolated from the essential oils of lavender, peppermint, and other plants. Medical interest in this compound was generated by research findings showing that POH was able to inhibit the growth of tumor cells in cell culture and exert cancer preventive and therapeutic activity in a variety of animal tumor models. Based on this promising preclinical work, POH was formulated in soft gelatine capsules and orally administered to cancer patients several times a day on a continuous basis. However, such clinical trials in humans yielded disappointing results, also because the large number of capsules that had to be swallowed caused hard-to-tolerate intestinal side effects, causing many patients to withdraw from treatment due to unrelenting nausea, fatigue, and vomiting. As a result, efforts to treat cancer patients with oral POH were abandoned and did not enter clinical practice. Intriguingly, clinical trials in Brazil have explored intranasal POH delivery as an alternative to circumvent the toxic limitations of oral administration. In these trials, patients with recurrent malignant gliomas were given comparatively small doses of POH via simple inhalation through the nose. Results from these studies show this type of long-term, daily chemotherapy to be well tolerated and effective. In this review, we will present the vicissitudes of POH’s evaluation as an anticancer agent, and its most recent success in therapy of patients with malignant brain tumors.     

Dietary fat and fatty acid intake and epithelial ovarian cancer risk: evidence from epidemiological studies

The associations between dietary fat and fatty acid (FA) intakes and epithelial ovarian cancer (EOC) risk have been inconsistent in previous studies. We conducted a meta-analysis of epidemiological studies to evaluate these associations. We identified relevant studies by searching PubMed, EMBASE, and Web of Science databases. We used random-effects models to estimate summary relative risks (RRs) and 95% confidence intervals (CIs). Overall, the search yielded 20 studies (1 pooled analysis of 12 cohort studies, 5 cohorts, and 14 case-control studies). The summary RR for EOC for the highest versus lowest categories of total dietary fat intake was 1.12 (95%CI= 0.95–1.33; I² = 77.4%; n = 14). The RRs were not significant when fats were divided into plant-based fats (RR = 0.93, 95%CI = 0.77–1.13; n = 6), animal-based fats (RR = 1.15, 95%CI = 0.95–1.39; n = 8), dairy-based fats (RR = 1.02, 95%CI = 0.88–1.18; n = 3), saturated FAs (RR = 1.04, 95%CI = 0.93–1.17; n = 12), monounsaturated FAs (RR = 0.98, 95%CI = 0.84–1.13; n = 10), polyunsaturated FAs (RR = 0.96, 95%CI = 0.81–1.12; n = 10), and trans-unsaturated FAs (RR = 1.15, 95%CI = 0.98–1.36; n = 3). Similar non-significant results were also observed in most of the subgroup and sensitivity analyses. The findings of this meta-analysis suggest a lack of evidence for associations between dietary fat and FA intakes and EOC risk. Further analyses should be conducted to assess the associations with other types of fat, and the results should be stratified by tumor invasiveness and EOC histology.     

Ellagic acid,sulforaphane, and ursolic acid in the prevention and therapy of breast cancer: current evidence and future perspectives

Globally, breast cancer is the most common cancer and the second leading cause of cancer-related death among women. Surgery, chemotherapy, hormonal therapy, and radiotherapy are currently available treatment options for breast cancer therapy. However, chemotherapy, hormonal therapy, and radiotherapy are often associated with side effects and multidrug resistance, recurrence, and lack of treatment in metastasis are the major problems in the treatment of breast cancer. Recently, dietary phytochemicals have emerged as advantageous agents for the prevention and therapy of cancer due to their safe nature. Ellagic acid (EA), sulforaphane (SF), and ursolic acid (UA), which are found in widely consumed fruits and vegetables, have been shown to inhibit breast cancer cell proliferation and to induce apoptosis. This review encompasses the role of EA, SF, and UA in the fight against breast cancer. Both in vitro and in vivo effects of these agents are presented.     

