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Book: Nucleic acid therapeutics in cancer

Gewirtz, Alan M.

[... results from that meeting, which was held in April of 2000 in Bryn Mawr, Pennsylvania]

(Cancer drug discovery and development)

2004

Author's details	ed. by Alan M. Gewirtz
Series title	Cancer drug discovery and development
Keywords	Neoplasms / therapy ; Nucleic Acids / therapeutic use ; Gene Therapy / methods
Language	English
Size	X, 219 S. : Ill., graph. Darst.
Publisher	Humana Press
Publishing place	Totowa, NJ
Publishing country	United States
Document type	Book
HBZ-ID	HT013916277
ISBN	1-58829-258-4 ; 978-1-58829-258-2
Database	Catalogue ZB MED Medicine, Health

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Article: RNA targeted therapeutics for hematologic malignancies.

Gewirtz, Alan M

Blood cells, molecules & diseases

2007 Volume 38, Issue 2, Page(s) 117–119

Abstract: In a variety of experimental systems, antisense nucleic acids (ASNA) of various composition, including antisense oligodeoxynucleotides (ODN) and siRNA, have been shown to have the ability to variably perturb gene expression in a sequence specific manner. ...

Abstract	In a variety of experimental systems, antisense nucleic acids (ASNA) of various composition, including antisense oligodeoxynucleotides (ODN) and siRNA, have been shown to have the ability to variably perturb gene expression in a sequence specific manner. Pilot clinical studies from our group, and others, have demonstrated that gene silencing is a therapeutic strategy that is starting to make a real contribution to the treatment of various diseases. The development of this field, with specific reference to hematologic malignancies, is reviewed very briefly below.
MeSH term(s)	Gene Silencing ; Hematologic Neoplasms/therapy ; Humans ; Oligodeoxyribonucleotides, Antisense/therapeutic use ; Oligonucleotides, Antisense/therapeutic use ; RNA, Small Interfering/therapeutic use
Chemical Substances	Oligodeoxyribonucleotides, Antisense ; Oligonucleotides, Antisense ; RNA, Small Interfering
Language	English
Publishing date	2007-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1237083-6
ISSN	1096-0961 ; 1079-9796
ISSN (online)	1096-0961
ISSN	1079-9796
DOI	10.1016/j.bcmd.2006.10.162
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Article: On future's doorstep: RNA interference and the pharmacopeia of tomorrow.

Gewirtz, Alan M

The Journal of clinical investigation

2007 Volume 117, Issue 12, Page(s) 3612–3614

Abstract: Small molecules and antibodies have revolutionized the treatment of malignant diseases and appear promising for the treatment of many others. Nonetheless, there are many candidate therapeutic targets that are not amenable to attack by the current ... ...

Abstract	Small molecules and antibodies have revolutionized the treatment of malignant diseases and appear promising for the treatment of many others. Nonetheless, there are many candidate therapeutic targets that are not amenable to attack by the current generation of targeted therapies, and in a small but growing number of patients, resistance to initially successful treatments evolves. This Review Series on the medicinal promise of posttranscriptional gene silencing with small interfering RNA and other molecules capable of inducing RNA interference (RNAi) is motivated by the hypothesis that effectors of RNAi can be developed into effective drugs for treating malignancies as well as many other types of disease. As this Review Series points out, there is still much to do, but many in the field now hope that the time has finally arrived when "antisense" therapies will finally come of age and fulfill their promise as the magic bullets of the 21st century.
MeSH term(s)	Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Pharmacopoeias as Topic ; RNA Interference/drug effects ; RNA Stability ; RNA, Small Interfering/chemistry ; RNA, Small Interfering/pharmacokinetics ; RNA, Small Interfering/therapeutic use
Chemical Substances	RNA, Small Interfering
Language	English
Publishing date	2007-10-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI34274
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Article ; Online: Embryonic and adult stem cell therapy.

Brignier, Anne C / Gewirtz, Alan M

The Journal of allergy and clinical immunology

2010 Volume 125, Issue 2 Suppl 2, Page(s) S336–44

Abstract: There are many types of stem cells. All share the characteristics of being able to self-renew and to give rise to differentiated progeny. Over the last decades, great excitement has been generated by the prospect of being able to exploit these properties ...

