Download The war against cancer: Suicide gene therapy

doi: 10.18282/amor.v2.i3.103
REVIEW ARTICLE
The war against cancer: Suicide gene therapy
Muzeyyen Izmirli1,2*, Dilara Sonmez2, Bulent Gogebakan1,2
1
Mustafa Kemal University, School of Medicine, Department of Medical Biology, Hatay, Turkey
Mustafa Kemal University, School of Medicine, Department of Molecular Biochemistry and Genetics, Hatay, Turkey
2
Abstract: The National Cancer Institute and the American Cancer Society announced that 1.6 million new cancer cases
are projected to occur in the USA in 2016. One of the most innovative approaches against cancer is suicide gene therapy,
in which suicide-inducing transgenes are introduced into cancer cells. When cancer treatments target the total elimination of tumor cells, there will be no side effects for normal cells. Cancer tissues are targeted through various targeted
transport methods, followed by tissue-specific enzymes converting a systemically suitable prodrug into an active drug
in the tumor. Suicidal genes are delivered by transporters, such as viral and non-viral vectors, into cancer cells. Suicide
gene therapeutic strategies currently pursued are herpes simplex virus thymidine kinase gene with prodrug ganciclovir,
cytosine deaminase gene, carboxyl esterase/irinotecan, varicella zoster virus thymidine kinase/6-methoxypurine arabinonucleoside, nitroreductase Nfsb/5-(aziridin-1-yl)-2,4-dinitrobenzamide, carboxypeptidase G2/4-[(2-chloroethyl) (2mesyloxyethyl)amino] benzoyl-L-glutamic acid, cytochrome p450-isofosfamide, and cytochrome p450-cyclophosphamide. The goal of this review is to summarize the different suicide gene systems and gene delivery vectors addressed to
cancer cells, with a particular emphasis on recently developed systems. Finally, we briefly describe the advantageous
clinical applications and potential side effects of suicide gene therapy.
Keywords: suicide gene therapy; cancer; vector
Citation: Izmirli M, Sonmez D, Gogebakan B. The war against cancer: Suicide gene therapy. Adv Mod Oncol Res 2016;
2(3): xx–xx; http://dx.doi.org/10.18282/amor.v2.i3.103.
*Correspondence to: Muzeyyen Izmirli, Mustafa Kemal University, School of Medicine, Department of Medical Biology, Hatay,
Turkey; [email protected]
Received: 16th February 2016; Accepted: 12th April 2016; Published Online: 13th June 2016
Introduction
In 2016, nearly 1.6 million new cases of cancer is projected to occur in the US[1]. Gene therapy delivers medicinal products via recombinant nucleic acid that
regulates, repairs, replaces, adds, or deletes genetic sequences, which directly affects therapeutic, prophylactic,
or diagnostic strategies. Gene therapy consists of two
categories: germ line gene therapy and somatic gene
therapy. Germ line gene therapy includes therapeutic or
modified genes, which will be passed on to the next generation, while somatic gene therapy consists of genetic
materials inserted into target cells but will not be passed
on to the next generation[2]. Suicide gene therapy is a
type of gene therapy using the insertion of genes into
tumor cells from a viral or a bacterial gene, resulting in
cancer cell death[3]. This therapy works on the basis of a
cell’s self-destruction by a vector transferring the suicide
gene that stimulates the apoptotic pathway with its product, thus allowing the conversion of a non-toxic prodrug
into a lethal drug (Figure 1)[4]. This cancer therapy still
remains as an integrated multimodality approach along
with chemotherapy, radiotherapy, and surgery. Suicide
gene therapy has been deemed safe and effective[5].
In this review, we discuss suicide gene therapy, summarizing the different suicide gene systems and gene
delivery vectors. Moreover, we highlight several strategies that have been used in combination with suicide
gene therapy and believe these approaches would be a
useful resource in the future for new ideas.
Copyright © 2016 Izmirli M, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial
4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.
