Mechanism of HES1 regulating herceptin resistance in gastric cancer cells by ferroptosis / 药学学报

Drug resistance of cancer cells is the main causes of chemotherapy failure, and gene mutation or function loss is key factor to induce drug resistance. Previous studies have shown that hairy and enhancer of split 1 (HES1) is up-regulated in herceptin-resistant gastric cancer cells, and inhibition of its activity can reverse its resistance while the potential mechanism has not yet been elucidated. In this study, we employed CRISPR/Cas9 to establish HES1 knock-out cell line (△HES1/NCI N87R) to investigate the functions of HES1 in herceptin resistance of NCI N87R cells and its potential mechanisms. We investigated proteomics profiling of △HES1/NCI N87R cells based on quantitative proteomics. Gene ontology analysis was conducted by GeneSet Enrichment Analysis (GSEA) and Metascape database, and pathway enrichment analysis was done using GeneAnalytics database. The selected molecules were quantified by Western blot and some pathways were verified by using inhibitors. The results showed that the resistance to herceptin of △HES1/NCI N87R cells decreased compared to NCI N87R cells. Proteomic data demonstrated that the expression of 1 263 genes changed significantly in △HES1/NCI N87R cells, among which 761 genes were up-regulated while 502 ones down-regulated comparing with NCI N87R cells. Pathway analysis showed that ferroptosis, fatty acid β-oxidation, autophagy and glutathione metabolism, etc. exhibited notable changes in △HES1/NCI N87R cells. The functional studies showed that the levels of iron ion and malondialdehyde increased, and glutathione decreased in △HES1/NCI N87R cells. It was further found that Fer-1, a ferroptosis inhibitor, could reverse the expression of pTP53, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in △HES1/NCI N87R cell, and reduce the sensitivity of △HES1/NCI N87R cells to herceptin. It is suggested that HES1 regulated the resistance of NCI N87R cells to herceptin through TP53/SLC7A11/GPX4 signaling pathway, and targeting TP53/SLC7A11/GPX4 signal axis mediated by HES1 is a potential strategy to reverse herceptin resistance in gastric cancer.

Dihydromyricetin reverses Herceptin resistance by up-regulating miR-98-5p and inhibiting IGF1R/HER2 dimer formation in SKBR3 cells / 南方医科大学学报

OBJECTIVE@#To explore the effect of dihydromyricetin on the expression of miR-98-5p and its mechanism in the development of Herceptin resistance in SKBR3 cells.@*METHODS@#The expression of IGF2 and miR-98-5p and their interaction relationship were analyzed by bioinformatics analysis through TargetScan online databases. SKBR3 cells and drug-resistant SKBR3-R cells were cultured in cell experiments. Xenograft tumor mice were constructed by SKBR3 and SKBR3-R cells. Proteins were detected by western blotting and immunohistochemistry. Transfected cells were constructed by shRNA lentivirus vectors. RT-QPCR was used to detect RNA. Cell proliferation was detected by MTS method. Cell jnvasion was detected by Transwell assay. Luciferase reporting assays were used to verify RNA interactions. IGF-1R/HER2 heterodimer was determined by immunocoprecipitation.@*RESULTS@#The expression of IGF2, p-IGF1R, p-Akt and p-S6K in SKBR3-R cells were significantly higher than those in SKBR3 cells, while the expression of PTEN protein was lower in SKBR3-R cells (P < 0.05). IGF1R/HER2 heterodimer in SKBR3-R cells was significantly increased (P < 0.01).The expression of IGF2 and invasion ability were significantly reduced while transfected with miR-98-5p in SKBR3-R cells (P < 0.05), but the IGF2 mRNA were no difference in both cells (P > 0.05). The expression of miR-98-5p was up-regulated and IGF2 was decreased in drug-resistant xenograft tumor mice after feeding with dihydromyricetin, and the tumor became more sensitivity to Herceptin (P < 0.05).@*CONCLUSION@#Dihydromyricetin could induce the expression of miR-98-5p, which binds to IGF2 mRNA to reduce IGF2 expression, inhibit the IGF-1R/HER2 formation, thereby reversing cell resistance to Herceptin in SKBR3-R cells.

