阿司匹林在结直肠癌防治中的研究进展

结直肠癌是我国常见的恶性肿瘤。尽管结直肠的致残率和致死率已有下降,且近十年对于结直肠癌的系统治疗有显著进展,但对其有效的预防措施与辅助疗法仍有待进一步研究。阿司匹林是解热镇痛类的经典药物,在风湿免疫疾病及心脑血管疾病有广泛的应用。近年来研究发现阿司匹林可降低结直肠腺瘤及结直肠癌的发病率。本文拟就阿司匹林对结直肠癌预防与治疗中的研究进展进行综述。     

Tumor-derived extracellular vesicles for the active targeting and effective treatment of colorectal tumors in vivo

Colorectal cancer remains one of the main causes of cancer-related deaths worldwide. Although numerous nanomedicine formulations have been developed to tackle the disease, their low selectivity still limits effective therapeutic outcomes. In this study, we isolated extracellular vesicles (EVs) from CT26 colorectal cancer cells and 4T1 murine mammary carcinoma cells, loaded them with the chemotherapeutic agent (doxorubicin, DOX). Then we evaluated the cellular uptake of the extracellular vesicles both in 2D monolayer and 3D tumor spheroid setups using confocal laser scanning microscope and flow cytometry. In vivo tumor homing of the extracellular vesicles was verified on CT26 tumor bearing BALB/c mice using in vivo imaging system. Finally, in vivo therapeutic effects were evaluated and compared using the same animal models treated with five doses of EV formulations. CT26-EV-DOX exhibited excellent biocompatibility, a high drug-loading capacity, controlled drug release behavior, and a high capability for targeting colorectal cancer cells. In particular, we verified that CT26-EV-DOX could preferentially be up taken by their parent cells and could effectively target and penetrate 3D tumor spheroids resembling colorectal tumors in vivo in comparison with their 4T1 derived EV partner. Additionally, treatment of colorectal tumor-bearing BALB/c mice with of CT26-EV-DOX significantly inhibited the growth of the tumors during the treatment course. The developed CT26-EV-DOX nanoparticles may present a novel and effective strategy for the treatment of colorectal cancer.     

Novel hyaluronic acid oligosaccharide-loaded and CD44v6-targeting oxaliplatin nanoparticles for the treatment of colorectal cancer

Oxaliplatin resistance is one of the main causes of failed colorectal cancer treatment, followed by recurrence and metastasis. In this study, we found that colorectal cancer cells secrete a high level of hyaluronic acid (HA), which interacts with its receptor CD44v6 to mediate colorectal cancer resistance to chemotherapy. HA oligosaccharide (oHA) is a degradation product of HA. We found that it competitively binds to CD44v6, reversing the HA–CD44v6-mediated effect of HA on oxaliplatin resistance. In addition, oHA showed no toxicity or immunogenicity but exhibited good biocompatibility and tumor-targeting capability. Therefore, we synthesized oHA-loaded oxaliplatin liposome nanoparticles (oHA-Lipid-Oxa) using a thin-film hydration method. The cytotoxicity of oHA-Lipid-Oxa was assessed in vitro using flow cytometry, which revealed greater lethality than oxaliplatin alone. Finally, we established a tumor-bearing nude mouse model and separately injected oHA-Lipid-Oxa, Lipid-Oxa, Oxa, oHA, and phosphate-buffered saline (PBS) into the tail vein to observe the antitumor effects of nanoparticles in vivo. The oHA-Lipid-Oxa group exhibited the highest tumor suppression rate, but the weight loss was not obvious. Hematoxylin and eosin staining showed greatest lymphocyte and macrophage infiltration in the oHA-Lipid-Oxa group. Moreover, oHA-Lipid-Oxa induced tumor cell apoptosis and necrosis most robustly compared with the other groups. We showed that oHA-Lipid-Oxa has excellent histocompatibility and CD44v6-targeting capabilities, thus greatly increasing the sensitivity to oxaliplatin and reducing adverse reactions. Accordingly, oHA-Lipid-Oxa has a broad potential for therapeutic application.     