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The war against cancer: Suicide gene therapy
Figure 1. Mechanism of the HSV-TK suicide gene therapy system. (1) Suicide genes transferred into viral vectors and infected tumor
cells; (2) Expression of the suicide gene and formation of the enzyme product; (3) The combination of the prodrug and enzyme
caused the conversion from non-toxic to toxic drug; (4) Owing to the apoptotic pathway, tumor cells are destroyed, induced by a
lethal drug.
The mechanisms of suicide gene therapy
Suicide gene therapy consists of different suicide systems. The most studied systems are herpes simplex virus
thymidine kinase gene (HSV-TK) with prodrug
ganciclovir (GCV), cytosine deaminase gene (CD), carboxyl esterase/irinotecan (CE/CPT-11), varicella zoster
virus thymidine kinase/6-methoxypurine arabinonucleoside (Vzvtk/araM), nitroreductase Nfsb/5-(aziridin
-1-yl)-2, 4-dinitrobenzamide (NTR/CB1954), carboxypeptidase G2/4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-L-glutamic acid (CPG2/CMDA), cytochrome p450-ifosfamide, and cytochrome p450- cyclophosphamide[6]. Additionally, there are other systems that are
not widely used such as the purine nucleoside phosphorylase (PNP), linamarase, β-galactosidase, and nitroreductase[7].
Herpes simplex virus thymidine kinase/ganciclovir
(HSV-TK/GCV). HSV-TK catalyzes the phosphorylation of GCV into GCV monophosphate. Cellular kinases
then convert GCV monophosphate to GCV triphosphate,
which is an analogue of deoxyguanosine triphosphate.
GCV triphosphate incorporates DNA polymerase and
this causes the termination of DNA replication and subsequently, apoptosis[8]. The potential immunogenicity of
the viral enzyme limits the HSV/TK-GCV suicide system[9]. However, GCV triphosphate passively enters cells
via gap junctions, which can potentially limit the overall
therapeutic effects[4]. Incorrect GCV triphosphate incorporation into DNA leads to a delayed S-phase and the
activation of several exonucleases and repair mechanisms of the G2-phase arrest cell cycle (Figure 2)[10].
Previous studies have found that apoptosis was induced by HSV-TK/GCV in several tumor cells including
melanoma[11], glioma[12], leukemia[13], bladder cancer[14],
intrahepatic metastasis of liver cancer[15], and prostate cancer[16].
Figure 2. The HSV-TK suicide gene therapy system
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Varicella zoster virus thymidine kinase/6-methoxypurine arabinonucleoside (Vzvtk/ araM). The varicella
zoster virus also expresses thymidine kinase (VZV-TK)
that is responsible for the activation of anti-herpetic nucleoside acyclovir. 6-Methoxy purine arabinonucleoside
(araM) plays the role of a prodrug for the VZV-TK enzyme. araM is monophosphorylated by VZV-TK, resulting in araM monophosphate (araMMP). Four cellular
enzymes – AMP deaminase, adenyl succinate synthetaselyase, AMP kinase, and nucleoside diphosphate kinase
– metabolize into the highly toxic adenine arabinonucleoside triphosphate (araATP). The VZV-TK suicide gene
system has generally poor efficacy on the activated prodrug against some cancer cell types. However, it
has been recently developed as improved potency anti-herpetic pyrimidine nucleoside analogues, including
the novel prodrug (E)-5-(2-bromo vinyl)-2-deoxyuridine
(BVDU) which is 80-fold more toxic to cells[6].