Adjuvant chemotherapy for rectal cancer: Current evidence and recommendations for clinical practice

While adjuvant chemotherapy is an established treatment for pathological stage II and especially stage III colon cancer, its role in the multimodal management of rectal cancer remains controversial. As a result, there is substantial variation in the use of this treatment in clinical practice. Even among centres and physicians who consider adjuvant chemotherapy as a standard treatment, notable heterogeneity exists with regard to patient selection criteria and chemotherapy regimens. The controversy around this topic is confirmed by the lack of full consensus among national and international clinical guidelines. While most of the clinical trials do not support the contention that adjuvant chemotherapy may improve survival outcomes if pre-operative (chemo)radiotherapy is also given, these suffer from many limitations that preclude drawing definitive conclusions. Nevertheless, in the era of evidence-based medicine, physicians should be guided by the available data and refrain from extrapolating results of adjuvant colon cancer trials to inform treatment decisions for rectal cancer. Patients should be informed of the evidence gap, be given the opportunity to carefully discuss pros and cons of all the possible management options and be empowered in the decision making. In this article we review the available evidence on adjuvant chemotherapy for rectal cancer and propose a risk-adapted decisional algorithm that largely relies on informed patient preferences.     

Role of neoadjuvant therapy for nonmetastatic pancreatic cancer: Current evidence and future perspectives

Pancreatic adenocarcinoma (PDAC) is one of the most common and lethal human cancers worldwide. Surgery followed by adjuvant chemotherapy offers the best chance of a long-term survival for patients with PDAC, although only approximately 20% of the patients have resectable tumors when diagnosed. Neoadjuvant chemotherapy (NACT) is recommended for borderline resectable pancreatic cancer. Several studies have investigated the role of NACT in treating resectable tumors based on the recent advances in PDAC biology, as NACT provides the potential benefit of selecting patients with favorable tumor biology and controls potential micro-metastases in high-risk patients with resectable PDAC. In such challenging cases, new potential tools, such as ct-DNA and molecular targeted therapy, are emerging as novel therapeutic options that may improve old paradigms. This review aims to summarize the current evidence regarding the role of NACT in treating non-metastatic pancreatic cancer while focusing on future perspectives in light of recent evidence.     

Neoadjuvant therapy for gastric cancer: current evidence and future directions

Although surgical resection remains the only potentially curative treatment for gastric cancer (GC), poor long-term outcomes with resection alone compel a multimodality approach to this disease. Multimodality strategies vary widely; while adjuvant approaches are typically favored in Asia and the United States (USA), a growing body of evidence supports neoadjuvant and/or perioperative strategies in locally advanced tumors. Neoadjuvant approaches are particularly attractive given the morbidity associated with surgical management of GC and the substantial risk of omission of adjuvant therapy. The specific advantages of chemoradiotherapy (CRT) compared to chemotherapy have not been well defined, particularly in the preoperative setting and trials aimed at determining the optimal elements and sequencing of therapy are underway. Future studies will also define the role of targeted and biologic therapies.     

乳腺癌导管内干预的研究进展

随着对乳腺癌生物学行为的深入认识,乳腺癌的根治术正向微创术式转变。对于早期乳腺癌特别是乳腺导管原位癌（duc-tal carcinoma in situ,DCIS）或癌前病变的患者,构建创伤性小、全身毒性低的干预措施是目前亟待解决的问题之一。乳腺癌导管内干预是通过乳腺天然的哺乳导管开口,借助合适的载体对乳腺导管系统病变进行诊疗干预,从而实现乳腺癌的微创治疗。将乳腺癌导管内干预与靶向治疗、内分泌治疗及免疫治疗等相结合,有望进一步提高精准治疗效果。结合我国乳腺癌患者临床病理特点,将纳米技术、分子影像技术及基因测序技术有机结合,进行乳腺癌导管内干预的机制研究,是临床应用、基础研究的重点内容之一。本文主要对乳腺癌导管内干预的研究进展进行综述。      

Early clinical detection of ovarian cancer: a review of the evidence

Subjective and objective evidence suggest that a third to half of patients developing ovarian cancer report symptoms at 3 or more months prior to diagnosis. Early ovarian cancer-associated symptoms constitute a constellation of mostly nongynecological complaints, suggesting a visceral disturbance, which do not point immediately to a pelvic origin. Abdominal bloating and pain predominate with recent onset and multiple symptomatic episodes. Gastrointestinal and urinary symptoms and fatigue/malaise may be part of the symptom complex. Women aged 50 years and older with this constellation of symptoms should have medical evaluation and, if symptoms are unexplained or persist, should undergo pelvic imaging (e.g., transvaginal ultrasound) and serum CA125.     