Regorafenib in the treatment of colorectal cancer

Introduction: Colorectal cancer (CRC) is among the most frequently diagnosed malignancies, and is commonly associated with metastatic disease at presentation. While chemotherapy represents a mainstay of management, options at the time of disease progression are limited. Regorafenib is a novel multikinase inhibitor which has been evaluated for patients with chemo-refractory metastatic CRC (mCRC) and is currently approved for use in a last-line-of-treatment setting.

Areas covered: Articles searchable on MEDLINE/PubMed were reviewed to provide context for use of regorafenib in the management of mCRC. Specific drug properties are discussed, including chemistry, pharmacodynamics, pharmacokinetics, and metabolism. Additionally, clinical efficacy is reported with consideration of Phases I–III data.

Expert opinion: Phase III evaluation has confirmed the efficacy of regorafenib for patients with chemo-refractory mCRC. Importantly, the rapid accrual of the CORRECT trial revealed the degree of unmet need for this patient population, and proved that it was feasible to compare novel agents to placebo when multiple lines of standard therapy have failed. In the coming years, the role of regorafenib in the management of mCRC should be further clarified, especially through identification of the patient population with greatest anticipated benefit and exploration of its use as an adjuvant or maintenance agent.     

Colon-specific delivery of celecoxib is a potential strategy to improve toxicological and pharmacological properties of the selective Cox-2 inhibitor: implication in treatment of familiar adenomatous polyposis

In general, colon-specific delivery of a drug decreases systemic absorption and increases therapeutic concentration of the drug at the target site. N-succinylglutam-1 or 5-yl celecoxib (SG1C and SG5C) were prepared as a colon-specific prodrug of celecoxib, a selective Cox-2 inhibitor, and investigated whether the celecoxib derivatives could deliver celecoxib to the target site and improve cardiovascular toxicity and therapeutic effectiveness for the treatment of familiar adenomatous polyposis. SG1C and SA5C were cleaved to release celecoxib in the cecal contents while stable in small intestinal contents. The cecal release of celecoxib was much greater for SG1C than SG5C. SG1C administered orally was barely detected in the blood and urine. SG1C delivered much greater amount of celecoxib to the large intestine while keeping the plasma concentration of celecoxib at much lower level compared with oral administration of free celecoxib. Consistent with these pharmacokinetic results, SG1C supplied a greater concentration of celecoxib for the entire colonic tissue and did not change the serum level of 6-keto-PGF_1α whose decrease is associated with the cardiovascular toxicity of celecoxib. Taken together, colon-specific delivery of celecoxib using a prodrug approach may be a useful strategy to improve toxicological and pharmacological properties of celecoxib.     

雷替曲塞以腹腔/静脉给药途径治疗结直肠癌腹水的疗效比较

目的探讨雷替曲塞以腹腔/静脉给药途径治疗结直肠癌腹水的疗效。方法经病理或细胞学确诊的50例晚期结直肠癌腹水患者分为观察组(n=25)和对照组(n=25)。观察组方案:雷替曲塞3 mg/m2腹腔灌注,奥沙利铂120 mg/m2静滴。对照组方案:雷替曲塞3 mg/m2静滴,奥沙利铂120 mg/m2静滴。两方案均3周为1周期,每周期评价不良反应,每3个周期评价疗效,直至疾病进展或毒性不能耐受,最多治疗12个周期,比较两组的有效率(RR)、疾病控制率(DCR)、中位肿瘤进展时间(m TTP)及不良反应发生率。结果两组RR分别为20%和8%(P<0.05),DCR分别为92%和84%(P>0.05)及m TTP分别为4.5个月和3.6个月(P<0.05)。观察组1、2级丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)升高发生率为4%,对照组为24%(P<0.05);对照组1、2级中性粒细胞减少、口腔黏膜炎的发生率(分别为48%与32%),均高于观察组(20%与8%)(P<0.05)。结论雷替曲塞腹腔给药疗效优于静脉给药,不良反应更轻,可以作为结直肠癌晚期腹水的有效姑息治疗方案。     

Overcoming formulation challenges for the next generation of vaccines

Introduction: In recent years, the number of active pharmaceutical ingredients with high therapeutic impact, but very low water solubility, has increased significantly. Thus, a great challenge for pharmaceutical technology is to create new formulations and efficient drug-delivery systems to overcome these dissolution problems.