Cytosine deaminase/5-FC system (CD/5-FC). Cytosine deaminase is expressed by bacteria and yeast but not
in mammalian cells. The CD enzyme catalyzes the hydrolytic deamination of cytosine into uracil. Hence, it
converts 5-FC (non-toxic) to 5-FU (toxic), an important
drug used in conventional cancer chemotherapy. It causes apoptosis via three pathways: thymidylate synthase
inhibition, formation of 5-FU RNA, and formation of
5-FU DNA complexes[12]. 5-FU enters the nucleotide
pathway and is converted to 5-fluoro-2′-deoxyuridine5′-monophosphate (5-FdUMP), 5-fluorouridine-diphosphate (5-FUDP), and 5-fluorouridine-triphosphate (5-FUTP). 5-FdUMP is an irreversible inhibitor of thymidylate
synthase, resulting in the limitation of thymidine and
inhibition of DNA synthesis. 5-FUDP is also converted
to 5-FdUTP, which can be inserted into DNA to cause
DNA damage and cell death. 5-FUTP can also be incorporated into RNA, replacing UTP and inhibiting RNA
processing[3]. Previous studies have shown that apoptosis
was induced by the CD/5-FC suicide system in several
tumor cells, including in colon cancer (Figure 3)[17]. A
uracil phosphoribosyl transferase (UPRT) gene, when
inserted into the CD/5-FC system, improves it [18]. Importantly, this CD-UPRT/5-FC suicide system has been
shown to be effective against 5-FU-resistant cancer cells.
CD activity is highly increased by the FCU protein[19]. A
number of clinical research have shown antitumor activities of the CD/5-FC suicide system in fibrosarcoma[20],
glioma[21], breast cancer[22], prostate cancer[23], and metastatic formations of different origin[24].
Carboxyl esterase/irinotecan system (CE/CPT-11).
Carboxyl esterase is a serine esterase, expressed in several tissues including serum, liver, and the intestines[25].
Carboxyl esterase participates in the metabolism of toxins or drugs and the resulting carboxylates are conjugated by other enzymes. This enhances the general bio-availability of many therapeutic agents. Irinotecan (or CPT-11) is a chemotherapy agent that is cleaved by carboxyl esterase to generate a potent antitumor
effect via 7-ethyl-10-hydroxycamptothecin (SN-38), an
inhibitor of topoisomerase I activity[26]. SN-38 is not
soluble and only acts locally. It inhibits topoisomerase I,
resulting in the accumulation of double-stranded
DNA breaks in actively dividing cancer cells. This would
then inhibit DNA replication and transcription. A preclinical study has found that CE/CPT-11 suicide system
reduces tumor size[27].
NitroreductaseNfsb/5-(aziridin-1-yl)-2,4-dinitrobenzamide system (NTR/CB1954). Nitroreductase NfsB
(NTR) is a flavoprotein, which plays a role by reducing
Figure 3. The CD/5-FC suicide gene therapy system
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The war against cancer: Suicide gene therapy
quinones and nitro aromatics via NADPH or NADH. The
prodrug 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954)
is catalyzed by NTR, resulting in the production of a
potent cellular cytotoxic agent [28]. Previous studies have
found the presence of cytotoxic agents of the NTR/
CB1954 system in several tumor cells including in prostate cancer[29].
Carboxypeptidase G2/4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-L-glutamic acid system (CPG2/CMDA). Carboxypeptidase G2 (CPG2) is a bacterial
enzyme which cleaves glutamic acid from the prodrug
4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-Lglutamic acid (CMDA). CPG2 gene mutants are created
from the result of targeting CPG2 to the cell membrane
and the expression of cell surface protein. CPG2 causes
the production of a DNA cross-linking mustard drug,
4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoic acid,
which acts as a potent cytotoxic agent. Several cells expressing CPG2 are sensitive to CMDA, but some tumors
are resistant to this toxin owing to limited uptake of the
prodrug[29].
Once a suicide gene system has been elected, the suicide
gene must be selectively transferred to the tumor cells[30].
Vectors enter via receptor-mediated endocytosis or membrane fusions. Targeted vectors require specific domains,
which facilitate entries into the cytoplasm and nucleus
via pathways that include endosomal, lysosomal, or nuclear pore complex. In designing suicide gene therapies,
these determinative parameters affect the choice of vectors[6]. The optimal transporter should have minimum
side effects and higher specificity, and would efficiently
transfer genes to the target cells[30].
In summary, a vector has to have the ability to deliver.
First of all, it must protect DNA from enzymatic degradation and must have receptors for specific targets on the
cell membrane. When a vector passes into target cells, it
must degrade its own membrane and deliver the cargo
smoothly[31].
