Document Detail


5-aza-2'-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma: immunotherapeutic implications.
MedLine Citation:
PMID:  12171902     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Limited therapeutic options are presently available for advanced renal cell carcinoma (RCC). This study was designed to define the clinical potential of the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-AZA-CdR) in human RCC, through its control of the expression of "therapeutic targets" of the cancer testis antigen (CTA) family, and of the tumor-associated antigen RAGE-1, in RCC cells.
EXPERIMENTAL DESIGN: Reverse transcription (RT)-PCR assays of a panel of RCC cells treated with 5-AZA-CdR, investigated the induction of the expression of several CTAs and of RAGE-1. Immunoprecipitation and Western blotting assessed whether the expression of CTA-specific mRNA induced by 5-AZA-CdR resulted in a translated protein of appropriate molecular weight. The functional activity of de novo expressed CTA was evaluated using (51)Cr release cytotoxicity assays of 5-AZA-CdR-treated HLA-A2-positive RCC cells using HLA-A2-restricted NY-ESO-1-specific CTLs.
RESULTS: Exposure to 5-AZA-CdR invariably induced the expression of the CTA MAGE-1, -2, -3, and -4, GAGE 1-6, and NY-ESO-1 in all of the RCC cells investigated. De novo expression of NY-ESO-1 was persistent, being still detectable 60 days after the end of treatment, and generated a functional protein efficiently recognized by HLA-A2-restricted NY-ESO-1-specific CTLs. 5-AZA-CdR also induced RAGE-1 expression in RAGE-1-negative RCC and sarcoma cells but not in neoplastic cells of different histology.
CONCLUSIONS: This study provides the scientific rationale to establish new strategies of chemoimmunotherapy in RCC patients. The well-defined immunogenicity of the investigated CTAs and of RAGE-1 suggest that systemic administration of 5-AZA-CdR represents a promising strategy to enhance the constitutively poor immunogenic potential of RCC cells, and to propose that virtually all RCC patients receive active and/or adoptive CTA- or RAGE-1-based immunotherapy.
Authors:
Sandra Coral; Luca Sigalotti; Maresa Altomonte; Arne Engelsberg; Francesca Colizzi; Ilaria Cattarossi; Eugene Maraskovsky; Elke Jager; Barbara Seliger; Michele Maio
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  8     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2002 Aug 
Date Detail:
Created Date:  2002-08-12     Completed Date:  2003-02-26     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2690-5     Citation Subset:  IM    
Affiliation:
Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, 33081 Aviano, Italy.
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MeSH Terms
Descriptor/Qualifier:
Antibodies, Monoclonal
Antigens, Neoplasm / biosynthesis*
Antimetabolites, Antineoplastic / pharmacology*
Azacitidine / analogs & derivatives*,  pharmacology*
Blotting, Western
Carcinoma, Renal Cell / drug therapy*,  therapy
Electrophoresis, Polyacrylamide Gel
Eye Proteins / biosynthesis
Humans
Immunotherapy / methods*
Kidney Neoplasms / drug therapy*,  therapy
Melanoma-Specific Antigens
Membrane Proteins*
Mitogen-Activated Protein Kinases
Neoplasm Proteins / biosynthesis
Precipitin Tests
Protein Biosynthesis
RNA, Messenger / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Time Factors
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antigens, Neoplasm; 0/Antimetabolites, Antineoplastic; 0/CTAG1B protein, human; 0/Eye Proteins; 0/MAGEA1 protein, human; 0/MAGEA3 protein, human; 0/Melanoma-Specific Antigens; 0/Membrane Proteins; 0/Neoplasm Proteins; 0/RNA, Messenger; 320-67-2/Azacitidine; 776B62CQ27/decitabine; EC 2.7.11.22/MOK protein, human; EC 2.7.11.24/Mitogen-Activated Protein Kinases

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