Areas covered: Drug formulation in solid dispersions (SDs) is one of the most commonly used techniques for the dissolution rate enhancement of poorly water-soluble drugs. Generally, SDs can be defined as a dispersion of active ingredients in molecular, amorphous and/or microcrystalline forms into an inert carrier. This review covers literature which states that the dissolution enhancement of SDs is based on the fact that drugs in the nanoscale range, or in amorphous phase, dissolve faster and to a greater extent than micronized drug particles. This is in accordance to the Noyes–Whitney equation, while the wetting properties of the used polymer may also play an important role.

Expert opinion: The main factors why SD-based pharmaceutical products on the market are steadily increasing over the last few years are: the recent progress in various methods used for the preparation of SDs, the effect of evolved interactions in physical state of the drug and formulation stability during storage, the characterization of the physical state of the drug and the mechanism of dissolution rate enhancement.     

A novel copper chelator for the suppression of colorectal cancer

Copper ions play a crucial role in the progression of cancers. Tumor tissue is rich in copper ions, and copper chelators could potentially scavenge these copper ions and thus exert an antitumor effect. In this study, we report the synthesis of a novel thieno[3,2-c]pyridine compound we have called “ JYFY-001 ” that can act as the copper chelator thanks to the inclusion of an N-(pyridin-2-yl)acetamide moiety that targets copper ions. JYFY-001 potently inhibited cancer proliferation, inducing cell apoptosis and impairing the extracellular acidification rate and oxygen consumption rate of colorectal cancer (CRC) cells. JYFY-001 also inhibited the growth of a CRC-transplanted tumor in a dose-dependent manner, inducing apoptosis of the tumor cells and promoting the infiltration of lymphocytes in the CRC-transplanted tumor tissues. JYFY-001 also enhanced the antitumor effects of the programmed cell death protein 1 (PD-1) inhibitor. The relatively benign nature of JYFY-001 was demonstrated by the effect on normal cell viability and acute toxicity tests in mice. Our findings suggest that JYFY-001 is a prospective copper chelator to be used as a targeted drug and a synergist of immunotherapy for CRC treatments.     

Synchronized release of Doxil and Nutlin-3 by remote degradation of polysaccharide matrices and its possible use in the local treatment of colorectal cancer

A novel approach to the prevention of colorectal cancer (CRC) recurrence by the local, luminal application of the combined therapies: Nutlin-3 (NUT) and the liposomal preparation of doxorubicin, Doxil^® (Doxil) is presented here. The two drug entities were loaded into calcium alginate beads, engineered to erode upon exposure to a de-crosslinking agent, to allow for the controlled, concomitant release of the two. The synchronized release-driven improved cytotoxicity of NUT and Doxil was tested in vitro in RKO (wild-type p53) and HT-29 (mutant p53) CRC cells, by measuring intracellular expression of p53, p21 and Mdm2, as well as monitoring cell proliferation and viable cell numbers. NUT treatment alone was identified to be cytotoxic exclusively towards RKO cells. However, coadministration of NUT enhanced Doxil’s anti-proliferative effects and cell death induction in a synergistic manner in both cell types. It was also identified that combinatorial treatment in a wt p53 context affected the p53 pathway by elevating the expression of p53 and its target p21. The capability of the formulation to erode in the presence of a de-crosslinking agent was demonstrated in vivo in the cecum of the anesthetized rat using indomethacin as a poorly water-soluble PK probe.     

