Blockade von Hsp90 hemmt den EGFR/HER-2/HIF-1α/STAT3 Signalweg in humanen Magenkarzinomzellen in vitro und reduziert Tumorwachstum und Angiogenese in einem experimentellen Modell in vivo

2006 ◽  
pp. 45-47
Author(s):  
O. Stöltzing ◽  
S. A. Lang ◽  
D. Klein ◽  
U. Bolder ◽  
H. J. Schlitt ◽  
...  
Keyword(s):  
Her 2

scholarly journals Study of the Effects of Homeopathic Medicine Carcinosinum on Mammary Adenocarcinoma (4T1 cells) in vitro.

2021 ◽  
Vol 17 (2) ◽  
pp. 22-23
Author(s):  
Leoni Villano Bonamin ◽  
Thaís Cristina Silva ◽  
William Alves Santos ◽  
Sandra AG Pinto ◽  
Vanessa Xavier ◽  
...  
Keyword(s):  
Pure Water ◽  
Alcoholic Solution ◽  
Mammary Adenocarcinoma ◽  
Clinical Effects ◽  
Apoptosis Index ◽  
Her 2 ◽  
4T1 Cells ◽  
One Way Anova

Background: There are few published researches about the exclusive use of Carsinosinum in several potencies to treat cancer. The name Carcinosinum refers to any homeopathic preparation of epithelial cancerous tissues and is especially indicated when there are any hereditary and familial antecedents of cancer, tuberculosis, diabetes, pernicious anemia or a combination of two or more of these diseases. Homeopathic complexes which include Conium Maculatum, Sabal Serrulata, Thuja Occidentalis and Carcinosinum can reduce in 23% the incidence of prostate cancer in vivo and in 38% the tumor volume, compared to untreated groups. Another in vivo study revealed reduction of symptoms and increase of survival time in mice bearing Ehrlich ascitic carcinoma, after treatment with Carcinosinum 200cH. In vitro, Carcinosinum 200cH can increase the expression of the pro-apoptotic gene p53. However, mice treated with Carcinosinum 6cH had the highest percentage and diversity of symptoms compared to other treatments, which demonstrate the importance of homeopathic potency in pro or anti-carcinogenic action. Considering that the literature on this subject is still rare and focused on genotypic and clinical effects, the present study was proposed, with the aim of identifying the possible phenotypic changes, including viability, HER-2 expression and metastatic skills, using 4T1 cells in vitro as a model, after treatment with Carcinosinum in different homeopathic working dilutions (12cH; 30cH; 200cH), prepared mechanically (Denise Machine, Autic®) in our laboratory using sterile pure water, from a commercial matrix (HN Cristiano, São Paulo, Brazil) stocked in 70% hydro-alcoholic solution. The final dilutions were inserted in the culture medium in a volume equal to 10%, at the time of cell seeding. The same succussioned vehicle used to prepare the medicines (70% hydro-alcoholic solution), from the same batch and diluted 1:100 in sterile pure water, was used as control. All treated cells were cultivated in bottles of 25ml with cell density of 5 x 105 cells / ml and, after 24 hours of treatment, they were analyzed for the apoptosis index using the Annexin V kit and measured by the Countess® system. The morphology of the 4T1 cells was monitored by staining fixed cell smears with hematoxylin-eosin method. The samples were evaluated in quadruplicate and the data were analyzed by one-way ANOVA. The results obtained up to now show that the treatment with Carcinosinum 12cH produced a different pattern of cell death compared to the other treatments, with significant reduction in apoptosis index (one-way ANOVA, p=0.01) and clear hydropic degeneration phenotypic pattern. The analysis of HER-2 expression and metastatic skill will be the next step of this research.

In vivo and in vitro activity of an immunoglobulin Fc fragment (Fcab) with engineered Her-2/neu binding sites

2014 ◽  
Vol 9 (6) ◽  
pp. 844-851 ◽  
Author(s):  
Max Woisetschläger ◽  
Bernhard Antes ◽  
Radha Borrowdale ◽  
Susanne Wiederkum ◽  
Manuela Kainer ◽  
...  
Keyword(s):  
Binding Sites ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Fc Fragment ◽  
Her 2

Androgen-dependent regulation of Her-2/neu in prostate cancer cells

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10099-10099
Author(s):  
R. Berger ◽  
D. I. Lin ◽  
M. Nieto ◽  
S. Signoretti ◽  
W. C. Hahn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Prostate Cancer Cells ◽  
In Vivo Experiments ◽  
Her 2

