Sacituzumab govitecan: breakthrough targeted therapy for triple-negative breast cancer

Introduction: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with an increased risk of recurrence and cancer-related death. Unlike hormone receptor-positive or HER2-positive breast cancers, there are limited targeted therapies available to treat TNBC and cytotoxic chemotherapy remains the mainstay of treatment. Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate targeting Trop-2 expressing cells and selectively delivering SN-38, an active metabolite of irinotecan.

Areas covered: This review covers the mechanism of action, safety and efficacy of sacituzumab govitecan in patients with previously treated, metastatic TNBC. Additionally, efficacy data in other epithelial malignancies is included based on a PubMed search for ‘sacituzumab govitecan’ and ‘clinical trial’.

Expert opinion: Sacituzumab govitecan has promising anti-cancer activity in patients with metastatic TNBC previously treated with at least two prior lines of systemic therapy based on a single arm Phase I/II clinical trial. A confirmatory Phase III randomized clinical trial is ongoing. Sacituzumab govitecan has a manageable side effect profile, with the most common adverse events being nausea, neutropenia, and diarrhea. The activity of sacituzumab govitecan likely extends beyond TNBC with promising early efficacy data in many other epithelial cancers, including hormone receptor-positive breast cancer.     

锗元素与抗肿瘤药物(Ⅱ)(续上期)

综述了有机锗抗肿瘤药物，对β－羧乙基锗倍半氧化物（Ｇｅ－１３２）和螺锗在肿瘤学中的作用以及抗癌效应机制作出评价。自８０年代起至今，又有含硫杂、柠檬酸、氨基酸、苯基的锗化合物，以及锗酵母、含锗中草药等被先后合成出来。在几类具有生物活性的有机锗化合物中，仍首推Ｇｅ－１３２，螺锗及其衍生物为低毒有效抗肿瘤候选药物，然而对于锗导致的毒性及其机理仍需进一步加以探讨。     

有机锗对大鼠实验性矽肺形成及脂质过氧化水平的影响

采用硫代巴比妥酸比色法和亚硝酸盐形成法，分别测定了实验性矽肺大鼠血清过氧化脂质（ＬＰＯ）及超氧化物歧化酶（ＳＯＤ）同工酶活力，同时观察了β羧乙基锗倍半氧化物（Ｇｅ－１３２）对实验性大鼠矽肺形成的阻断作用及对自由基代谢的影响。结果显示矽肺大鼠血清ＬＰＯ含量显著高于对照组，而血清总ＳＯＤ和ＣｕＺｎＳＯＤ活力显著下降。提示矽肺的发生可能与机体自由基代谢的失衡有关。使用Ｇｅ－１３２可显著提高大鼠机体的抗氧化能力，降低脂质过氧化作用，并可明显干预矽肺病变的形成。     

AN-132 block of cardiac sodium channels: A gate-related receptor analysis

Summary Based on the gate-related receptor hypothesis, an analysis of kinetics of AN-132, a new antiarrhythmic agent, blockade of cardiac sodium channels and the gate-related receptor which is bound by the drug was performed by computer simulation. Model-predicted apparent rates of onset of AN-132 (30 μmol/L) blocking were 0.051, 0.038, and 0.034 AF⁻¹ at stimulation frequencies of 1.0, 2.0 and 3.0 Hz, respectively. The time constant of recovery from block by AN-132 at resting potential -90 mV was 39.5 s. These findings are in agreement with those experimental data documented. The analysis of gate-related receptor shows that AN-132 binds the inactivation gate-related receptor, and the binding and unbinding are modulated by the inactivation process.     

PCR detection of amplified 132 bp repeats in Marek's disease virus type 1 (MDV-1) DNA can serve as an indicator for critical genomic rearrangement leading to the attenuation of virus virulence

A radioactive PCR test was developed that amplified the very virulent Marek's disease virus-1 (vvMDV-1) DNA sequence containing the 132 bp repeats. In apathogenic MDV-1 (CVI 988, Rispens), amplified DNA bands containing multiple copies of 132 bp repeats were identified. In the present study this PCR technique was used to monitor the passage level of vvMDV-1 in chicken embryo fibroblasts (CEF) in which the number of tandem 132 bp repeats was increased. It was found that at passage level 32 of vvMDV-1-B isolate, the 132 bp tandem repeat was already markedly amplified and its pattern resembled that of the MDV-1 (CVI 988, Rispens) vaccine virus DNA. In the vvMDV-1Z strain, amplification of the 132 bp repeat was not detectable at a similar passage level. The PCR test demonstrated that the apathogenic MDV-1 Md11/75c virus developed by extensive in vitro passaging has amplified 132 bp DNA repeats similar to those of the commercial vaccine virus (CVI 988, Rispense). It was also found that the pattern of viral RNA from infected cells detectable by Northern blot hybridization was markedly changed from a 2.4 kb RNA species in cells infected with vvMDV-1 viruses, to four RNA species (ranging from 2.2 to 4.4 kb) in cells infected with passage 32 of MDV-1-B strain, to a very large number of undefined RNA species synthesized in cells infected with attenuated MDV-1 viruses (CVI 988, Rispens and Md 11/75c).     