There are several transfer methods by using vectors,
such as viral and non-viral vectors[30]:
replication or pathogenic protein production with foreign
therapeutic genes. The selection of viral system depends
on several parameters: characteristics of the tumor type,
suicide gene system, and therapeutic strategy. There are
numerous viral vectors such as adenoviruses, retroviruses,
vaccinia viruses, poxviruses, adeno-associated viruses,
herpes simplex viruses, and lentiviruses[32].
Adenoviruses. The most popular viral vector owing
to their ability to introduce dividing and non-dividing
cells[33]. Adenoviruses are DNA viruses without envelopes, consisting of double stranded linear DNAs and
capsids. When adenoviruses enter the target cell via adenovirus receptor-mediated endocytosis into nasal, tracheal, and pulmonary epithelia, it is transported to the
nucleus where viral genes and proteins are expressed.
The suicide gene is inserted into the adenovirus genome,
leading to the expression of the inserted gene in host
cells (cancerous cells). However, the main challenge of
this approach is that gene expression is temporary because adenoviruses do not integrate into the target cell
genome. New methods, such as arming chimeric adenovirus-based vectors with the capacity to integrate into
target cells’ genome, should be developed. There is also a
serious problem with adenoviral-based gene therapy as it
has the ability to arouse lethal and intense immune reactions in some patients, causing ornithine transcarbamylase deficiency and resulting in the death of a study
patient due to an anaphylactic shock[34].
Herpes simplex virus (HSV). HSV has an envelope
encasing its DNA. It enters target cells by receptor-mediated ligand glycoproteins (including gB, gH, and
gL) into oral, ocular, genital epithelia, and nervous system cells[6].
Lentivirus. Lentivirus is a retrovirus with a single
stranded RNA encased in an envelope. It has the ability
to introduce dividing and non-dividing cells. The human
immunodeficiency virus (HIV) is the most recognized
member of lentiviruses. The ligands of the lentivirus bind
to cluster differentiation 4 (CD4) receptors, which exist
on CD4+ T cells, macrophages, and dendritic cells. The
viral RNA is reverse transcribed into double-stranded
DNA, which enters into the nucleus and is inserted into
the target DNA[6].
Viral vectors
Non-viral vectors
Viruses are perfect vectors to transfer foreign DNA. It
replicates its genome in host cell by integrating with host
DNA, or via plasmid replication if it has a region of
origin. Viral-based vectors are efficient means to transfer
suicide genes into cancer cells. These vectors are designed by introducing therapeutic genes involved in viral
There are several non-viral vectors, including physical
vectors, cellular vectors, and inorganic vectors[35]:
Vectors and cargo elements
Physical vectors
Physical vectors include the injection of naked
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DNA, ballistic DNA injection, electroporation, sonoporation, magnetofection, and hydroporation[36].
Injection of Naked DNA. Naked DNA or plasmid injection is a type of non-viral vector. Direct injection of
free DNA into targeted tissues (tumor tissues) has been
shown to produce high levels of gene expression and
causes the expression of tumor antigens that can function
as a cancer vaccine. This method is simple and exhibits
low cellular uptake. In short, the injection of naked DNA
is used when low gene transfer efficiency can be changed by the activation of immunity. On the other hand,
naked DNA is not suitable for systemic administration because of serum nucleases. Moreover, direct injection of naked DNA has other limitations – it is suitable
for only a few applications involving tissues that are easily accessible to direct injection such as skin and muscle
cells[4].
Ballistic DNA injection. This technology is also known as the gene gun, particle bombardment or micro projectile, and is a gene transfer technique that was first
used in plants. Ballistic DNA injection consists of passing through the target tissue with DNA-coated heavy
metal particles at adequate speeds. The metal particles
could comprise silver, gold, or tungsten. Its advantage is
the sensitive delivery of DNA doses[36]. On the other
hand, the drawback of this technique is the short-term
expression of transferred genes and cellular damage[37].
Electroporation. This technique is based on loading
the cell membrane with high capacity electrical field for
a nanosecond to open a pore. During this time, DNA
molecules could pass through the pore in approximately
ten seconds. However, cells can be damaged due to pulse
duration and the severity of the electrical field during
electroporation. Electrical strength must be about 700 V/
cm while the pulses must be in micro- or milliseconds[36].