Label-free quantitative proteomic study of RUNX3 regulating Herceptin resistance in gastric cancer cells / 药学学报

Resistance of tumor cells is a complex biological process involving multiple mechanisms and factors, in which anti-apoptosis is the most important cause of drug resistance. Previous studies have shown that the DNA binding activity of Runt related transcription factor 3 (RUNX3) increased prominently in Herceptin resistant gastric cancer cells (NCI N87R) while the relevance of which to drug resistance has not yet been confirmed. In this study, we employed CRISPR/Cas9 to establish RUNX3 knock-out cell line (△RUNX3/NCI N87R) to investigate the functions of RUNX3 in Herceptin resistance of NCI N87R cells and its potential mechanisms. We investigated proteomics profiling of △RUNX3/NCI N87R cells based on label free quantitative proteomics. Differentially expressed proteins were screened out according to fold change and significance level between △RUNX3/NCI N87R and NCI N87R cells. Pathway enrichment analysis was done using GeneAnalytics database, and gene ontology analysis was conducted by DAVID Bioinformatics Resources database. Protein-protein interaction networks were constructed based on STRING database. The results showed that △RUNX3/NCI N87R cells increased the sensitivity to Herceptin. Proteomic data demonstrated that the expression of 577 genes changed significantly in △RUNX3/NCI N87R cells, among which 191 genes were up-regulated while 386 ones down-regulated comparing with NCI N87R cells. Pathway analysis showed that autophagy, cell cycle, apoptosis, mitochondrial fatty acid β oxidation, neurogenic locus notch homolog protein 1 (NOTCH1), mammalian target of rapamycin (mTOR), Hedgehog and DNA damage response pathways exhibited notable changes based on pathway enrichment ratio and significance level (P < 0.05). These results indicated that RUNX3 knock-out altered multiple signaling pathways of NCI N87R cells. Western blotting manifested that the expression of autophagy regulatory molecules autophagy-related protein (ATG) 13, 7 and BECN1 increased remarkably while cell cycle molecules serine/threonine-protein kinase Chk2 (CHEK2) and apoptosis regulator Bcl-2 (BCL2) decreased prominently in △RUNX3/NCI N87R cells. The p-AKT expression decreased significantly in △RUNX3/NCI N87R cells compared with NCI N87R cells (P < 0.01) and was suppressed by Herceptin. These results indicated that RUNX3 knock-out altered cell cycle, increased inhibition to p-AKT by Herceptin, promoted autophagy and induced cell apoptosis of NCI N87R cells. These results suggested that RUNX3 may be a potential therapeutic target for reversing or reducing Herceptin resistance in gastric cancer cells.

The significance of expression of Her2neu in squamous cell carcinoma of uterine cervix

Background: Cervical cancer is one of the leading causes of cancer related deaths among females. It arises from precursor lesions i.e. squamous intraepithelial lesions which are closely associated with infection by HPV. The ERBB2 protooncogene encodes for a cellular transmembrane protein (erb-b2) which has tyrosine kinase activity and has been implicated in the regulation of cellular growth and proliferation in various cancers. Application of monoclonal antibodies against Her2neu has shown higher response and improved survival. The aim of the study was to evaluate the expression of Her2neu in squamous cell carcinoma of cervix in relation to tumor characteristics and to compare the expression with normal control subjects.Methods: It was a cross-sectional analytical study. Paraffin embedded tissue blocks from 30 cases of squamous cell carcinoma were obtained from the archives. Twenty age matched cases of normal cervix removed for lesions other than that related to cervix (like leiomyoma) were taken as control. Tumour characteristics were noted from the records. Her2neu immunostaining was done. Her2neu expression was scored as positive or negative according to the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) scoring system for Her2neu. The Chi-square test was used to compare and find association between the variables. Student t-test was used to compare the variable between cases and controls.Results: Her2neu was positive in 20% and negative in 80% cases of the study group. Her2neu positivity is not associated with size, histological grade and FIGO stage of the tumor. We found that all Her2neu positive cases showed no lymph node metastasis. This association between Her2neu positivity and lymph node status was statistically significant.Conclusions: Her2neu immunoexpression is variable across various categories of squamous cell carcinoma. Her2neu positivity might be negatively associated with lymph node metastasis. However, a more comprehensive study encompassing various factors related to Her2neu overexpression is required to validate these results.