蛋白酶体抑制剂MG132诱导肿瘤细胞凋亡机制的研究进展

MG132(Z-Leu-Leu-Leu-CHO)是一种蛋白酶体抑制剂,能进入细胞中可逆性地抑制蛋白酶体的活性,从而抑制泛素—蛋白酶体通路所介导蛋白质的降解,进而影响细胞周期进程和诱导细胞凋亡。目前,许多文献报道MG132能够诱导多种肿瘤细胞发生凋亡,是一种潜在的抗肿瘤药物。     

抗CD132抗体介导同种异型抗原激活的T细胞凋亡

目的研究抗CD132单抗在体外对T细胞增殖的抑制作用以及其可能的临床应用价值。方法分离BALB/c、C57BL/6小鼠的脾细胞进行双向混合淋巴细胞培养(MLC)。分别于第一天(组1)或第三天(组2)加入抗CD132单抗(终浓度达到100mg·L-1)。用流式细胞技术检测细胞增殖(CFSE),T细胞凋亡(PE-CD3,FITC-Annexin-v)以及细胞分裂周期(propidiumiodidestain)。T细胞Survivin的表达则用免疫化学染色法检测。结果混合淋巴细胞培养的结果显示CFSE标记的脾细胞出现了不同程度的荧光强度减弱,提示不同分裂次数的细胞存在。与MLC组比较,组1和组2中均未发现有进一步细胞分裂的迹象存在。在第3天时,组1可以检测到部分T细胞凋亡,而在培养的最初两天并无此现象。在组2中,第4天处于G2/M期的细胞出现减少而凋亡细胞增多。对照组无此现象发生(P<0.01)。同时,在MLC组中可检测到survivin在T细胞表达,而在组1和组2中则未能检测到。结论研究表明阻断CD132信号途径可以通过诱导同种异型抗原活化的T细胞凋亡而抑制T细胞增殖。因此,抗CD132单抗很有希望成为器官移植中抗排斥的临床药物。     

Automatic Actin Filament Quantification of Osteoblasts and Their Morphometric Analysis on Microtextured Silicon-Titanium Arrays

Microtexturing of implant surfaces is of major relevance in the endeavor to improve biorelevant implant designs. In order to elucidate the role of biomaterial’s topography on cell physiology, obtaining quantitative correlations between cellular behavior and distinct microarchitectural properties is in great demand. Until now, the microscopically observed reorganization of the cytoskeleton on structured biomaterials has been difficult to convert into data. We used geometrically microtextured silicon-titanium arrays as a model system. Samples were prepared by deep reactive-ion etching of silicon wafers, resulting in rectangular grooves (width and height: 2 µm) and cubic pillars (pillar dimensions: 2 × 2 × 5 and 5 × 5 × 5 µm); finally sputter-coated with 100 nm titanium. We focused on the morphometric analysis of MG-63 osteoblasts, including a quantification of the actin cytoskeleton. By means of our novel software FilaQuant, especially developed for automatic actin filament recognition, we were first able to quantify the alterations of the actin network dependent on the microtexture of a material surface. The cells’ actin fibers were significantly reduced in length on the pillared surfaces versus the grooved array (4–5 fold) and completely reorganized on the micropillars, but without altering the orientation of cells. Our morpho-functional approach opens new possibilities for the data correlation of cell-material interactions.     

Biodegradable poly(ester urethane) urea scaffolds for tissue engineering: Interaction with osteoblast-like MG-63 cells

Porous three-dimensional scaffolds with potential for application as cancellous bone graft substitutes were prepared from aliphatic segmented poly(ester urethane) urea using the phase-inverse technique. Proton nuclear magnetic resonance, size-exclusion chromatography, electron spectroscopy for chemical analysis, secondary ion mass spectrometry, infrared spectroscopy, scanning electron microscopy, differential scanning calorimetry, computed tomography and mechanical tests were carried out, to characterize the scaffolds’ physicochemical properties. Human osteosarcoma MG-63 cells were seeded into the scaffolds for 1, 2, 3 and 4 weeks to evaluate their potential to support attachment, growth and proliferation of osteogenic cells. The scaffold–cell interaction was assessed by analysis of DNA content, total protein amount, alkaline phosphatase activity and WST-1 assay. The scaffolds supported cell attachment, growth and proliferation over the whole culture period of 4 weeks (DNA, total protein amount). There was, however, a reduction in the WST-1 assay values at 4 weeks, which might suggest a reduction in the rate of cell proliferation at this time.