Sonoporation. Sonoporation changes the permeability of cell plasma membrane with sonication. Therapeutic
gene is delivered via a microbubble, of which its outer
shell is covered with lipids, proteins, or synthetic biopolymers. The interior is suffused with air/nitrogen/
inert gas of high-molecular weight. Microbubbles are
transferred with the therapeutic gene and circulated into
the blood. Sonic waves bump with intensity in pulses
over the target tissue[36,37].
Magnetofection. This technique is based on an in
vitro research using magnetic nanoparticle-transferred
therapeutic genes. This system captures and holds target
cells with a magnet. Therapeutic genes can pass through
cell membranes when the pulses of magnetic nanoparticles cause the degradation of cell membrane, enzymatic
cleavage of cross-linking molecule, or charge interaction[36].
Hydroporation. This technique injects DNA solutions into the target tissue, which penetrates the cell membrane via hydrodynamic pressure. In literature, this technique has been used for gene therapy research of
hepatic cells[36].
Cellular vectors
Cellular vectors consist of bacterial and mammalian cell
vectors.
Bacterial vectors. Commonly used bacteria are obligate or facultative anaerobic bacteria such as strains of
Clostridia, Bifidobacteria, and Salmonella. These have
the ability to infect hypoxic areas of tumors and have
presented efficient antitumor activity against chemoresistant cancer cell lines[35]. Bacterial vectors can be
modified to deliver bacterially-expressed therapeutic
genes[38].
Mammalian cell vectors. Several mammalian cells
exhibiting tumor tropism have been recently suggested as
transporters for gene therapy, such as bone marrow stromal cells (MSC)[39], neural stem cells (NSC)[40], endothelial progenitor precursor, and blood outgrowth endothelial cells[41]. MSCs are pluripotent progenitor cells,
which maintain and regenerate diverse tissues after injury and during chronic inflammation. These features have
led to the use of MSCs as gene delivery transporters for
tumor cells[42]. NSCs have an inherent tumor tropism and
are therefore reliable delivery agents for target therapeutic gene products to primary and metastatic tumors[43].
Blood outgrowth endothelial cells are withdrawn to the
tumor vasculature. In addition, erythrocyte ghosts are
also used as vectors for suicide gene therapy[44].
Inorganic vectors
Calcium phosphate, silica, gold, and several magnetic
compounds. These are inorganic particles that are used as
vectors for gene transport. Their structures have different
formats and porosities. An example of biocompatible
structures is silica-coated nanoparticles, which can be
used for gene therapy[45]. There are several studies that
highlight silica and magnetic inorganic nanoparticles
(such as Fe3O4 and MnO2) for gene delivery[46,47]. One of
the main candidates that is currently investigated for
gene therapy is gold nanoparticles, which are recommended for transferring nucleic acids into tumors[46].
Nanoparticles. A novel form of gene transfer vehicle
is nanoparticles that include a cationic core. They have been
investigated as effective suicide gene vectors for gene
therapy. Nanoparticles have the ability to diffuse within
the tumor tissue via passive transport and have enhanced
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permeability and retention effect in tumor tissues. This is
a combined result of an increased permeability of tumor blood vessels and a decreased rate of clearance within the tumor[48]. This method is usually used for interference RNA delivery but not for DNA plasmid delivery[4].
Synthetic or natural biodegradable particles. Synthetic or natural biodegradable particles are composed of
three subtypes, which are: polymeric-based vectors [poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA),
chitosan, dendrimers, polymethacrylates], cationic lipid-based vectors (cationic liposomes, cationic emulsions, solid lipid nanoparticles), and peptide-based
vectors (poly-L-lysine, protamine). Cationic liposomes
and cationic polymers are commonly used as non-viral
gene delivery methods to deliver genes into cells[49].
Negatively charged liposomes can interact spontaneously
with negatively charged DNA to form clusters of aggregated vesicles along the nucleic acid. Liposomes with
suicidal genes can interact with negatively charged cell
membranes. The interaction of DNA and liposomes, or
polyplexes, leads to the formation of lipoplexes[50].
