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5-aza-2'-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma: Immunotherapeutic implications

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 targ...

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Published in:Clinical cancer research 2002-08, Vol.8 (8), p.2690-2695
Main Authors: CORAL, Sandra, SIGALOTTI, Luca, ALTOMONTE, Maresa, ENGELSBERG, Arne, COLIZZI, Francesca, CATTAROSSI, Ilaria, MARASKOVSKY, Eugene, JAGER, Elke, SELIGER, Barbara, MAIO, Michele
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container_issue 8
container_start_page 2690
container_title Clinical cancer research
container_volume 8
creator CORAL, Sandra
SIGALOTTI, Luca
ALTOMONTE, Maresa
ENGELSBERG, Arne
COLIZZI, Francesca
CATTAROSSI, Ilaria
MARASKOVSKY, Eugene
JAGER, Elke
SELIGER, Barbara
MAIO, Michele
description 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. 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. 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. 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.
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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. 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. 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. 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Drug treatments</topic><topic>Precipitin Tests</topic><topic>Protein Biosynthesis</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - metabolism</topic><topic>Time Factors</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CORAL, Sandra</creatorcontrib><creatorcontrib>SIGALOTTI, Luca</creatorcontrib><creatorcontrib>ALTOMONTE, Maresa</creatorcontrib><creatorcontrib>ENGELSBERG, Arne</creatorcontrib><creatorcontrib>COLIZZI, Francesca</creatorcontrib><creatorcontrib>CATTAROSSI, Ilaria</creatorcontrib><creatorcontrib>MARASKOVSKY, Eugene</creatorcontrib><creatorcontrib>JAGER, Elke</creatorcontrib><creatorcontrib>SELIGER, Barbara</creatorcontrib><creatorcontrib>MAIO, Michele</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CORAL, Sandra</au><au>SIGALOTTI, Luca</au><au>ALTOMONTE, Maresa</au><au>ENGELSBERG, Arne</au><au>COLIZZI, Francesca</au><au>CATTAROSSI, Ilaria</au><au>MARASKOVSKY, Eugene</au><au>JAGER, Elke</au><au>SELIGER, Barbara</au><au>MAIO, Michele</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>5-aza-2'-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma: Immunotherapeutic implications</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2002-08-01</date><risdate>2002</risdate><volume>8</volume><issue>8</issue><spage>2690</spage><epage>2695</epage><pages>2690-2695</pages><issn>1078-0432</issn><abstract>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. 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. 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. 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.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>12171902</pmid><tpages>6</tpages></addata></record>
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source Freely Accessible Science Journals - check A-Z of ejournals
subjects Antibodies, Monoclonal
Antigens, Neoplasm - biosynthesis
Antimetabolites, Antineoplastic - pharmacology
Antineoplastic agents
Azacitidine - analogs & derivatives
Azacitidine - pharmacology
Biological and medical sciences
Blotting, Western
Carcinoma, Renal Cell - drug therapy
Carcinoma, Renal Cell - therapy
Chemotherapy
Electrophoresis, Polyacrylamide Gel
Eye Proteins - biosynthesis
Humans
Immunotherapy - methods
Kidney Neoplasms - drug therapy
Kidney Neoplasms - therapy
Medical sciences
Melanoma-Specific Antigens
Membrane Proteins
Mitogen-Activated Protein Kinases
Neoplasm Proteins - biosynthesis
Pharmacology. Drug treatments
Precipitin Tests
Protein Biosynthesis
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - metabolism
Time Factors
Tumor Cells, Cultured
title 5-aza-2'-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma: Immunotherapeutic implications
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