Label-free quantitative proteomic analysis of acquired herceptin resistance in gastric cancer cells / 药学学报

This study was designed to explore proteins differentially expressed in HER2 positive gastric cancer N87 cells and N87/R cells with an acquired resistance to herceptin based on label-free quantitative proteomics. The extracted proteins were reduced and alkylated, then digested using filter aided sample preparation (FASP); peptides were separated via small manual reversed phase column, analyzed by LC-MS/MS, and identified with protein database 2.1 search engine. Proteins were quantified by intensity based quantification (IBQ) to search for differential proteins by comparison with relatively quantified proteins. The enrichment and network construction in gene ontology (GO) terms, genes-disease and Wikipathway of differential proteins were established through Web Gestalt. A total of 8 509 proteins were detected, among them, 7 163 proteins were further analyzed by bioinformatics, of which 110 proteins were up-regulated and 70 were down-regulated in N87/R cells. The differential proteins showed a significant difference in cellular component, biological process and molecular function in GO terms, respectively. Genes-disease network analysis indicated the association of these differential proteins with neoplasm metastasis, neoplasm invasiveness and inflammation, etc. Wikipathway enrichment analysis revealed the relevance of several signaling pathways to herceptin resistance, which included IL-2, MAPK/ERK, mTOR, aurora A, Ret, NF-κB, immune-regulatory and metabolic pathway. Western blot showed a significant increase of ERK1/2 activities in N87/R cells compared with N87 cells. Correspondingly, SCH772984, a MAPK/ERK inhibitor, preferentially reduced the viability of N87/R cells. Taken together, our data suggested that the MAPK/ERK signaling pathway is one of the key pathways that mediate herceptin resistance. This study provides the basic information for exploring the mechanisms of acquired resistance to herceptin in gastric cancer cells.

A Cost-Effectiveness Analysis of Adjuvant Trastuzumab Regimens in HER2-Positive Early Breast Cancer / 中国药学杂志

OBJECTIVE: To advocate Patient Assistant Program Projects (PAP Projects) decision-making, this study assesses the long-term cost-effectiveness of 1-year adjuvant trastuzumab therapy for women with human epidermal growth factor receptor 2 (HER2) positive early breast cancer. METHODS: A Markov model tracked yearly patients' transitions between five health states. The cycle length was 1 year and the sum was 45. From the perspective of the China health insurance system, the direct medical cost was estimated based on a survey of clinical expert panels. A discounting rate of 3% was used to discount direct medical cost and health outcomes. Utility and transition probabilities were retrieved from the HERA trial and literature. To estimate the direct medical cost, a survey of clinical expert panels was conducted. The cost of trastuzumab and HER2 test based on Roche. The key factor of the model was realized by one-way sensitivity analysis. The result of a probability sensitivity analysis conducted by Monte Carlo simulation was expressed as an incremental cost-effectiveness scatter plot. RESULTS: Without PAP Projects in Guangzhou, the adjuvant trastuzumab treatment prolonged 1.79 QALYs when the cost increased ¥53 301 and the Incremental cost-effectiveness ratio (CER) was ¥29 731/QALY, which is cost-effective based on Guangzhou's per capita GDP in 2015. With PAP Projects, the adjuvant trastuzumab treatment was totally cost-effectiveness. The sensitivity analysis demonstrated that the model was moderate. CONCLUSION: One year adjuvant trastuzumab treatment is a cost-effective therapy for patients with HER-2 positive breast cancer. With PAP Projects in Guangzhou, the adjuvant trastuzumab treatment is projected to be associated with improved QALYs and reduces direct medical costs, compared with the standard chemotherapy, represents a dominant treatment option among patients with HER2-Positive Early Breast Cancer. PAP Projects in Guangzhou should be persisted and spread in China.