Liposomes have some advantages including the capacity to transport large amounts of genetic material.
Their physico-chemical versatilities allow innumerous
modifications and liposomes can be easily and inexpensively produced on a large scale. Moreover, liposomes
are safer than viral vectors owing to their reduced chance
for insertional mutagenesis or side effects from immune
reactions to the vector. However, liposomes have some
disadvantages including poor levels of transfection, considerable reduction of biological activity by serum components, and toxic effects[51,52]. Gene transport using
liposomes was first demonstrated using a synthetic lipid,
N-[1-(2,3- dioleyloxy)propyl]-N,N,N-trimethyl ammonium chloride (DOTMA). DOTMA contains unilamellar
liposomes, which interact with DNA to form lipid-DNA
complexes. Subsequently, DOTMA facilitates the fusion
of suicide gene complex with the plasma membrane of
target cells, resulting in both uptake and expression of
the DNA[53].
Cancer-specific promoters
There are several cancer-specific promoters, including
epidermal growth factor receptor (EGFR), human epidermal growth factor receptor/neu (Her2/Neu), carcinoma embryonic antigen (CEA), vascular endothelial growth factor receptor (VEGFR)[54], cluster differentiation 71 (CD71), CD44, CD133, breast cancer 1 (BRCA1),
BRCA2, stage-specific embryonic antigen-4 (SSEA-4)[55],
prostate-specific antigen (PSA), folate receptor (FR),
transferrin receptor (TfR), mucins, tumor resistance anti-
gen-1-60 (TRA-1-60), cyclooxygenase (Cox), cytokeratin
18, cytokeratin 19, telomerase (hTERT)[6], and chimeric
antigen receptors (CAR)[56]. Gene promoters regulate the
expression of related genes in cells and consequently,
promoters are used as biomarkers via regulation of the
genes. Promoters of the mentioned genes are engineered
into DNA constructs, effectively driving the expression
of suicide gene cancer therapy. Therefore, cancer suicide
genes are expressed only in tumor cells.
EGFR (ErbB1). This receptor is present on healthy
and cancerous cells. The number of EGFR receptors may
differ on cells. The number of EGFR receptors is approximately 3×104 on healthy glial cells and approximately 2–3×106 on tumor cells. The recombinant adenoviral vector and genetically engineered variable fragment antibodies target EGFR receptors of ovarian and breast cancers[57].
Her2 (ErbB2) is a member of the human epidermal
growth factor receptors. Over-expressed Her2 indicates
poor prognosis in breast and other cancers. Genetically
engineered agents of suicide gene therapy are delivered
to this receptor by viral vectors in gene therapy[58].
Carcinoembryonic antigen (CEA). This is a cancer biomarker that is shed by tumor cells into the blood,
and thus is routinely detected. It is also the target for
vectors delivering therapeutic genes[59].
Folic acid receptor (FR). Folic acid plays a role in
the synthesis and repair of genomic DNA and RNA, as
well as methylation reactions. Folic acid cannot directly
penetrate the cell membrane. In fact, it penetrates by
endocytosis through the FR. Hence, FR is absolutely over-expressed on the surfaces of various tumor types including ovarian, kidney, lung, brain, endometrial, colorectal, pancreatic, gastric, prostate, testicular, bladder, head
and neck, breast, and lung cancers. Therefore, FR is viewed as a therapeutic target that may provide an effective
option for targeted suicide cancer therapy[60].
Cluster of differentiation 44 (CD44). This is present
on cells from a variety of tissues, including those of epithelial origin such as prostate, ductal epithelium of the breast, mucosa, lungs, and bladder of cancerous cells.
CD44 variant 6 and CD133 are specific to epithelial cancers and are used as lentivirus-driven suicidal genes[61].
Transferrin receptor (TfR). Transferrin carries iron
into cells, which in turn express the TfR. Iron-bound Tf
is transported by TfR, which is over-expressed in tumor
cells[62]. One of the therapeutic strategies of suicide cancer therapy is to decrease the level of iron[63].
