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Antisense Technology: From Unique Laboratory Tool to Novel Anticancer Treatments

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From Nucleic Acids Sequences to Molecular Medicine

Part of the book series: RNA Technologies ((RNATECHN))

Abstract

Antisense reagents and technology have developed as extraordinarily useful tools for the analysis of gene function. The capacity of antisense to reduce expression of RNA (including protein-encoding mRNA and noncoding RNA) important in a multitude of diseases has led to the concept of using antisense molecules as drugs to treat those diseases. Antisense oligonucleotides (ASOs) are being developed for this purpose, with single-stranded DNA ASOs currently the most advanced in clinical testing. Phase I to III clinical trials of ASOs are either completed or in progress for a number of diseases, including cancer. In this review, we focus on progress in developing antisense drugs to downregulate genes mediating malignant characteristics in tumors originating in multiple tissues. In addition, we review progress in (1) ASO targeting of microRNAs (miRNAs) to repress malignant characteristics in multiple tumor types including use of MT-AMOs (multiple-target anti-miRNA oligonucleotides); (2) combining ASOs with each other to generate “synthetic lethality” that enhances chemotherapeutic drug activity; (3) the use of RASONs (radiolabeled antisense ODNs) to image tumors for diagnostic purposes and to monitor therapeutic activity; (4) “on-target” and “off-target” effects of ASOs that lead to both decreases and increases in therapeutic benefit; (5) the chemistries of ASOs that enhance ASO stability, specificity, and activity and reduce undesirable toxicity; and (6) the relative advantages and disadvantages of RNAi-dependent and other ASOs for future application as therapeutic agents to diagnose, monitor, and treat cancer.

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Abbreviations

ACRBP:

Acrosin-binding protein

AD–PEG:

Adamantane–polyethylene glycol

AD–PEG–Tf:

Adamantane–polyethylene glycol–transferrin

Ago 2:

Argonaute 2

AKT:

Serine–threonine protein kinase B

AMO:

Anti-miRNA antisense oligodeoxynucleotide inhibitors

APC/C:

Anaphase-promoting complex/cyclosome

APE1:

Apurinic/apyrimidinic endonuclease-1

ATM:

Ataxia telangiectasia mutated

ATR:

Ataxia telangiectasia and Rad3 related

AuNPs:

Gold nanoparticles

Bcl-2:

B-cell lymphoma-2

Bcl-xL:

B-cell lymphoma extra long

BRCA1:

Breast cancer susceptibility gene 1

BRCA2:

Breast cancer susceptibility gene 2

CDK:

Cyclin-dependent kinase

Chk1:

Checkpoint kinase 1, S- and G2-checkpoint protein

Chk2:

Checkpoint kinase 2, a serine–threonine kinase

c-Raf:

Proto-oncogene c-Raf

DDB1:

Damage-specific DNA-binding protein 1

DHFR:

Dihydrofolate reductase

DNA-PKcs:

DNA-dependent protein kinase catalytic subunit

DR5:

Death receptor 5, officially TNFRSF10B, or tumor necrosis factor receptor superfamily, member 10b

ECT2:

Epithelial cell transforming sequence 2 (exchange factor for GTPases)

EGFR:

Epidermal growth factor receptor; Her-1

FANCD2:

Fanconi anemia complementation group D2

FEN:

Flap 5′-endonuclease

GEF-H1:

Rho/Rac guanine nucleotide exchange factor

GSK-3B:

Glycogen synthase kinase 3 beta

HIV:

Human immunodeficiency virus

HR:

Homologous recombination

H-Ras:

GTPase H-Ras (a.k.a. transforming protein p21)

HSP90:

90-kDa heat shock protein

IPMK:

Inositol polyphosphate multikinase

KSP:

Kinesin spindle protein

Ki-RAS:

RAS-family member K

LNA:

Locked nucleic acid

MDR:

Multidrug resistance

MGMT:

O6-methylguanine-DNA methyltransferase

MK2:

Officially MAPKAPK2, mitogen-activated protein kinase-activated protein kinase 2

MLH1:

mutL homolog 1, colon cancer, nonpolyposis type 2

MMR:

Mismatch repair

MPO or PMO:

Morpholino phosphoroamide

MRI:

Magnetic resonance imaging

MSH2:

mutS homolog 2, nonpolyposis type 1

MSH6:

mutS homolog 6

mTOR:

Mammalian target of rapamycin

NGR peptide:

Asparagine–glycine–arginine peptide

NOTCH-1:

Notch homolog 1

NSCLC:

Non-small cell lung carcinoma

PAK3:

p21 protein (Cdc42/Rac)-activated kinase 3

PARP:

Poly(ADP-ribose) polymerase

PEI-C:

Catechol-conjugated polyethylenimine

Pgp:

P-glycoprotein

PINK1:

PTEN-induced putative kinase 1

PKCα:

Protein kinase C alpha

PLK1:

Polo-like kinase 1

pol:

Polymerase

PSMA:

Prostate-specific membrane antigen

PSMA6:

Proteasome (prosome, macropain) subunit, alpha type, 6, a subunit of proteasome 20S

PTEN:

Phosphatase–tensin homolog

PTP-1B:

Protein tyrosine phosphotase-1B

RAD51:

DNA repair protein, homolog of Saccharomyces cerevisiae rad51 protein that is a determinant of radiation sensitivity

RAD52:

DNA repair protein, homolog of Saccharomyces cerevisiae rad52 protein that is a determinant of radiation sensitivity

RB:

Retinoblastoma protein

ROS:

Reactive oxygen species

RRM2:

Ribonucleotide reductase M2

SGK2:

Serum/glucocorticoid regulated kinase 2

SKP2:

S-phase kinase-associated protein 2 (p45)

SNAIL2:

Also known as SNAI2, homolog of Drosophila sna, a zinc-finger, DNA-binding transcriptional factor

SNALP:

Stable nucleic acid-lipid particle

STK33:

Serine–threonine kinase

tb-FGF:

Truncated human basic fibroblast growth factor

TBK1:

TANK-binding kinase

TGF-β2:

Transforming growth factor-beta 2

TNF-α:

Tumor necrosis factor-alpha

topo:

Topoisomerase

TS:

Thymidylate synthase

TSC2:

Tuberous sclerosis 2

TUBGCP2:

Tubulin, gamma complex associated protein 2

VEGF:

Vascular endothelial growth factor

VHL:

von Hippel–Landau protein

WEE1:

G2-checkpoint protein (mitotic inhibitor) that is a homolog of the wee1 yeast kinase

XAB2:

XPA-binding protein 2a, also known as pre-mRNA-splicing factor SYF1; a transcription-coupled DNA repair protein

XIAP:

X-linked inhibitor of apoptosis

XRCC1:

X-ray repair cross-complementing protein 1

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Western Ontario, London, ON, Canada, N6A 4L6

    Christine Di Cresce, Colin Way, Mateusz Rytelewski, Saman Maleki Vareki & James Koropatnick

  2. London Regional Cancer Program and Lawson Health Research Institute, London, ON, Canada

    Christine Di Cresce, Colin Way, Mateusz Rytelewski, Saman Maleki Vareki, Mark D. Vincent, James Koropatnick & Peter J. Ferguson

  3. Faculty of Science, University of Western Ontario, London, ON, Canada

    Supritha Nilam

  4. Department of Oncology, University of Western Ontario, London, ON, Canada

    Mark D. Vincent, James Koropatnick & Peter J. Ferguson

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  1. Christine Di Cresce
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  2. Colin Way
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  4. Saman Maleki Vareki
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  5. Supritha Nilam
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  8. Peter J. Ferguson
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Correspondence to Christine Di Cresce or Peter J. Ferguson .

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Editors and Affiliations

  1. Institute of Chemistry/Biochemistry, Free University Berlin, Thielallee 63, Berlin, 14195, Berlin, Germany

    Volker A. Erdmann

  2. Inst. Bioorganic Chemistry, PAN Poznan, ul. Z. Noskowskiego 12/14, Poznan, 61-704, Poland

    Jan Barciszewski

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Di Cresce, C. et al. (2012). Antisense Technology: From Unique Laboratory Tool to Novel Anticancer Treatments. In: Erdmann, V., Barciszewski, J. (eds) From Nucleic Acids Sequences to Molecular Medicine. RNA Technologies. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-27426-8_7

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