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。     

Sequence of Echinochloa hoja blanca tenuivirus RNA-5

The sequence is presented of RNA-5 of Echinochloa hoja blanca tenuivirus, a second tenuivirus associated with rice cultivation in Latin America (after rice hoja blanca virus). The RNA is 1334 nucleotides long and contains in the complementary sense RNA a single long open reading frame. The deduced amino acid sequence of this open reading frame shows that it encodes a highly basic and hydrophilic 44 kD protein (pc5) with about 50% similarity to the pc5 protein of maize stripe virus (MStV). This and other features of the RNA are discussed.The GenBank accession number of the sequence reported in this paper is L47430.     

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。     

Dissociation of E-cadherin/β-catenin complex by MG132 and bortezomib enhances CDDP induced cell death in oral cancer SCC-25 cells

E-cadherin/β-catenin complex plays an important role in maintaining the homeostasis of tissues and regulating cell proliferation, survival and apoptosis. To address the relationships between the change of E-cadherin/β-catenin complex and cell apoptosis, human oral squamous carcinoma SCC-25 cells were used to investigate whether the dissociation of the E-cadherin/β-catenin complex was the main reason of MG132- or bortezomib-induced apoptosis. We found that MG132 or bortezomib alone induced remarkable loss of cell integrity and contact, inhibited cell growth, survival, migration and caused cell cycle arrest, intracellular ROS production. Further experiments showed that colony formations were significantly decreased by MG132 and bortezomib alone or plus cis-diaminedichloroplatinum (CDDP). Immunofluorescence staining showed that SCC-25 cells exhibited remarkable accumulations of β-catenin in cytoplasm and few E-cadherin in cell membranes after MG132 or bortezomib treatment. Western blot results showed that MG132 or bortezomib induced high accumulation of ubiquitinated proteins and activation of apoptosis related protein caspase-3. Meanwhile, the combinational use of MG132 or bortezomib with CDDP led to synergistic effects on SCC-25 cells. However, knockdown of β-catenin could decrease MG132 or bortezomib induced cell death. Taken together, our data suggest that the regulation of E-cadherin/β-catenin complex could be a promising therapeutic target to overcome the multidrug resistance of oral cancer.     

Electrophysiologic abnormalities of children with ostium secundum atrial septal defect

Sinus node (SN) and atrioventricular node (AVN) function were evaluated in 49 patients with secundum type atrial septal defect (ASD). Automaticity and conduction system function were assessed by intracardiac recording of the AH and HV intervals at rest, corrected SN recovery time, sinoatrial conduction time, AVN refractory period and the ability of the AVN to conduct rapidly paced atrial beats to the ventricles. Electrophysiologic abnormalities were found in 41% of the 34 patients who were studied before surgery. However, no preoperative abnormalities were present in children younger than 2.5 years. If only children older than 2.5 years were analyzed, the incidence of conduction abnormalities was similar for the patients studied before operation (62%) and those studied after operation (71%). The size and ejection fractions of the right and left ventricles, the magnitude of shunt flow and the size of the ASD did not differ between the patients with and those without electrophysiologic abnormalities. AVN dysfunction was present in 40% of the patients who were studied after surgical repair. While this frequency was more than twice the preoperative incidence of AVN dysfunction, it was not statistically significant. The data suggest that patient age is the major factor that influences the presence of conduction system dysfunction in patients with ASD.