Abstract	There are many types of stem cells. All share the characteristics of being able to self-renew and to give rise to differentiated progeny. Over the last decades, great excitement has been generated by the prospect of being able to exploit these properties for the repair, improvement, and/or replacement of damaged organs. However, many hurdles, both scientific and ethical, remain in the path of using human embryonic stem cells for tissue-engineering purposes. In this report we review current strategies for isolating, enriching, and, most recently, inducing the development of human pluripotent stem cells. In so doing, we discuss the scientific and ethical issues associated with this endeavor. Finally, progress in the use of stem cells as therapies for type 1 diabetes mellitus, congestive heart failure, and various neurologic and immunohematologic disorders, and as vehicles for the delivery of gene therapy, is briefly discussed.
MeSH term(s)	Adult Stem Cells/transplantation ; Animals ; Cell Differentiation/genetics ; Cell- and Tissue-Based Therapy/trends ; Embryonic Stem Cells/transplantation ; Humans ; Regenerative Medicine/ethics ; Regenerative Medicine/methods ; Regenerative Medicine/trends ; Stem Cell Niche ; Stem Cell Transplantation ; Tissue Engineering ; Transcriptional Activation
Language	English
Publishing date	2010-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2009.09.032
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Article ; Online: A prototype nonpeptidyl, hydrazone class, thrombopoietin receptor agonist, SB-559457, is toxic to primary human myeloid leukemia cells.

Kalota, Anna / Gewirtz, Alan M

Blood

2009 Volume 115, Issue 1, Page(s) 89–93

Abstract: Biologic characterization of SB-559457 (SB), a nonpeptidyl hydrazone class of thrombopoietin receptor (Mpl) agonist, revealed toxicity toward human leukemia cells. Antiproliferative effects followed by significant, nonapoptotic, cell death within 72 ... ...

Abstract	Biologic characterization of SB-559457 (SB), a nonpeptidyl hydrazone class of thrombopoietin receptor (Mpl) agonist, revealed toxicity toward human leukemia cells. Antiproliferative effects followed by significant, nonapoptotic, cell death within 72 hours occurred in 24 of 26 acute myeloid leukemia, 0 of 6 acute lymphoblastic leukemia, and 3 of 6 chronic myeloid leukemia patient samples exposed to SB, but not recombinant human thrombopoietin (rhTpo), in liquid suspension culture. Further investigation revealed increased phosphorylation of p70S6/S6 kinases in SB-, but not in rhTpo-, treated cells. Expression profiling of cells exposed to SB versus rhTpo revealed statistically significant, more than 2-fold changes in GAPDH and REDD1 gene expression, confirmed by quantitative reverse-transcribed polymerase chain reaction. These genes, induced in energy or hypoxia stressed cells, have been implicated in cell death pathways, and may provide important clues to the mechanism of SB-induced, leukemic cell death. These results suggest that nonpeptidyl, hydrazone class Mpl agonists may be clinically useful antileukemic agents by virtue of their combined thrombopoietic and antileukemic effects.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/toxicity ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Drug Screening Assays, Antitumor ; Gene Expression Regulation, Leukemic/drug effects ; Humans ; Hydrazones/chemistry ; Hydrazones/pharmacology ; Hydrazones/toxicity ; Leukemia, Myeloid/enzymology ; Leukemia, Myeloid/genetics ; Leukemia, Myeloid/pathology ; Peptides/pharmacology ; Phosphorylation/drug effects ; Receptors, Thrombopoietin/agonists ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Tumor Cells, Cultured
Chemical Substances	Antineoplastic Agents ; DDIT4 protein, human ; Hydrazones ; Peptides ; Receptors, Thrombopoietin ; SB-559457 ; Transcription Factors ; Ribosomal Protein S6 Kinases, 70-kDa (EC 2.7.11.1)
Language	English
Publishing date	2009-10-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2009-06-227751
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Article ; Online: Longitudinal multi-omics analyses of the gut-liver axis reveals metabolic dysregulation in hepatitis C infection and cirrhosis.

Nature microbiology

2022 Volume 8, Issue 1, Page(s) 12–27

Abstract: The gut and liver are connected via the portal vein, and this relationship, which includes the gut microbiome, is described as the gut-liver axis. Hepatitis C virus (HCV) can infect the liver and cause fibrosis with chronic infection. HCV has been ... ...