结直肠癌肝转移的诊治

结直肠癌是常见恶性肿瘤,其中肝转移是影响结直肠癌的生存率的重要因素。重视肝转移的早期诊断和适当的治疗,是社区医生必须掌握和了解的知识和技能。     

Synthesis of novel tanshinone derivatives for treatment of castration‐resistant prostate cancer

Prostate cancer is the second leading cause of death in USA and has developed serious resistance to current drugs. Thus, development of new drugs for the treatment of castration‐resistant prostate cancer (CRPC) is urgently needed. In this study, 25 novel derivatives of tanshinone IIA as potential androgen receptor (AR) suppression reagents for the treatment of CRPC have been synthesized. The inhibition on DHT‐mediated AR transactivation and cell viability assay were performed to test the synthesized compounds. The results showed that among 25 new compounds, seven methoxy‐substituted tanshinone IIA derivatives showed significant inhibition effect on DHT‐mediated AR transactivation. In particular, TAN‐24 that contains three methoxy groups showed the strongest inhibition effect on DHT‐mediated AR transactivation. In addition, TAN‐24 also suppressed DHT‐AR transactivation more effectively than those of tanshinoneIIA and enzalutamide. In cytotoxicity against human prostate cancer cell lines assay, TAN‐24 exhibited the most potent in vitro cytotoxicity against LNCaP and CWR22Rv1 cells, with IC₅₀ values 20‐ and 19‐times lower than those of tanshinone IIA and comparable to enzalutamide. TAN‐24 reported in the present work represents a novel and effective AR suppression drug, showing great potential for the treatment of CRPC.     

DNA/RNA-based formulations for treatment of breast cancer

Introduction: To develop a successful formulation for the gene therapy of breast cancer, an effective therapeutic nucleic acid and a proper delivery system are essential. Increased understanding of breast cancer, and developments in biotechnology, material science and nanotechnology have provided a major impetus in the development of effective formulations for the gene therapy of breast cancer.

Areas covered: We discuss DNA/RNA-based formulations that can inhibit the growth of breast cancer cells and control the progress of breast cancer. Targets for the gene therapy of breast cancer, DNA/RNA-based therapeutics and delivery systems are summarized. And examples of successful DNA/RNA-based formulations for breast cancer gene therapy are reviewed.

Expert opinion: Several challenges remain in developing effective DNA/RNA-based formulations for treatment of breast cancer. Firstly, most of the currently utilized targets are not effective enough as monotherapy for breast cancer. Secondly, the requirements for co-delivery system make the preparation of formulation more complicated. Thirdly, nanoparticles with the modification of tumor-targeting ligands could be more unstable in circulation and normal tissues. Lastly, immune responses against the viral vectors are unfavorable for the gene therapy of breast cancer because of the damage to the host and the impaired therapeutic ability.     

Xelox与mFOLFOX-6方案治疗晚期结直肠癌的药物经济学比较

目的：通过前瞻性研究,观察比较Xelox与mFOLFOX-6方案治疗晚期结直肠癌的疗效、毒副作用及药物经济学指标,为临床医生选择药物提供参考。方法：初治的晚期结直肠癌患者分两组进行姑息化疗：Xelox组（奥沙利铂联合卡培他滨3周方案）和mFOLFOX-6组（奥沙利铂联合亚叶酸钙、氟尿嘧啶2周方案）,密切随访,统计疗效、毒性及药物经济学数据并进行统计学分析。结果：共84例患者完成既定治疗方案,其中Xelox组有效率47.4%,mFOLFOX-6组有效率52.2%,差别无统计学意义（P〉0.05）;mFOLFOX-6组粒细胞减少和神经毒性发生率较高,Xelox组腹泻和手足综合征发生率较高,差异有统计学意义（P〈0.05）。两组平均住院总费用相似;Xelox组平均住院7.3次、住院55.0d,显著低于mFOLFOX-6组的9.3次和88.3d（P〈0.05）。但Xelox组药品所占费用比例65.6%,高于mFOLFOX-6组的50.2%（P〈0.05）。结论：两个方案的疗效相似,毒性不同。与mFOLFOX-6方案相比,Xelox方案住院总费用与之相似,药品费用比例较高,但住院次数少,住院天数较短,临床实践中医生可以根据实际情况选择不同化疗方案。     

Topical delivery for the treatment of psoriasis

Importance of the field: Psoriasis is one of the most common human skin diseases. Topical therapy forms the cornerstone in the management of mild-to-moderate psoriasis. Topical therapies are also used as adjunctive to systemic therapy in moderate and severe forms of the disease.