10099 Background: The mechanisms underlying the progression of prostate cancer to androgen independence remain poorly understood. Overexpression of Her-2/neu (c-ErbB2) activates the androgen receptor pathway and confers a survival and growth advantage to prostate cancer cells in an androgen-deficient milieu. Methods: Androgen-sensitive prostate cancer cell line LNCaP was used as a model system in vitro and in vivo. Experiments in mice were undertaken by injecting cells orthotopically into the ventral lobe of the mice prostate. Results: Here, we report that androgen receptor (AR) and Her-2/neu reciprocally regulate each other in LNCaP human prostate cancer cells. Absence of androgens, AR blockade with Casodex (bicalutamide) or suppression of AR with RNAi induced Her-2/neu protein expression and phosphorylation in vitro and in vivo. Similarly, suppression of Her-2-neu expression resulted in AR upregulation. In contrast, upon re-administration of androgens, Her-2/neu mRNA, protein and phosphorylation levels decreased linearly with increasing concentrations of androgens as LNCaP cells re-entered the cell cycle. Conclusions: Thus, induction and activation of Her-2/neu occurs in an androgen-depleted environment or as a result of AR inactivation, promoting androgen-independent survival of prostate cancer cells. No significant financial relationships to disclose.

scholarly journals The Potential Utility of Curcumin in the Treatment of HER-2-Overexpressed Breast Cancer: AnIn VitroandIn VivoComparison Study with Herceptin

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Hung-Wen Lai ◽  
Su-Yu Chien ◽  
Shou-Jen Kuo ◽  
Ling-Ming Tseng ◽  
Hui-Yi Lin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signal Transduction ◽  
Cell Growth ◽  
Xenograft Model ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Her 2 ◽  
Mcf 7

HER-2 is an important oncoprotein overexpressed in about 15–25% of breast cancers. We hypothesized that the ability of curcumin to downregulate HER-2 oncoprotein and inhibit the signal transduction pathway of PI3K/Akt, MAPK, and NF-κB activation may be important in the treatment of HER-2-overexpressed breast cancer. To examine the effect of curcumin on breast cancer cells, MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr (a herceptin resistant strain from SK-BR-3) cells were used forin vitroanalysis. Thein vivoeffect of curcumin on HER-2-overexpressed breast cancer was investigated with the HER-2-overexpressed BT-474 xenograft model. Cell growth, cell cycle change, the antimobility effect, signal transduction, and xenograft volume analysis between groups treated with herceptin and/or curcumin were tested. Curcumin decreased the cell growth of various breast cancer cell lines (MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr). In Western blot analysis, the phosphorylation of Akt, MAPK, and expression of NF-κB were reduced in BT-474 cells, but not in SK-BR-3-hr cells, after treatment with herceptin. When treated with curcumin, the HER-2 oncoprotein, phosphorylation of Akt, MAPK and expression of NF-κB were decreased in both BT-474 and SK-BR-3-hr cells. In the BT-474 xenograft model, though not as much as herceptin, curcumin did effectively decrease the tumor size. The combination of curcumin with herceptin was not better than herceptin alone; however, the combination of taxol and curcumin had an antitumor effect comparable with taxol and herceptin. The results suggested that curcumin has potential as a treatment for HER-2-overexpressed breast cancer.

Intradermal RNA-Vaccination of Patients with Metastatic Renal Cell Carcinoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3881-3881 ◽  
Author(s):  
Jan Wierecky ◽  
Martin R. Müller ◽  
Maik Häntschel ◽  
Marius S. Horger ◽  
Steve Pascolo ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cell ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Immunological Responses ◽  
Gm Csf ◽  
Her 2