Zoledronic acid to prevent bone loss in Chinese men receiving androgen deprivation therapy for prostate cancer

Aim: To explore the bone mineral density (BMD) preservation effect of zoledronic acid and its renal safety and tolerability in Chinese patients with prostate cancer on androgen deprivation therapy (ADT). Methods: Overall 26 prostate cancer patients with ADT were given zoledronic acid 4 mg by a 15‐min i.v. infusion every 3 months for up to 12 months. Assessment was made at baseline and at 3, 6, 9 and 12 months. Dual‐energy X‐ray absorptiometry was used to measure the BMD of the lumbar spine and the femoral neck at baseline and 12 months. Results: A total of 23 of 26 recruited patients completed the study. Seven patients had bone metastases. The overall mean increase in BMD (T‐score) of the lumbar spine and femoral head from baseline to follow up at 12 months was significant (−2.32 ± 0.98 to −2.03 ± 1.08, P = 0.02 and −1.77 ± 0.72 to −1.63 ± 0.76, P = 0.01, respectively). In subgroup analyses, significant BMD improvement was observed independent of the status of bone metastasis and the means of ADT. Zoledronic acid had no adverse effect on renal function. Adverse events related to zoledronic acid were minimal. Conclusion: Zoledronic acid administered every 3 months significantly increased BMD in prostate cancer patients receiving ADT. It had a satisfactory adverse event profile and imposed minimal risk on patients' renal function.     

Combined effects of the bisphosphonate, zoledronic acid and the aromatase inhibitor letrozole on breast cancer cells in vitro: evidence of synergistic interaction

Background:

Aromatase inhibitors are widely used in the treatment of oestrogen receptor-positive post-menopausal breast cancer. These patients may also be receiving the bisphosphonate, zoledronic acid (ZA) to prevent bone loss or reduce skeletal morbidity in the setting of advanced disease. The potential biological interaction of these two drugs in breast cancer has not been assessed.

Methods:

Aromatase-expressing breast cancer cells were treated with letrozole and ZA either simultaneously or in sequence, and the resulting apoptosis was assessed by staining with Hoechst 33342 and propidium iodide and examined using a fluorescent inverted Leica DMIRB microscope and a UV filter.

Results:

We found that letrozole and ZA induce levels of apoptosis in breast cancer cells in vitro that are significantly greater compared with treatment with each drug alone. However, this potentially, synergistic relationship is drug-sequence dependent, occurring only when cells are treated with letrozole, followed by ZA. The converse sequence, or administering drugs simultaneously, induces levels of apoptosis no greater than each drug alone.

Conclusion:

Owing to the enhanced anti-tumour efficacy of sequential drug administration, our findings may indicate that, for post-menopausal women who require treatment with letrozole, ZA should also be considered.     

Nanoformulation of natural products for prevention and therapy of prostate cancer

There is a need for developing improved therapeutic options for the management of prostate cancer, able to inhibit proliferation of precancerous and malignant lesions and/or to improve the effectiveness of conventional chemopreventive and chemotherapeutic agents. In this perspective, application of nanotechnology based strategies for the delivery of natural compounds for effective management of the disease is being actively researched. Here, after highlighting the most promising natural compounds for chemoprevention and chemotherapy of prostate cancer, the state of the art nanotherapeutics and the recent proof-of-concept of “nanochemoprevention”, as well as the clinical development of promising targeted nanoprototypes for use in the prostate cancer treatment are being discussed.     

Preclinical and clinical strategies for development of telomerase and telomere inhibitors

Background: Telomerase is an important enzyme whose activity has been convincingly demonstrated in humans recently. It is required for maintenance of ends of chromosomes (telomeres) during cell division. Since its presence has been selectively demonstrated in dividing cells including tumor cells, it has generated considerable excitement as a potential anti-cancer strategy.Design: In this article, we review the current relevant biology of the enzyme, the challenges encountered in the preclinical phase of target development and the current efforts that focus on telomeres and telomerase as therapeutic targets. We also speculate on the potential toxicities and mechanisms of resistance that may be encountered during use of such therapies.     

蛋白质组学在肿瘤防治研究中的应用

随着人类基因组测序计划 (humangenomesequenceproject)的完成 ,产生了蛋白质组学 (proteomics) --研究细胞内全部蛋白质的组成及动态变化的一门新兴学科。恶性肿瘤是一种多种基因和蛋白质参与的复杂疾病。综述了在肿瘤防治中蛋白质组学的主要策略和技术 ,及其在肿瘤标志物的筛选和鉴定、肿瘤分类、预后、治疗效果的评价及肿瘤发生机制等方面的研究。