Document Detail


5-Aza-2'-deoxycytidine induces growth inhibition and upregulation of epidermal growth factor receptor on human epithelial cancer cells.
MedLine Citation:
PMID:  7514437     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: The epidermal growth factor (EGF-R) receptor is an important growth regulator of epithelial cancer cells, and is presently considered a tumor-associated antigen (TAA) which is overexpressed by several human cancers and barely detectable in most normal tissues. Since TAA density at the tumor cell surface is a critical factor regulating the efficiency of immunotargeting procedures, a therapeutic advantage may derive from the pharmacologic enhancement of membrane expression of such antigens on tumor cells.
MATERIALS AND METHODS: Utilizing a panel of different human cancer cell lines of epithelial derivation, we have investigated in the in vitro effects of 5-aza-2'-deoxycytidine (5azaCdR), an antineoplastic agent able to induce gene activation and phenotypic modulation, on the surface expression of EGF-R by tumor cells.
RESULTS: 5azaCdR (10-1000 nM) induced growth inhibition, in the absence of acute cell kill, on KB (human oropharyngeal carcinoma), LoVo and the drug-resistant clone LoVo-DX (colon carcinoma) and A549 (lung adenocarcinoma) cell lines, along with a significant enhancement of EGF-R expression at the tumor cell surface. A single 24 h pulse of 5azaCdR, followed by 96 h of culture in drug-free medium, induced 50% growth inhibition on KB cells at a concentration (IC50) of 500 nM, on A549 (IC50 = 490 nM), LoVo (IC50 = 400 nM) and LoVo-DX (IC50 = 100 nM) cell lines. Under these conditions the specific binding of 125I-EGF was significantly upregulated at the surface of growth-inhibited cancer cells. Scatchard analysis of EGF-binding data revealed no changes in the Kd of EGF-R for its ligand in 5azaCdR-treated tumor cells and demonstrated a significant increase in the number of both the high- and low-affinity EGF-binding sites on KB cells, while only one class of EGF-binding site was detectable on A549, LoVo and LoVo-DX tumor cell lines before and after exposure to 5azaCdR. The EGF-R upregulation induced by 5azaCdR was paralleled by the increased binding of the anti-EGF-R monoclonal antibody (MAb) 108.1 on the surface of cancer cells. Finally, the rate of endocytosis of the anti-EGF-R MAb by KB cells was not modified by drug treatment, indicating that exposure to 5azaCdR does not hamper MAb internalization by the tumor cells. This latter represents an essential process for the cytotoxic effects of immunoconjugate drugs or toxins.
CONCLUSIONS: We suggest a role for 5azaCdR in enhancing the efficacy of therapeutic approaches involving the use of anti-EGF-R immunoconjugated for the imaging and the treatment of human epithelial neoplasias.
Authors:
M Caraglia; A Pinto; P Correale; V Zagonel; G Genua; A Leardi; S Pepe; A R Bianco; P Tagliaferri
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Annals of oncology : official journal of the European Society for Medical Oncology / ESMO     Volume:  5     ISSN:  0923-7534     ISO Abbreviation:  Ann. Oncol.     Publication Date:  1994 Mar 
Date Detail:
Created Date:  1994-06-23     Completed Date:  1994-06-23     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  9007735     Medline TA:  Ann Oncol     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  269-76     Citation Subset:  IM    
Affiliation:
Cattedra di Oncologia Medica, Facoltà di Medicina, Università Federico II, Naples, Italy.
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / metabolism,  pathology*
Antibodies, Monoclonal / diagnostic use
Antineoplastic Agents / pharmacology*
Azacitidine / analogs & derivatives*,  pharmacology
Carcinoma, Squamous Cell / metabolism,  pathology*
Cell Division / drug effects
Endocytosis / drug effects
Humans
KB Cells
Receptor, Epidermal Growth Factor / biosynthesis,  drug effects*
Tumor Cells, Cultured / drug effects,  metabolism,  pathology
Up-Regulation
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antineoplastic Agents; 320-67-2/Azacitidine; 776B62CQ27/decitabine; EC 2.7.10.1/Receptor, Epidermal Growth Factor

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