Abstract Background: The use of in vitro transcribed RNA isolated from tumor cells or coding for defined tumor associated antigens was shown to be a very powerfull method to generate antigen specific T cells upon transfection into dendritic cells (DC). More recently it was demonstrated in a mouse model that application of RNA intra dermaly can elicit both, CD8 and CD4 mediated immune responses. Furthermore, in Her-2-neu transgenic mice vaccinations with naked RNA were able to elicit a specific immune response in vivo and delay the development of breast cancer in treated animals. Based on these results we analyzed the clinical and immunological responses in patients with metastatic renal cell carcinoma (RCC) vaccinated with mRNA encoding for tumor associated antigens (TAA) using two different treatment arms. Methods: In vitro transcribed RNA was generated using plasmids coding for the tumor antigens MUC1, CEA, Her-2/neu, telomerase, survivin and MAGE-1. RNA coding for HbsAg and Influenza matrix protein were included as controls. Vaccinations were performed intradermally on day 1,14, 28 and 42 in a first group of patients and on day 0–3, 7–10, 28 and 42 in a second group (intensified arm). Vaccinations were repeated afterwards monthly until tumor progression. One day after each RNA injection patients additionally received 1 injection of GM-CSF (250 μg) sc. The enhancement of T cell precursor was monitored using IFN-g ELISPOT and tetramer staining.. Results: 25 patients were included in this study. In 3 patients regression of metastases was induced and 6 patients had a stabilization of the disease. Specific CD8 and CD4 T cell responses in vivo were detected in the first analyzed patients. The treatment was well tolerated with no severe side effects. In most cases erythema and induration were observed after injections of GM-CSF. One patient developed an allergic exanthema after GM-CSF application. Conclusions: This study demonstrates that intradermal RNA-vaccination can be effective in the treatment of metastatic RCC and induces clinical and immunological responses.

Trastuzumab mimotope vaccination of HER-2/neu transgenic mice results in prolonged tumor-free survival and reduced tumor load

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12510-12510
Author(s):  
A. B. Riemer ◽  
K. H. Brämswig ◽  
H. Pehamberger ◽  
O. Scheiner ◽  
C. C. Zielinski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Development ◽  
Active Immunization ◽  
Receptor Internalization ◽  
Control Group ◽  
Free Survival ◽  
Tumor Load ◽  
Her 2

12510 Background: Passive immunotherapy with the humanized monoclonal antibody trastuzumab (Herceptin) to date is the most effective treatment for patients with HER-2/neu overexpressing breast cancer. In previous studies we could show that active immunization with peptide mimotopes, i.e. structural mimics of the epitope recognized by trastuzumab, leads to formation of antibodies again recognizing HER-2/neu in mice. Functional in vitro analyses of the induced antibodies demonstrated “trastuzumab-like” properties, such as receptor internalization, inhibition of signaling, and antibody-mediated cytotoxicity against HER-2/neu overexpressing breast cancer cells. The aim of the present study was to test the effects of trastuzumab mimotope vaccination in vivo, namely in a HER-2/neu transgenic mouse model. Methods: We used BALB-neuT mice, which carry the activated neu oncogene on the BALB/c background. These mice constitute the most aggressive animal model for HER-2/neu driven carcinogenesis, as all females uniformly develop mammary carcinomas at the age of 12 weeks. One group of mice was immunized with the previously described trastuzumab mimotope - KLH conjugate, a control group with the carrier protein KLH alone, and a further control group was left naïve. Mice were palpated weekly to monitor tumor development and size, and blood samples were taken at regular intervals to follow up the induced immune responses. Results: Trastuzumab mimotope immunizations lead to delayed tumor development and thus to an increase in tumor-free survival. When tumors occurred, they were smaller and grew more slowly than in the control mice. In contrast, control KLH immunizations did not affect tumor growth kinetics as compared to the naïve mice. Serum analysis demonstrated that all immunized animals had mounted an anti-KLH immune response, so we accredit the observed tumor-inhibitory effects in the mimotope group to the biologic properties of induced anti-HER-2/neu antibodies. Conclusion: These results indicate that epitope-specific vaccination with mimotopes elicits trastuzumab-like antibodies that are effective in vivo against HER-2/neu overexpressing tumor cells also in HER-2/neu expressing organisms. [Table: see text]

scholarly journals Expression of tyrosine kinases in human malignancies as potential targets for kinase-specific inhibitors

2004 ◽  
Vol 11 (4) ◽  
pp. 861-869 ◽  
Author(s):  
Christian F Singer ◽  
Gernot Hudelist ◽  
Wolfgang Lamm ◽  
Ruth Mueller ◽  
Klaus Czerwenka ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Expression ◽  
Malignant Tumors ◽  
Growth Factor Receptor ◽  
Specific Pattern ◽  
Distinct Pattern ◽  
Systematic Analysis ◽  
Her 2

