Gene Therapy for Cancer

Gene therapy is the replacement (in vitro or in vivo) of a faulty gene from a cell with its normal functioning counterpart (5). Cancer gene therapy is the most widely explored application of gene therapy and more than half of the clinical trials of gene therapy have been centered around cancer treatment (6). Numerous preclinical experiments have been conducted on animal models to explore the possibility of cancer vaccines, induced cell apoptosis, reduction of blood supply to tumors and targeting viruses to kill cancerous cells (7).

Types of Cancer Gene Therapies

The complexity in the treatment of cancer has led to the development of various approaches to gene therapy which are mainly categorized into five types (8).

  1. Suicide Gene Therapy
    In suicide gene therapy, a therapeutic gene (transgene) is introduced to the tumor cells via a vector. When expressed in the tumor cells, the product of this gene has the capability to convert a non-toxic prodrug into an active cytotoxic drug against tumor cells (9, 10).
  2. Restoration of Normal Cell Cycle
    There are two major gene categories that are responsible for cancer development – oncogenes and tumor suppressor genes (11). Many studies have targeted these genes in an attempt to restore the normal cell cycle and treat cancer.
    Oncogenes such as MYC, ras and bcl-2 are extensively studied for cancer treatment. Many studies show that these can be regulated on DNA (by antigene oligonucleotides) as well as RNA (by antisense oligonucleotides) level (12-14). Tumor suppressor genes such as p53, PTEN, CDKN2, and Rb (Retinoblastoma gene) have been widely used for cancer gene therapy experiments to restore their normal functionality by replacing the genes with their normal functioning counterparts (15-17).
  3. Gene Therapy for regulating multidrug resistance
    Tumors can develop multidrug resistance (MDR) against the many drugs administered during chemotherapy. To tackle this issue, researchers have vastly studied the MDR1 gene both for its upregulation as a protection mechanism and its inhibition to reduce tumor resistance to certain drugs. The protein product of this gene has the capability to flush out most of the important drugs used in chemotherapy from the host system. (18, 19).
  4. Anti-Angiogenesis Gene Therapy
    Angiogenesis is the process of capillary formation for the supply of blood to tumors and is one of the essential factors for the survival of tumors (20). Anti-angiogenic drugs have proven to be inefficient against angiogenic growth factors (21, 22). Scientists hope gene therapy may be used to transfect and express angiogenic genes for inhibiting tumor growth (23).
  5. Immunoregulatory Gene Therapy
    Immunoregulatory Gene therapy aims to enhance the host immune responses against cancerous cells through gene vaccines and cytokines. The transgenes are utilized to generate a T- cell mediated immune response using genetically modified antigen presenting cells to directly kill the tumor cells. Genes such as IL-2, MUC1 and IFN-β have shown promising results in decreasing tumor growth and metastasis (24-26).

Gene Delivery Methods in Cancer Gene Therapy

Targeted delivery of a therapeutic gene is one of the most important aspects of gene therapy. Over the years, several strategies to improve gene delivery methods have been studied. Vectors used for gene delivery in cancer gene therapy are described below.

ClassVectorPropertiesAdvantagesDisadvantagesReferences
Viral
vector
Retroviral
vectors
Single
stranded RNA
molecules
Can replicate
in the host
genome by
RNA reverse
transcriptase.
Capable of
long-term
integration into the
host cell genome.
Safe due
removal of virulent
genes.
Incapability
to transfect
nonproliferating
cells
Low tumor
infiltration.
May
cause
insertional
mutations in
the host
(27, 28)
Herpes
simplex virus
vectors
Two
serotypes:
HSV1 and 2
Neurotropic
virus
Capability to
transfect nondividing cells
Strong growth
within tumors
High capacity
for transgenes.
Short term
expression of
genes.
May
cause
cytotoxicity.
(29)
Adenoassociated
virus vectors
Single
stranded DNA
viruses
Parvovirus
family
Very low host
immune response.
Transfects nonproliferating cells
Poor
capacity for
transgenes
(30, 31)
Adenoviral
vectors
Episomal
replication
Require a
helper virus for
replication in
host.
Capability to
transfect nonproliferating as well as proliferating cells
Low chances
of insertional
mutations in host
Short term
expression of
genes.
May
cause
undesirable
host immune
responses
(32, 33)
Poxviral
vectors
Doublestranded DNA
viruses.
Large viral
genome
Replication
occurs in host
cytoplasm.
Can transfer
genes to tumors
Can induce
oncolytic activity.
Low
cytotoxicity
High transgene
capacity
Short term
expression of
genes.
Generates
undesirable
host immune
responses.
(34,35)
BacterialBifidobacterial
vectors
Common
intestinal flora
Most studied
strain is
Bifidobacterium
longum
Low diseasecausing risk
Ease of
administration
both oral and
intravenous
Are not
oncolytic.
Vulnerable to
harsh
environments
Difficult
storage and
handling.
Low
tumor
colonization
Low
transgene
expression.
(36, 37)
Salmonella
vectors
Nonpathogenic
strain:
Salmonella
typhimurium
Is a
facultative
anaerobe
Capability to
multiply in all cells
of a solid tumor
(both active and
dormant tumor
cells).
Relatively
high cancer to
normal cell
colonization
ratio.
(36, 38)
Clostridial
vectors
Nonpathogenic
species
Absolute
anaerobes
Relatively safe
Low generation
of host immune
response
High affinity
towards solid
tumors
Ability to
survive hypoxic
environment
No insertional
mutations in host
High capacity
for transgenes.
Relatively
low cancer
cell
colonization.
(38)
Synthetic
vectors
Synthetically
produced from
liposomes and
polymers.
Capable of
carrying
chemotherapeutics
and synthetic
oligonucleotides to
cancer cells
Low
efficiency as
compared to
viral and
bacterial
vectors.
(39, 40)

Cancer gene therapy is constantly developing; it has wide-ranging prospects and promises to improve both treatment and diagnosis of cancer. However, leading thinkers in medicine believe research and development in gene delivery systems such as synthetic, non-virulent and anaerobic vectors are essential for success of this new technology.

References

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