Effects of herceptin on the serum tumor markers in patients with HER-2 positive advanced breast cancer treated with chemotherapy and its influence on the immune function / 中国综合临床

Objective To explore the effects of herceptin on the serum tumor markers in patients with HER-2 positive advanced breast cancer treated with chemotherapy and its influence on the immune function.Methods Seventy-six patients with HER2-positive advanced breast cancer from January 2013 to June 2014 in Xiangyang No.1 People's Hospital Affiliated to Hubei University of Medicine were divided into the observation group (38 cases) and the control group (38 cases),fifty healthy subjects in the same period were selected as the blank group.The control group received gemcitabine combined with capecitabine,gemcitabine 1000 mg / m2 via intravenous infusion in the first and eighth day,capecitabine 2500 mg/m2 via intravenous drip from the first day to fourteenth day;the observation group were given trastuzumab on the basis of the control group,4 mg/kg for the first time,then 2 mg/kg,1 time/week,three weeks for a course,have been given for four courses.The peripheral blood lymphocyte subsets were detected by flow cytometry,the Carcinoembryonic antigen (CEA),cancer-associated glycoprotein antigen (CA153) and tissue polypeptide specific antigen (TPS) were detected by enzyme-linked immunoassay.The short-term efficacy,survival and adverse reactions incidence rate in the two groups were compared.Results (1) The clinical benefit rate of the observation group was higher than that of the control group (89.47% vs.63.15%,χ2=8.508,P0.05),the CD3+,CD4+,CD4+/CD8+ of the observation group and the control group after treatment were significantly lower than those of the blank group (F=14.484,9.371,8.213,P<0.01).(3) The CEA,CA153 and TPS of the observation group and the control group after treatment were (5.05±2.03) μg/L,(7.25±2.70)μg/L,(36.04±12.05) IU/ml,(55.42±18.23) IU/ml,(262.43±53.38) IU/ml,(355.21±47.80) IU/ml,which were significantly lower than those before treatment (t=8.743,3.805,7.929,5.271,9.512,6.389,P<0.05),the observation group was significantly lower than the control group (t=3.353、3.665、3.442,P<0.05).(4) The incidence rate of pain and fever in the observation group were 34.21% and 28.95%,respectively,which were significantly higher than those in the control group,the difference was statistically significant (χ2=15.683,12.862,P<0.01).Conclusion Trastuzumab can synergistically reduce the serum tumor marker content in the treatment of patients with HER 2-positive advanced breast cancer,effectively improve the short-term efficacy of conventional chemotherapy,extend the life span,without the cause of significant damage to the immune function,but it can significantly increase the incidence rate of pain and fever,so it is necessary to carry out targeted method to improve chemotherapy compliance.

Mechanism of Herceptin enhancing apoptosis and improving sensitivity to chemotherapy in Ishikawa cells / 中国病理生理杂志

AIM:To investigate the role of Herceptin in the apoptosis and drug sensitivity of endometrial canc -er Ishikawa cells .METHODS: The IC50 values of Herceptin , adriamycin ( ADR ) , cisplatin ( DDP ) and paclitaxel ( PTX) for Ishikawa cells were detected by MTT method .Ishikawa cells were treated with single drug and combined chemo-therapy for 24 h, the cell cycle and the apoptosis ratio were determined by flow cytometry .RESULTS:The IC50 values of Herceptin, ADR, DDP and PTX were 57.12 mg/L, 0.572μmol/L, 67.4μmol/L and 719.5 nmol/L, respectively.Her-ceptin significantly enhanced the cytotoxicity of the chemotherapeutic drugs , and increased apoptosis ratio statistically . CONCLUSION:Herceptin enhances the apoptosis-inducing ability of the chemotherapeutic drugs and improves the che-motherapeutic sensitivity in Ishikawa cells .

The Research Progress of Herceptin in Treatment of HER-2 Overexpressing Breast Cancer / 昆明医科大学学报

Oncogene activation and inactivation of tumor suppressor genes is an important molecular mechanism of tumor formation. HER-2 oncogene is associated with breast cancer invasion and metastasis and prognosis, HER-2 overexpressing breast cancer progresses rapidly and has poor prognosis. In recent years, the emergence of targeted therapeutic monoclonal antibody drug Herceptin which built its structure for the HER-2 has significantly inproved HER-2-positive advanced breast cancer.

