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1.

001-es BibID:BIBFORM005174
035-os BibID:(scopus)38349044364 (wos)000253278400023
Első szerző:Barok Márk (biofizikus)
Cím:Trastuzumab decreases the number of circulating and disseminated tumor cells despite trastuzumab resistance of the primary tumor / Márk Barok, Margit Balázs, Péter Nagy, Zsuzsa Rákosy, Andrea Treszl, Enikő Tóth, István Juhász, John W. Park, Jorma Isola, György Vereb, János Szöllősi
Dátum:2008
ISSN:304-3835 (Print)
Megjegyzések:We have recently shown that despite of the fact that the ErbB2-positive JIMT-1 human breast cancer cells intrinsically resistant to trastuzumab in vitro, trastuzumab inhibited the outgrowth of early phase JIMT-1 xenografts in SCID mice via antibody-dependent cellular cytotoxicity (ADCC). Here we show that trastuzumab significantly reduces the number of circulating and disseminated tumor cells (CTCs and DTCs) in this xenograft model system at a time when the primary tumor is already unresponsive to trastuzumab. This observation suggests that ErbB2 positive CTCs and DTCs might be sensitive to trastuzumab-mediated ADCC even if when the primary tumor is already non-responsive. Thus, trastuzumab treatment might also be beneficial in the case of patients with breast cancer that is already trastuzumab resistant.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
analysis
Animals
antagonists and inhibitors
Antibodies
Antibodies, Monoclonal
Antigens
Antigens, CD45
Antineoplastic Agents
article
Biophysics
blood
Bone Marrow
Breast Neoplasms
Cell Line, Tumor
Cells
Chromosomes, Human,X
drug effects
Drug Resistance, Neoplasm
drug therapy
EGFR
Epidermal Growth Factor
ErbB2
Female
genetics
Histocompatibility Antigens
Histocompatibility Antigens Class I
Human
Humans
Hungary
Immunohistochemistry
immunology
In Situ Hybridization,Fluorescence
In Vitro
metabolism
Mice
Mice, Scid
mouse
Neoplasm Circulating Cells
Neoplasm Metastasis
pathology
pharmacology
Receptor, Epidermal Growth Factor
Research
Research Support
Support
therapeutic use
Time Factors
Trastuzumab resistance
Xenograft Model Antitumor Assays
egyetemen (Magyarországon) készült közlemény
Megjelenés:Cancer Letters. - 260 : 1-2 (2008), p. 198-208. -
További szerzők:Balázs Margit (1952-) (sejtbiológus, molekuláris genetikus) Nagy Péter (1971-) (biofizikus) Rákosy Zsuzsa (1978-) (sejtbiológus, molekuláris biológus, genetikus) Treszl Andrea (1974-) (molekuláris biológus) Tóth Enikő Juhász István (1956-) (bőrgyógyász, bőrsebész, kozmetológus, klinikai onkológus) Park, John W. Isola, Jorma Vereb György (1965-) (biofizikus, orvos) Szöllősi János (1953-) (biofizikus)
Internet cím:elektronikus változat
DOI
Borító:

2.

001-es BibID:BIBFORM001053
035-os BibID:(scopus)34447298092 (wos)000248154300017
Első szerző:Barok Márk (biofizikus)
Cím:Trastuzumab causes antibody-dependent cellular cytotoxicity-mediated growth inhibition of submacroscopic JIMT-1 breast cancer xenografts despite intrinsic drug resistance / Barok M., Isola J., Pályi-Krekk Zs., Nagy P., Juhász I., Vereb Gy., Kauraniemi P., Kapanen A., Tanner M., Vereb Gy., Szöllősi J.
Dátum:2007
Megjegyzések:Trastuzumab is a recombinant antibody drug that is widely used for the treatment of breast cancer. Despite encouraging clinical results, some cancers are primarily resistant to trastuzumab, and a majority of those initially responding become resistant during prolonged treatment. The mechanisms of trastuzumab resistance have not been fully understood. We examined the role of antibody-dependent cellular cytotoxicity (ADCC) using JIMT-1 cells that are ErbB2 positive but intrinsically resistant to trastuzumab in vitro. Unexpectedly, in experiments mimicking adjuvant therapy of submacroscopic disease in vivo (JIMT-1 cells inoculated s.c. in severe combined immunodeficiency mice), trastuzumab was able to inhibit the outgrowth of macroscopically detectable xenograft tumors for up to 5-7 weeks. The effect is likely to be mediated via ADCC because trastuzumab-F(ab')(2) was ineffective in this model. Moreover, in vitro ADCC reaction of human leukocytes was equally strong against breast cancer cells intrinsically sensitive (SKBR-3) or resistant (JIMT-1) to trastuzumab or even against a subline of JIMT-1 that was established from xenograft tumors growing despite trastuzumab treatment. These results suggest that ADCC may be the predominant mechanism of trastuzumab action on submacroscopic tumor spread. Thus, measuring the ADCC activity of patient's leukocytes against the tumor cells may be a relevant predictor of clinical trastuzumab responsiveness in vivo.
Tárgyszavak:Orvostudományok Természettudományok Elméleti orvostudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
ErbB2 receptor
trastuzumab
breast cancer
antibody therapy
Megjelenés:Molecular Cancer Therapeutics. - 6 : 7 (2007), p. 2065-2072. -
További szerzők:Isola, Jorma Pályiné Krekk Zsuzsanna (1974-) (molekuláris biológus) Nagy Péter (1971-) (biofizikus) Juhász István (1956-) (bőrgyógyász, bőrsebész, kozmetológus, klinikai onkológus) Vereb György (1938-) (biokémikus, sejtbiológus) Kauraniemi, Päivikki Kapanen, Anita I. Tanner, Minna Vereb György (1965-) (biofizikus, orvos) Szöllősi János (1953-) (biofizikus)
Internet cím:elektronikus változat
DOI
Borító:

3.

001-es BibID:BIBFORM042484
035-os BibID:(scopus)23844475901 (wos)000231845600013
Első szerző:Mocanu, Maria-Magdalena
Cím:Associations of ErbB2, beta1-integrin and lipid rafts on Herceptin (Trastuzumab) resistant and sensitive tumor cell lines / Maria-Magdalena Mocanu, Zsolt Fazekas, Miklós Petrás, Péter Nagy, Zsolt Sebestyén, Jorma Isola, József Tímár, John W. Park, György Vereb, János Szöllősi
Dátum:2005
ISSN:0304-3835
Megjegyzések:ErbB2-mediated transmembrane signaling is a key target of novel anticancer agents such as Herceptin. Our comparison of Herceptin resistant (JIMT-1, MKN-7) and sensitive (SKBR-3, N-87) cell lines demonstrates the importance of ErbB2 association patterns involving integrins and lipid rafts. Flow cytometric FRET and confocal microscopic measurements revealed colocalization and molecular proximity between b1-integrins and ErbB2, as well as their association with lipid rafts. A weak functional interaction between ErbB2 and b1-integrin and the fact that ErbB2 did not co-patch with b1-integrins uponcrosslinking imply that ErbB2 and b1-integrin define two distinct molecular association clusters from a functional point of view. Although Herceptin-sensitive cell lines expressed more ErbB2 and fewer b1-integrin molecules on their surface than their resistant counterparts, this finding probably does not explain the Herceptin resistant phenotype due to the weak interaction between b1-integrins and ErbB2. Our results imply that the true significance of the expression profile of proteins involved inoncogenesis can only be understood after characterizing their molecular interactions.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Antibodies
Antibodies,Monoclonal
Antigens,CD29
Biophysics
Breast Neoplasms
Cell Line
Cell Membrane
Drug Resistance,Neoplasm
Humans
Hungary
Membrane Microdomains
metabolism
pathology
pharmacology
Phenotype
physiology
Proteins
Receptor,erbB-2
Research
Support
Tumor Cells,Cultured
egyetemen (Magyarországon) készült közlemény
Megjelenés:Cancer Letters. - 227 : 2 (2005), p. 201-212. -
További szerzők:Fazekas Zsolt (1971-) (biofizikus) Petrás Miklós (1977-) (orvos) Nagy Péter (1971-) (biofizikus) Sebestyén Zsolt Isola, Jorma Timár József Park, John W. Vereb György (1965-) (biofizikus, orvos) Szöllősi János (1953-) (biofizikus)
Internet cím:Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
Borító:

4.