Abstract	The gut and liver are connected via the portal vein, and this relationship, which includes the gut microbiome, is described as the gut-liver axis. Hepatitis C virus (HCV) can infect the liver and cause fibrosis with chronic infection. HCV has been associated with an altered gut microbiome; however, how these changes impact metabolism across the gut-liver axis and how this varies with disease severity and time is unclear. Here we used multi-omics analysis of portal and peripheral blood, faeces and liver tissue to characterize the gut-liver axis of patients with HCV across a fibrosis severity gradient before (n = 29) and 6 months after (n = 23) sustained virologic response, that is, no detection of the virus. Fatty acids were the major metabolites perturbed across the liver, portal vein and gut microbiome in HCV, especially in patients with cirrhosis. Decreased fatty acid degradation by hepatic peroxisomes and mitochondria was coupled with increased free fatty acid (FFA) influx to the liver via the portal vein. Metatranscriptomics indicated that Anaerostipes hadrus-mediated fatty acid synthesis influences portal FFAs. Both microbial fatty acid synthesis and portal FFAs were associated with enhanced hepatic fibrosis. Bacteroides vulgatus-mediated intestinal glycan breakdown was linked to portal glycan products, which in turn correlated with enhanced portal inflammation in HCV. Paired comparison of patient samples at both timepoints showed that hepatic metabolism, especially in peroxisomes, is persistently dysregulated in cirrhosis independently of the virus. Sustained virologic response was associated with a potential beneficial role for Methanobrevibacter smithii, which correlated with liver disease severity markers. These results develop our understanding of the gut-liver axis in HCV and non-HCV liver disease aetiologies and provide a foundation for future therapies.
MeSH term(s)	Humans ; Multiomics ; Liver Cirrhosis ; Hepatitis C/complications ; Hepacivirus/genetics
Language	English
Publishing date	2022-12-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural
ISSN	2058-5276
ISSN (online)	2058-5276
DOI	10.1038/s41564-022-01273-y
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Article ; Online: The histone acetyltransferase TIP60 interacts with c-Myb and inactivates its transcriptional activity in human leukemia.

Zhao, Huiwu / Jin, Shenghao / Gewirtz, Alan M

The Journal of biological chemistry

2011 Volume 287, Issue 2, Page(s) 925–934

Abstract: The histone acetyltransferase TIP60 is a coregulator of transcription factors and is implicated in tumorigenesis. In this study, we explored potential regulatory relationships between TIP60 and the c-Myb oncoprotein in hematopoietic cells. We first ... ...

Abstract	The histone acetyltransferase TIP60 is a coregulator of transcription factors and is implicated in tumorigenesis. In this study, we explored potential regulatory relationships between TIP60 and the c-Myb oncoprotein in hematopoietic cells. We first showed that TIP60 is a c-Myb interacting protein and that the interaction is dependent on the TIP60 acetyltransferase domain and c-Myb transactivation domain. We then found that coexpressing TIP60 decreases the transcriptional activation ability of c-Myb in functional reporter assays. A ChIP assay also revealed that TIP60 binds to the c-Myb target gene c-Myc promoter in a c-Myb-dependent manner. Consistently, knockdown of Tip60 expression by siRNA increased endogenous c-Myc expression. Furthermore, coimmunoprecipitation of Jurkat cell lysates revealed that c-Myb is associated with histone deacetylases HDAC1 and HDAC2, known to interact with TIP60 and repress transcription. Finally, we compared Tip60 expression in six primary AML samples with three normal CD34(+) cell samples using quantitative RT-PCR. Tip60 expression was significantly (∼60%) lower in the AML samples. In summary, these studies demonstrate that TIP60 negatively modulates c-Myb transcriptional activity by recruiting histone deacetylases in human hematopoietic cells, leading us to hypothesize that TIP60 is a normal regulator of c-Myb function and that dysregulated or mutated TIP60 may contribute to c-Myb-driven leukemogenesis.
MeSH term(s)	Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Leukemic ; HEK293 Cells ; HL-60 Cells ; Hematopoietic Stem Cells/metabolism ; Hematopoietic Stem Cells/pathology ; Histone Acetyltransferases/biosynthesis ; Histone Acetyltransferases/genetics ; Histone Deacetylase 1/genetics ; Histone Deacetylase 1/metabolism ; Histone Deacetylase 2/genetics ; Histone Deacetylase 2/metabolism ; Humans ; K562 Cells ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Lysine Acetyltransferase 5 ; Mutation ; Proto-Oncogene Proteins c-myb/genetics ; Proto-Oncogene Proteins c-myb/metabolism ; Transcription, Genetic
Chemical Substances	Proto-Oncogene Proteins c-myb ; Histone Acetyltransferases (EC 2.3.1.48) ; KAT5 protein, human (EC 2.3.1.48) ; Lysine Acetyltransferase 5 (EC 2.3.1.48) ; HDAC1 protein, human (EC 3.5.1.98) ; HDAC2 protein, human (EC 3.5.1.98) ; Histone Deacetylase 1 (EC 3.5.1.98) ; Histone Deacetylase 2 (EC 3.5.1.98)
Language	English
Publishing date	2011-11-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M111.279950
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Article ; Online: RNA interference for treating haematological malignancies.