Preparation and targeting study of Herceptin loaded PLGA-COOH-targeted ultrasound contrast agent / 中华超声影像学杂志

Objective To preparation a kind of Herceptin loaded and breast cancer targeted high molecular polymer ultrasound contrast agent and investigate their affinity for breast cancer in vitro. Methods The high molecular polymer PLGA-COOH ultrasound contrast agents were produced by the double emulsion technique. Herceptin was covalently linked to the PLGA-COOH nanoparticle surface using a carbodiimide technique. Its physical property was determined. The combination of Herceptin with the PLGA-COOH nanoparticle was proved by immunofluorescent assay,and the PLGA-COOH nanoparticle targeting specifity to breast cancer cells was observed with light microscope and confocal microscope,normal PLGA-COOH nanoparticle was served as control group. Results The diameter range of targeted high molecular polymer ultrasound contrast agents was 466.8～857.6 nm, the average diameter was (662.2 ± 69. 7) nm,85.9% of the diameter was in the range. Green punctiform fluorescence was observed by fluorescence microscope,and the conjugation of the targeted high molecular polymer ultrasound contrast agents with MCF-7 cells was tight while the conjugation in control group was negative. Conclusions The Herceptin loaded PLGA-COOH targeted ultrasound contrast agents was prepared successfully. The targeted ultrasound contrast agents can bind to breast cancer effectively in vitro.

An updated review of the research on Her-2-targeted antibody resistance mechanisms / 中国癌症杂志

Human epidermal growth factor receptor 2(Her-2),which is often over-expressed in 20%-25% of invasive breast cancer patients,is associated with an aggressive tumor phenotype and therefore,a reduced survival rate.As a widely clinically applied Her-2-targeted monoclonal antibody,herceptin,when combined with chemotherapy,significantly increases the survival time of patients without tumors.However,the majority of the cancers that initially respond positively to herceptin begin to counteract against the treatment within just 1 year.This study described several important and well-known mechanisms as well as the updates and advancement in this field.These mechanisms include over-activation of the P13K/AKT pathway,abnormal expression in the EGFR family and their ligands,the masking of the Her-2 receptor,herceptin,activation of PI3K/AKT via an alternative pathway,over-expression of Darpp-32 and t-Darpp.autophagy of tumor cells and over-expression of HSP27,and more.

Short-term therapeutic effect of neoadjuvant chemotherapy with herceptin and docetaxel in patients with localized advanced breast cancer / 中国综合临床

Objective To investigate the efficacy and adverse effect of herceptin combined with docetaxel in patients with localized advanced breast cancer. Methods 16 patients with localized advanced breast cancer were treated with herceptin (8 mg/kg in the first cycle and 6 mg/kg from 2 to 4 cycles,d1) and docetaxel (75 mg/m2 ,d2) for 4 cycles. Three weeks were taken as a cycle. Following chemotherapy, the patients underwent improved radical operation of breast cancer or radical operation of preserving breast. Results The overall response rate (oRR) was 87.5%. The complete clinical remission rate (cCR) was 56. 3%. The complete pathologic remission rate (pCR) was 25.0%. The mainly adverse effects were bone marrow depression and gastrointestinal toxicity. Conclusion The regimen of herceptin combined with docetaxel is effective and can be well-tolerated by patients with localized advanced breast cancer. It shows promising prospect in clinical application.

Effect of Herceptin on apoptosis and cell cycle in breast cancer cell line SKBR-3 / 基础医学与临床

Objective To study the effect of an immuno-targeted therapy drug Herceptin on apoptosis and cell cycle of overexpressing HER2 breast cancer cells.Methods Breast cancer cell line SKBR-3 was treated with Herceptin at most effective dosage and exposure time were selected by MTT assay.Then the apoptotic features,the apoptotic rate and the change of cell cycle of breast cancer cells were detected by fluorescent microscope(FM),laser confocal microscope(LCM),scanning electron microscope(SEM),transmission electron microscope(TEM)and flow cytometry(FCM).Results With the treatment of Herceptin,the visible apoptosis features of SKBR-3 cells were observed by FM,LCM,SEM and TEM.Compared to the control cell group,the rate of initial apoptotic cells detected by FCM with Annexin V/PI staining increased significantly(P

Reversal of drug resistance of trastuzumab-resistant human breast cancer cells by recombinant adenovirus carrying PTEN gene / 中国肿瘤生物治疗杂志

