195Synthetic short segments of DNA or RNA are referred to as oligonucleotides. The
literal meaning of this word is a polymer made of few nucleotides. Naturally occur-
ring RNA or DNA oligonucleotides may or may not have antisense properties.
Antisense therapy is considered to be form of gene therapy because it is modulation
of gene function for therapeutic purposes. However, oligonucleotides differ from
standard gene therapies because they cannot give rise to proteins but can only block
the expression of existing genes. Several antisense approaches use gene therapy
technologies, e.g., ribozymes and antisense RNA using vectors.
Emerging clinical evidence supports the notion that antisense oligonucleotides
stand a realistic chance of developing into one of the main players of rationally
designed anticancer agents. Antisense therapies lend themselves to customization
more readily than many other drugs. The reasons are as follows:
- Antisense compounds target a disease at its genetic origin and modulate expres-
sion of the gene product whereas conventional pharmaceuticals merely counter-
act the manifestations of the disease by inhibiting gene products (proteins). - Antisense compounds can be easily designed and only require information on
the nucleic acid sequence encoding a given protein without prior knowledge of
the function of that protein. - Antisense DNA and RNA have an extremely high specifi city for their target
which cannot be usually achieved by conventional pharmaceuticals. - Antisense may also provide more disease-specifi c therapies and have less adverse
reactions than conventional pharmaceuticals.
RNA Interference
A refi ned version of antisense, RNA interference (RNAi), is a cellular mechanism
to regulate the expression of genes. RNAi or gene silencing involves the use of a
double-stranded RNA (dsRNA), which enters the cell and is processed into short,
21–23 nucleotide dsRNAs termed small interfering RNAs (siRNAs) that are used in
a sequence-specifi c manner to recognize and destroy complementary RNAs (Jain
2015c ). RNAi has been shown to control tumor cell growth in vitro. siRNA or plas-
mids expressing sequences processed to siRNA could provide an exciting new ther-
apeutic modality for treating cancer. Intradigm Corporation (Rockville, MD) is
using a siRNA targeting system to modulate the rate of tumor growth and to deter-
mine which genes correlate with therapeutic effi ciency.
Allele-specifi c inhibition (ASI) is an approach where cancer cells are attacked at
site of loss of heterozygosity (LOH). RNAi approach using oligonucleotide-based
drugs may provide the required selectivity for ASI therapeutic approach. siRNAs
can not only be used as a tool to study gene function, but might also be used as
genotype-specifi c drugs to mediate ASI. siRNA has been shown to produce
genotype- specifi c inhibition of tumor growth in vivo, by targeting an SNP in
POLR2A ( gene of the large subunit of RNA polymerase II located in close proximity
Antisense Therapy