Mucins. Mucins are glycosylated proteins on cell surfaces and their major function involves imparting protection against inflammation, bacteria, virus, pollutants, and
pH, among other things. The structure and localization of
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mucins are specific for every cell type, and mucins play
key roles in cell-cell and cell-extracellular matrix interactions as well as in cell signaling for cancerous cells.
Specific expression of mucins is important for tumor
progression and therefore can be used as biomarkers and
therapeutic targets in epithelial cancers[64]. Moreover,
mucins are present on breast, pancreatic, and ovarian cancer cells. MUC-1/Z is also a form of mucin and is exploited for the production of specific antibodies. These
antibodies lead as vectors with the therapeutic transporter
to cancer cells[65].
Telomerase. Telomerase is a form of RNA polymerase and is generally over-expressed in cancerous cells.
Therefore, it is used as a promoter of suicidal genes in
cancer cells. For example, such strategies involve the
transduction of ovarian cancers with HSV-TK under the
telomerase promoter[66].
Cytokeratin 18 and 19 (CK18-19). Cytokeratins are
present in epithelial cells and are biomarkers of the neoplasms of epithelial cells. They can occur during tumor
genesis and metastasis. Moreover, cytokeratins are biomarkers of differentiation into one of the three germ
layers for human embryonic stem cells[6].
Stage-specific embryonic antigen-4 (SSEA-4) and
tumor resistance antigen 1-60 (TRA-1-60). SSEA-4 is
a glycoprotein and is expressed in embryonic stem cells
during embryonic development. It is identified as a biomarker for cancerous embryonic testes and ovaries. TRA-1-60 is also a marker for human embryonic stem cells
and carcinomatous cells. TRA-1-60 is also suggested as
a biomarker for testes and ovarian cancer stem cells.
These biomarkers of pluripotency are expressed upon the
differentiation of cells[67].
Cyclooxygenase (Cox). It is also known as prostaglandin-endoperoxide synthase (PTGS) and is responsible for catalyzing prostaglandins, prostacyclin, and
thromboxane. Aspirin inhibits Cox. Due to the expression of the Cox gene in colorectal cancer, it is used as
a biomarker in suicide gene therapy[67].
Chimeric antigen receptors (CAR). CARs are cell
surface antigens and are known as artificial T-cell receptors and chimeric immune receptors. CARs present another autologous cell-based therapy aiming at tumorassociated cell surface antigens. CARs are engineered
receptors and add an optional specificity onto an immune
effector cell. Therefore, CARs are composed of parts
from different sources. This approach brings together the
permanence of cytotoxic T-cells with the specificity of
monoclonal antibodies and expansion potential[68].
Vascular endothelial growth factor (VEGF). VEGF
is a growth factor and it stimulates vasculogenesis and
angiogenesis. VEGF is expressed by cancer cells and it
stimulates the proliferation of endothelial and cancerous
cells. The inhibition of angiogenesis and vasculogenesis
is a new target for cancer in suicide gene therapy. Liu et
al. investigated a model of suicide gene therapy system
using anti-VEGF with a triple-gene vector expressing
VEGF-shRNA and CD/TK[69].
Clinical applications
Gene therapy is a good alternative to conventionally used
medical therapies and holds a great promise for the
treatment of various diseases, especially cancer [70,71]. At
present, most of the clinical applications in suicide gene
therapy have been aimed at the treatment of cancer (64.4%
of all gene therapies)[71]. Suicide gene therapies have targeted several cancers including lung, gynecological, skin,
urological, neurological, and gastrointestinal tumors as
well as hematological malignancies and pediatric tumors[71].
Glioblastoma multiforme (GBM) and medulloblastoma. GBMs and medulloblastomas are the most
regularly found and most aggressive form of brain tumors in adults[72]. GBM treatment involves conventional
cancer therapy including chemotherapy, radiotherapy,
and surgery as well as suicide gene therapy. Eight patients with GBM were treated with a HSV-TK
gene-bearing liposomal vector, followed by the systemic
application of GCV. Connexin 43 (Cx43), which is differently expressed in different glioblastoma cell lines,
was used as a biomarker[73]. This therapy resulted in a
greater than 50% reduction of tumor volume in two patients and showed local effects in the remaining patients[74].