Areas covered in this review: In this review, an overview of psoriasis pathogenesis, new topical medications for psoriasis, new targets and molecules, combination topical therapies and combination of topical and phototherapy is provided. Over the past decade several efficacious and acceptable treatment options have emerged from the age-old therapies. The development of sophisticated formulation options has led to an enhancement in the rate and extent of drug delivery across the skin, increasing therapeutic value and improving patient compliance.

What the reader will gain: Readers will learn about monotherapy and combination topical products as well as new topical drug delivery technology to achieve optimal clinical outcomes. This review will highlight the need to generate more dermal pharmacokinetic data for better understanding of the impact of formulation change on skin pharmacokinetics to help design improved topical drug delivery systems.

Take home message: New topical formulations have the potential to achieve better efficacy with improved safety profile.     

植入氟尿嘧啶缓释剂预防大肠癌术后复发的疗效观察

目的探讨预防进展期大肠癌术后局部复发和全身转移的新途径。方法将55例Dukes B、C期大肠癌患者按时间分为根治切除加植入氟尿嘧啶组(治疗组)和单纯根治术切除组(对照组),随访3年期间,局部复发和全身转移及生存情况。结果治疗组3年局部复发率和全身转移率均低于对照组。3年局部复发数22例,Dukes B期治疗组和对照组分别为3例和5例,33例Dukes C期治疗组和对照组分别为4例和14例,经统计学分析,Dukes B期,P0.05,Dukes C期P0.05;3年全身转移数治疗组29例中有2例,对照组26例中有5例,经统计学分析P0.05。3年生存数治疗组29例中有23例生存,生存率为79.31%;对照组26例中有12例生存,生存率为46.15%,经统计学分析,P0.05。结论大肠癌根治术中植入缓解氟尿嘧啶可有效降低局部复发率和全身转移率,可提高3年生存率。     

In‐vitro characterisation of the nebulised dose during non‐invasive ventilation

Objectives Non‐invasive ventilation (NIV) with nebulised bronchodilators helps some patients to maintain effective ventilation. However, the position of the nebuliser in the ventilation circuit may affect lung delivery. Methods We placed the nebuliser proximal (A) and distal (B) to a breathing simulator in a standard NIV circuit with inspiratory (I) and expiratory (E) pressures of 20 and 5 cm H₂O, 1 : 3 I : E ratio, 15 breaths/min and a tidal volume of 500 ml. Five milligrams of terbutaline solution was nebulised using an Aeroneb Pro (AERO) and a Sidestream (SIDE) nebuliser. The fate of the nebulised dose was determined and the aerodynamic droplet characteristics were measured using a cooled Next Generation Impactor. Key findings More terbutaline was entrained on the inhalation filter in position A than in position B (P < 0.001) for both nebulisers. These amounts were greater (P < 0.001) for AERO than SIDE due to a smaller (P < 0.001) residual volume. The mean (SD) fine particle doses for AEROA, AEROB, SIDEA and SIDEB were 1.31 (0.2), 1.13 (0.14), 0.56 (0.03) and 0.39 (0.13) mg. These amounts from AEROA were significantly greater (P < 0.001) than those of the other three methods. Conclusions The results highlight the differences between nebulisers and the influence on the placement of the nebuliser in the NIV circuit.     

The safety of ramucirumab for the treatment of colorectal cancer

Introduction: Ramucirumab, a human monoclonal antibody against vascular endothelial growth factor receptor 2 (VEGFR-2), is an antiangiogenic therapy that has been approved in combination with FOLFIRI in second-line treatment of metastatic colorectal cancer (mCRC), after progression on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. A thorough review of the safety of ramucirumab in this setting and in the context of other antiangiogenic agents is merited.

Areas covered: We provide an overview of activity and summarize in detail the overall safety and tolerability profile of ramucirumab in mCRC patients on the basis of a literature review of all published clinical trials in this setting, including both single-agent and combination studies. A focus on adverse events of interest and specific populations is included, as well as a critical comparison with other antiangiogenic therapies.

Expert opinion: As an effective agent in pretreated mCRC patients, the toxicity profile of ramucirumab is similar to those of other angiogenesis inhibitors used in the second-line mCRC setting. The next challenge will be to find biomarkers of response and toxicity to antiangiogenic therapies in order to more effectively implement personalized medicine in these patients.