Objective:To study the role of adenoviral-mediated PTEN gene transfection in reversing drug resistance of trastuzumab-resistant human breast cancer.Methods:Recombinant adenoviruses carrying PTEN gene(AdPTEN) were constructed and transfected into trastuzumab-resistant human breast cancer cell line BT474.Proliferation and apoptosis of BT474 cells treated with AdPTEN and trastuzumab were measured by MTT assay and FCM.Time course of BT474 cells apoptosis induced by AdPTEN was analyzed by detection of DNA fragmentation.Western blotting was employed to measure phosphorylated-Akt expression levels in AdPTEN treated BT474 cells.The nude mice model of BT474 cells was employed to observe the effects of AdPTEN and trastuzumab on trastuzumab-resistant human breast cancer in vivo.The expression of PTEN gene,cancer cells apoptosis and ultrastructural changes were evaluated after the mice were sacrificed.Results:We successfully constructed recombinant AdPTEN;and the titer of the recombinant adenovirus was about 4.2?1011TCID50/ml.PTEN gene expression was identified by PCR,RT-PCR and Western blotting assay.Combinatorial AdPTEN and trastuzumab significantly suppressed the proliferation of BT474 cells and induced the apoptosis.The percentage of apopotosis cells treated with AdPTEN was(20.7?5.82)%,companied by cells cycle arrest in G1 phrase(P

Synergistic effects of Herceptin and 9-cis-RA on MDA-MB-453 breast cancer cells / 第三军医大学学报

Objective To investigate the synergistic effects of Herceptin and 9-cis-RA on the proliferation, cell cycle and apoptosis of HER2-positive breast cancer cells. Methods MDA-MB-453 breast cancer cells were treated with 5 ?g/ml Herceptin or 1 ?mol/L 9-cis-RA or both for 24, 48 or 72 h. The proliferation of MDA-MB-453 breast cancer cells was determined by MTT, the pro-apoptotic effects were detected by TUNEL, the cell cycle phase was detected by FCM. Results As compared with control group, Herceptin and 9-cis-RA synergistically inhibited the proliferation of MDA-MB-453 breast cancer cells, and the percentage of G_ 0 /G_ 1 cells increased after treatment with Herceptin and 9-cis-RA for 72 h. Simultaneously, Herceptin and 9-cis-RA synergistically induced the apoptosis of MDA-MB-453 cells. Conclusion Herceptin and 9-cis-RA could synergistically and effectively inhibit MDA-MB-453 breast cancer cells by blocking their cell cycle progression and inducing their apoptosis.

THE THERAPEUTIC EFFECTS OF RECOMBINANT HUMANIZED ANTI-HER2 ANTIBODY (HERCEPTIN) ON HER-2/ NEU-OVEREXPRESSING METASTATIC IRJMAN BREAST CANCER / 解放军医学杂志

To investigate the therapeutic effects of recombinant humanized anti-HER2 antibody (Herceptin) on Her-2/neu-overexpressing metastatic human breast cancer, 7 patients with Her-2/neu-overexpressing metastatic human breast cancer were involved in this study. The results indicated that the therapeutic effective rate was 71. 4%. CR. PR, SD. PI) were seen in 2. 3, 1, 1 cases, respectively. No side reactions were observed. The results revealed that the therapeutic effect of Herceptin is intimately linked to Her-2/neu expression of breast cancer.

Herceptin combined with carboplatin inhibiting cervical cancer cells and the related mechanism / 中国肿瘤生物治疗杂志

Objective:To evaluate the inhibitory effect of Herceptin on HeLa,SiHa cells and to investigate the synergistic mechanism of Herceptin and Carboplatin.Methods:HeLa and SiHa cells were treated with Herceptin(at 5,10,20,40,and 80 ?g/ml),Carboplatin(at 0.5,1,2,4,and 8 ?g/ml),and Her+CBP[(10+1),(20+2),and(40+4)?g/ml] separately.The untreated cells were taken as control.SP immunohistochemical method was used to detect the protein expression of HER-2/neu and downstream Ras oncogene.MTT method was used to study the inhibition effect of Herceptin on HeLa,SiHa cells and its synergetic effect with carboplatin.FCM was used to detect the cell apoptosis and cell cycle.The mRNA expression of her-2/neu and ras were assessed by RT-PCR;the protein expression of HER-2/neu and Ras were studied by Western blotting.Results:Herceptin significantly inhibited cervical cancer cells proliferation,and there was a synergistic effect when combined with carboplatin(P