001-es BibID:BIBFORM004879
Első szerző:Nagy Péter (biofizikus)
Cím:Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line / Nagy, P., Friedlander, E., Tanner, M., Kapanen, A. I., Carraway, K. L., Isola, J., Jovin, T. M.
Dátum:2005
ISSN:0008-5472
Megjegyzések:Overexpression of erbB2 in breast tumors is associated with poor prognosis and is a target of receptor-oriented cancer therapy. Trastuzumab (Herceptin), a monoclonal antibody against a membrane-proximal epitope in the extracellular region of erbB2, shows a therapeutic effect against a fraction of erbB2-amplified breast tumors. Unfortunately, resistance to Herceptin is common, and its cause is as yet unclear. Here we investigated the properties of erbB2 in a Herceptin-resistant cell line, JIMT-1, established from a breast cancer patient showing erbB2 gene amplification and primary resistance to Herceptin. The expression profile of erbB proteins, Herceptin-induced erbB2 internalization, and down-regulation in JIMT-1 were similar to those in Herceptin-sensitive lines. However, the mean number of Herceptin Mab binding sites in JIMT-1 was 1/5 that of the expressed erbB2 molecules, although 5% to 10% of the cells showed a approximately 10-fold higher Herceptin binding than the main population. Herceptin Fab and Mab 2C4, an antibody binding to an epitope in the ectodomain further removed from the membrane, bound more efficiently to JIMT-1 cells than Herceptin Mab, implying that erbB2 was partly masked. The expression of MUC4, a membrane-associated mucin that according to reports contributes to the masking of membrane proteins, was higher in JIMT-1 than in Herceptin-sensitive lines, and its level was inversely correlated with the Herceptin binding capacity of single cells. Knockdown of MUC4 expression by RNA interference increased the binding of Herceptin. Western blotting showed a low level of proteolytic processing, shedding, and tyrosine phosphorylation of erbB2 in JIMT-1. The latter finding may explain its Herceptin-resistant phenotype characterizing both the low and high Herceptin binding subpopulations. We conclude that masking of erbB2 in JIMT-1 leads to diminished Herceptin binding and isolation of erbB2 from its normal interaction and activation partners.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Antibodies
Antibodies,Monoclonal
Antineoplastic Agents
Binding Sites
biosynthesis
Breast Neoplasms
Cell Line
Cell Line,Tumor
Cells
chemistry
Down-Regulation
Drug Resistance,Neoplasm
drug therapy
Enzyme Activation
enzymology
Epitopes
Gene Amplification
Humans
immunology
Membrane Proteins
metabolism
Metalloproteases
Mucins
pharmacology
Phenotype
Phosphorylation
Proteins
Receptor,erbB-2
Research
Support
therapy
Tyrosine
Megjelenés:Cancer Research. - 65 : 2 (2005), p. 473-482. -
További szerzők:Friedländer Elza (1980-) (biofizikus) Tanner, Minna Kapanen, Anita I. Carraway, Kermit L. Isola, Jorma Jovin, Thomas M.
Internet cím:elektronikus változat
Borító:

5.

001-es BibID:BIBFORM002762
035-os BibID:(scopus)35448969823 (wos)000251600200021
Első szerző:Pályiné Krekk Zsuzsanna (molekuláris biológus)
Cím:Hyaluronan-induced masking of ErbB2 and CD44-enhanced trastuzumab internalisation in trastuzumab resistant breast cancer / Palyi-Krekk Z., Barok M., Isola J., Tammi M., Szollosi J., Nagy P.
Dátum:2007
Megjegyzések:Although trastuzumab, a recombinant humanised anti-ErbB2 antibody, is widely used in the treatment of breast cancer, neither its mechanism of action, nor the factors leading to resistance are fully understood. We have previously shown that antibody-dependent cellular cytotoxicity is pivotal in the in vivo effect of trastuzumab against JIMT-1, a cell line showing in vitro resistance to the antibody, and suggested that masking of the trastuzumab-binding epitope by MUC-4, a cell surface mucin, took place. Here, we further explored the role of masking of ErbB2 in connection with CD44 expression and synthesis of its ligand, hyaluronan. We show that high expression of CD44 observed in JIMT-1 cells correlates with ErbB2 downregulation in vivo, while siRNA-mediated inhibition of CD44 expression leads to decreased rate of trastuzumab internalisation and low cell proliferation in vitro. An inhibitor of hyaluronan synthesis, 4-methylumbelliferon (4-MU) significantly reduced the hyaluronan level of JIMT-1 cells both in vivo and in vitro leading to enhanced binding of trastuzumab to ErbB2 and increased ErbB2 down-regulation. Furthermore, the inhibitory effect of trastuzumab on the growth of JIMT-1 xenografts was significantly increased by 4-MU treatment. Our results point to the importance of the CD44-hyaluronan pathway in the escape of tumour cells from receptor-oriented therapy
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Antibodies
Biophysics
Cell Line
Cell Proliferation
Cells
Down-Regulation
Hungary
In Vitro
therapy
Megjelenés:European Journal of Cancer. - 43 : 16 (2007), p. 2423-2433. -
További szerzők:Barok Márk (1976-) (biofizikus) Isola, Jorma Tammi, Markku (kutatóorvos) Szöllősi János (1953-) (biofizikus) Nagy Péter (1971-) (biofizikus)
Internet cím:elektronikus változat
DOI
Borító:
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