Hexner, Elizabeth O / Gewirtz, Alan M

Expert opinion on biological therapy

2005 Volume 5, Issue 12, Page(s) 1585–1592

Abstract: RNA interference (RNAi) is a method for silencing gene expression. It is relatively gene-specific, potent, and minimally toxic. For these reasons, RNAi holds great promise for the treatment of haematological malignancies. Much has already been learned ... ...

Abstract	RNA interference (RNAi) is a method for silencing gene expression. It is relatively gene-specific, potent, and minimally toxic. For these reasons, RNAi holds great promise for the treatment of haematological malignancies. Much has already been learned about RNAi in the laboratory, although many fundamental questions about its mechanisms remain to be elucidated. For human trials, major hurdles to be overcome include the induction of a nonspecific immune response to RNAi, the selection of the most appropriate targets, the design of more specific molecules, and the assurance of efficient delivery and safety in patients. Translational research efforts are currently well on their way to solving these problems, and will be reviewed here.
MeSH term(s)	Animals ; Gene Targeting/methods ; Genetic Therapy/methods ; Hematologic Neoplasms/genetics ; Hematologic Neoplasms/therapy ; Humans ; RNA Interference ; RNA, Double-Stranded/therapeutic use
Chemical Substances	RNA, Double-Stranded
Language	English
Publishing date	2005-11-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2052501-1
ISSN	1744-7682 ; 1471-2598
ISSN (online)	1744-7682
ISSN	1471-2598
DOI	10.1517/14712598.5.12.1585
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Article ; Online: Therapeutic potential of antisense nucleic acid molecules.

Opalinska, Joanna B / Gewirtz, Alan M

Science's STKE : signal transduction knowledge environment

2003 Volume 2003, Issue 206, Page(s) pe47

Abstract: Elucidation of many disease-related signal transduction and gene expression pathways has provided unparalleled opportunities for the development of targeted therapeutics. The types of molecules in development are increasingly varied and include small- ... ...

Abstract	Elucidation of many disease-related signal transduction and gene expression pathways has provided unparalleled opportunities for the development of targeted therapeutics. The types of molecules in development are increasingly varied and include small-molecule enzyme inhibitors, humanized antibodies to cell surface receptors, and antisense nucleic acids for silencing the expression of specific genes. This Perspective reviews the basis for various antisense strategies for modulating gene expression, including RNA interference, and discusses the prospects for their clinical use.
MeSH term(s)	Animals ; Antisense Elements (Genetics)/pharmacology ; Antisense Elements (Genetics)/therapeutic use ; Gene Silencing/drug effects ; Humans ; Oligonucleotides, Antisense/pharmacology ; Oligonucleotides, Antisense/therapeutic use ; Organothiophosphorus Compounds/pharmacology ; Organothiophosphorus Compounds/therapeutic use ; Thionucleotides
Chemical Substances	Antisense Elements (Genetics) ; Olg antisense phosphorothioate oligonucleotide ; Oligonucleotides, Antisense ; Organothiophosphorus Compounds ; Thionucleotides
Language	English
Publishing date	2003-10-28
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1525-8882
ISSN (online)	1525-8882
DOI	10.1126/stke.2003.206.pe47
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Article: Nucleic acid therapeutics: a work in progress.

Opalinska, Joanna B / Gewirtz, Alan M

Current opinion in investigational drugs (London, England : 2000)

2002 Volume 3, Issue 6, Page(s) 928–933

MeSH term(s)	Clinical Trials, Phase I as Topic ; Clinical Trials, Phase II as Topic ; Crohn Disease/drug therapy ; Drug Stability ; Gene Silencing ; Gene Targeting ; Humans ; Neoplasms/drug therapy ; Nucleic Acids/chemistry ; Nucleic Acids/therapeutic use ; Oligonucleotides, Antisense/chemistry ; Oligonucleotides, Antisense/therapeutic use ; Protein Biosynthesis/drug effects ; Transcription, Genetic/drug effects
Chemical Substances	Nucleic Acids ; Oligonucleotides, Antisense
Language	English
Publishing date	2002-06
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2027913-9
ISSN	2040-3429 ; 1472-4472 ; 0967-8298
ISSN (online)	2040-3429
ISSN	1472-4472 ; 0967-8298
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