Mesothelioma and lung cancer. Mesothelioma is a
deadly cancer of the pleura[75]. In a previous study, human PA1STK cell line transduced with the HSV-TK gene
was directly infused into malign pleural effusions and
subsequently, GCV was infused intravenously for seven
days. However, this study did not achieve the desired
suicide therapy effect[76].
Lung cancer is the deadliest type of cancer[1] and this
has facilitated the growth of targeted cancer suicide gene
therapy trials. CD/5-FC suicide and NTR/CB1954 systems are used on small cell lung cancer (SCLC)[77,78]. In this
cancer, insulinoma-associated 1 (INSM1) promoter and
nuclear factor kappa B (NFκB) are used as biomarkers[79].
Gastrointestinal cancers. These cancers include gastric, hepatocellular, pancreatic, and colon cancers. Gastric cancer is the fourth most common type of cancer and
the second highest cause of death[1]. Hepatocellular carcinoma is the sixth most prevalent cancer and the third
most frequent cause of cancer-related death[1]. Many
Americans are affected by pancreatic cancer[1] and a
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The war against cancer: Suicide gene therapy
growing number of people are diagnosed with colon
cancer[82]. Suicide gene systems including HSV-TK have been used to treat gastrointestinal cancers. Several biomarkers including CEA, CD44, CD133, and
hTERT are investigated on gastrointestinal cancer
cells[80]. These biomarkers facilitate early diagnosis for
the abovementioned cancer types and are targets for diagnostic molecular imaging and targeted therapies[41,81].
Gynecological and andrological cancers. These include prostate cancer, endometrial cancer, and ovarian
cancer. Prostate cancer is the second leading cause of
death in men in the United States[1]. There are numerous
studies on HSV-TK suicide genes, 5-FC+GCV prodrug
therapy, NTR/CB1954, and nitro reductase system on
prostate cancer. Several biomarkers including prostatespecific antigen (PSA), prostate-specific membrane antigen (PSMA), androgen, C-X-C chemokine receptor
type 4 (CXCR4), and epithelial cell adhesion molecule
(EpCAM) have been identified for prostate cancer[82–84].
Consequently, promoters of the aforementioned genes
are incorporated into the constructs of cancer suicide
genes, which are expressed in prostate cancer cells [61,65].
Endometrial cancer is the most common cancer affecting the gynecologic system and ovarian cancer is the
deadliest cancer among all female gynecologic cancers[85]. HSV-TK suicide gene system and SSEA-4, TRA1-60, CD44, CD133, BRCA1 as well as BRCA2 biomarkers are used in endometrial and ovarian cancer therapies[55].
Breast cancer. Breast cancers are diagnosed in about
229,060 women in the USA[86]. HSV-TK suicide gene
system and Her2/neu proto-oncogene, along with the
epidermal growth factor variant III (EGFRvIII) biomarkers, are used for breast cancer suicide gene therapy[54].
sion, suicide gene therapy is a hopeful approach in overcoming cancer. Highly specific research efforts are necessary to address these existing shortcomings in developing suicide gene therapy into a real benefit for cancer
patients.
Conclusion
7.
Currently, there are different available vectors and several delivery and effector systems for suicide gene therapy,
and these techniques are being used for cancer therapy.
Suicide gene therapy has demonstrated that a drug that is
injected at a distant site of the primary tumor tissue can
still efficiently affect the primary tumor. Moreover, suicide gene therapy enhances the immune system’s response on primary and metastatic tumor tissues. However,
there are obvious problems associated with the therapy,
which include the activation of specific prodrugs, introduction of suicide genes into cancerous cells without
damaging healthy cells, and host immune response to the
vector and suicide gene product [34]. Furthermore, preclinical applications have only been undertaken in animal
models for short periods. Thus, the lifetime risk of mutagenesis in a human is difficult to predict [87]. In conclu-
Conflict of interest
The authors declare no potential conflict of interest with
respect to the research, authorship and/or publication of
this article.
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