Tyrosine kinase (TK) inhibition has been identified as a promising strategy in the treatment of human malignancies and several synthetic inhibitors have been developed. While the selective blockage of specific TKs is highly effective in vitro, clinical results have been less impressive. It has been suggested that the simultaneous inhibition of multiple TKs might lead to more favorable therapeutic results in vivo. We have therefore performed a systematic analysis of intratumoral TK expression in order to identify potential targets for a simultaneous kinase inhibition. To this end, we have analyzed the protein expression of membrane-associated epidermal growth factor receptor (EGF-R), Her-2/neu, platelet-derived growth factor receptor (PDGF-R), insulin-like growth factor receptor (IGF-R), c-Kit and of cytoplasmatic c-Abl in 500 human tumors of epithelial, stromal and mesenchymal origin by immunohistochemistry, and found a distinct pattern of kinase expression: EGF-R, PDGF-R and c-Abl were expressed in the majority of malignant tumors, whereas c-Kit, Her-2/neu and IGF-R protein expression was considerably less frequent. Overall, the EGF-R protein expression was correlated with PDGF-R, c-Kit and c-Abl immunoreactivity (P = 0.003, P = 0.001 and P < 0.001, respectively). c-Abl was co-expressed with IGF-R and PDGF-R (P = 0.003 and P < 0.001, respectively). Kinase co-expression was also seen in tumor subgroups and was particularly significant in breast cancer where IGF-R protein was expressed together with PDGF-R and c-Abl (P = 0.003 and P = 0.004, respectively), and in colon cancer where PDGF-R was correlated with EGF-R (P < 0.001). With the exception of Her-2/neu expression and age, intra-tumoral TK expression was not associated with parameters such as grading or histological subtypes. Taken together, we have found a specific pattern of kinase co-expression and have identified several potential targets for a tumor-specific multimodal TK inhibition.

Results from the first phase I clinical study of the novel Ii-Key/HER2/neu(776–790) hybrid peptide vaccine in patients with prostate cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3011-3011
Author(s):  
S. A. Perez ◽  
S. Bisias ◽  
N. L. Kallinteris ◽  
A. Ardavanis ◽  
K. G. Georgakopoulou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Mhc Class Ii ◽  
Peptide Vaccine ◽  
Hormonal Treatment ◽  
Gm Csf ◽  
Additional Chemotherapy ◽  
Her 2

3011 Background: HER-2/neu(776–790) represents an immunogenic epitope from the HER-2/neu oncoprotein whose immunogenicity is highly potentiated upon linkage with the Ii-Key moiety (LRMK) from the MHC class II invariant chain. Herein, we present the results of the first phase I clinical trial of the Ii-Key/HER-2/neu(776–790) (AE37) vaccine in patients (pts) with prostate cancer. Methods: Androgen-dependent (AD) and androgen-independent (AI) pts with HER-2/neu+ (IHC: 1–3) prostate adenocarcinomas were eligible. Concomitant medication with bicatulamide and LHRH or docitaxel was allowed. All pts received 6 monthly vaccinations with the AE37 vaccine (500 μg of AE37 plus 125 μg of GM-CSF) administered in two doses intradermally 5cm apart in the same extremity for each vaccination cycle. Immunologic responses were measured monthly in vitro by the IFNγ-based ELISPOT assay using pts’ PBMC and in vivo at the beginning and end of immunizations using DTH. Local dermal reactions were also measured after each vaccination. Results: Eligible pts [AD (n=18), AI (n=10)] were at stages T1–3N0M0, GS: 3–7 (n=18); T1–3N+M0, GS: 6–7 (n=2); T1–3N0M+, GS: 6–9 (n=4) and T1–3N+M+, GS: 6–9 (n=4). All pts had standard treatment prior to vaccinations, including surgery (S) (n=9); hormonal treatment (HT) (n=4); S+HT (n=6); S+HT+radiotherapy (RT); (n=2); S+chemotherapy (CH) (n=2); HT+RT (n=2); CH (n=3) and S+HT+CH (n=2). During vaccinations, 11 pts were free of any treatment, while 5 pts who had progressive disease received additional chemotherapy; the remainder received HT alone or combined with RT. 25 pts completed all vaccinations. Toxicity and side effects beyond grade-2 were not observed. GM-CSF was reduced by 50% for subsequent vaccinations when a local reaction of 100mm or greater was observed. DTH reactions to the parent HER-2/neu(776–790) peptide were increased (compared to pre-vaccination) for all pts, while approximately half the pts responded with significantly increased IFNγ responses to AE37 and/or parent HER-2/neu(776–790) peptide in at least 2 sequential vaccination cycles. Conclusions: The AE37 vaccine is safe and well tolerated. AE37 is also capable of eliciting potent and specific immunologic responses in prostate cancer pts. [Table: see text]

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