Targeted therapy with herceptin to rat bladder tumor model / 第三军医大学学报

Objective To investigate the therapeutic effect of herceptin to rat bladder cancer. Methods Totally 50 SD rats were randomly divided into experimental group (n=40) and control group (n=10). The rats of experimental group received a perfusion into the bladder with N-methyl-N-nitrosourea (MNU) at 2.5 mg every time, once per 3 weeks for 4 times in all, while those of the control group underwent a perfusion with normal saline instead of MNU. In 1 week after the last perfusion, the bladders were slited for gross observation and the biopsies were carried out for pathological observation with HE staining. Immunohistochemical SP method and RT-PCR were applied to detect HER-2 protein and mRNA expression in tumor tissues. Then 16 rats with HER-2 positive bladder cancer were randomly and equally divided into treatment group (herceptin, 20 mg/kg by intraperitoneal injection, once per week for 6 weeks) and non-treatment group (normal saline, 0.5 ml). Tumor weight, size and shape were measured and calculated for the inhibitory rate of herceptin. HE staining was carried out for the morphology of the tumor mass. The expression of HER-2 protein was detected with immunohistochemical SP method, and apoptosis in bladder tumor tissues with TUNEL method. Results The results of inhibitory rate was 50.0%, and it showed that the differences were statistically significant in treatment group compared with non-treatment group (P

Anti-tumor effect of anti-HER-2 engineering antibodies Herceptin and chA21 on nude mice xenografts of human ovarian cancer SKOV3 cells / 西安交通大学学报(医学版)

Objective To study the anti-tumor effect of anti-HER-2 engineering antibodies chA21 and Herceptin on nude mice xenografts of human ovarian cancer SKOV3 cells and explore its mechanism.Methods An animal model with human ovarian cancer SKOV3 cells involved in nude mice was established and the mice were randomized into 3 groups: normal saline(NS),chA21 and Herceptin.The mice were respectively administrated with Herceptin(30mg/kg) and chA21(30mg/kg) via caudal vein injection twice a week for consecutive 6 weeks,and then were killed after 44 days adminstration of the drugs.The volumes of the xenografts were measured twice a week.The tumor weight and inhibition ratio were measured after mice were killed.Ki67 and NF?B expression in the three groups was quantificationally analyzed by immunohistochemistry on tissue microarray sections combined with a micro-image analysing system.Results The growth of xenografts of human ovarian cancer SKOV3 cells in nude mice was significantly inhibited by either Herceptin or chA21. Both Ki-67 labeling indices and NF?B levels in chA21 and Herceptin groups were lower than those in the control(P

THE SYNERGISTIC EFFECTS OF HERCEPTIN AND 9-CIS-RETINOIC ACID ON HER2/NEU POSITIVE BREAST CANCER CELLS IN VIVO / 营养学报

Objective To observe the synergistic effects of Herceptin(HER)and 9-cis-retinoic acid (9-cis-RA) on HER2/neu positive breast cancer cells in vivo. Method MCF-7 breast cancer cells transfected with exogenous HER2 gene were inoculated into athymic nude mice. Four weeks after tumor inoculation,mice bearing a tumor of 200 mm3 in volume approximately were selected to be treated with HER and/or 9-cis-RA(SC) for 20d. After that tumor volume was precisely measured,concurrently the HE staining and Ki-67 immunohistochemical (IHC) assay were performed to detect the anti-proliferative effect of HER in combination with 9-cis-RA in vivo. Results After 3 w of treatment,HER and 9-cis-RA synergistically decreased the tumor volume as compared with control group. IHC results showed that Ki-67 expression was significantly inhibited by co-treatment of HER and 9-cis-RA,which means the arrest of cell cycle progression. Conclusion Herceptin and 9-cis-RA could synergistically inhibit the proliferation of HER2 positive breast cancer cells in vivo.