Current Cancer Drug Targets, Volume 1, No. 3, 2001
Antisense Oligonucleotide Therapeutics
Antisense
Anticancer Oligonucleotide Therapeutics Pp.177-196
Hui Wang, Gautam
Prasad, John K. Buolamwini and Ruiwen Zhang
Antisense
and/or Immunostimulatory Oligonucleotide Therapeutics Pp. 197-209
Sudhir Agrawal and
Ekambar R. Kandimalla
Modification of
Alternative Splicing by Antisense Oligonucleotides as a Potential Chemotherapy
for Cancer and Other Diseases Pp.211-230
D. R. Mercatante, P.
Sazani and R. Kole
Targeting of
Cancer-Related Proteins with PNA Oligomers Pp.231-239
Margus Pooga, and
Ülo Langel
D-RNAi
(Messenger RNA-antisense DNA Interference) as a Novel Defense System Against
Cancer and Viral Infections Pp. 241-247
Shi-Lung Lin and
Shao-Yao Ying
[Back to top] Antisense
Anticancer Oligonucleotide Therapeutics
Hui Wang, Gautam Prasad, John K. Buolamwini
and Ruiwen Zhang
Recent progress made in molecular biology, biotechnology,
and genetics, especially in identifying, cloning, sequencing and
characterization of normal and pathogenic genes, has led to the development of
genetic therapy. Major efforts in the field can be summarized in two general
approaches: gene therapy and antisense therapy. The second is to deliver to the
target cells antisense molecules that target to mRNA with which they can
hybridize and specifically inhibit the expression of pathogenic genes.
Antisense oligonucleotides offer the possibility of specific, rational,
genetic-based therapeutics. With encouraging results from preclinical and
clinical studies of antisense oligonucleotides in the past decade, significant
progress has been made in developing antisense therapy, with the first
antisense drug now being approved for clinical use. In this article, we will
discuss approaches to developing these drugs from preclinical to clinical
settings. Of particular interest for the area of human cancer therapy, several
cancer targets, including bcl-2, BCR-ABL, C-raf-1, Ha-ras, c-myc, PKC, PKA, p53
and MDM2, are reviewed as examples to illustrate the progress in this field and
emphasize the importance of target selection and advanced antisense chemistry
in the development of antisense therapy.
[Back to top] Antisense and/or
Immunostimulatory Oligonucleotide Therapeutics
Sudhir Agrawal and Ekambar R. Kandimalla
Antisense technology, which is based on a simple and rational principle of Watson-Crick complementary base pairing of a short oligonucleotide with the targeted mRNA to downregulate the disease-causing gene product, has progressed tremendously in the last two decades. Antisense oligonucleotides targeted to a number of cancer-causing genes are being evaluated in human clinical trials. While the first-generation phosphorothioate antisense oligonucleotides are in clinical trials, a number of factors, including sequence motifs that could lead to unwanted mechanisms of action and side effects, have been identified. The severity of the side effects of first-generation antisense oligonucleotides is mostly dependent on the presence of certain sequence motifs, such as CpG dinucleotides. A number of second-generation chemical modifications have been proposed to overcome the limitations of the first-generation antisense oligonucleotides. The safety and efficacy of several second-generation mixed-backbone antisense oligonucleotides are being evaluated in clinical trials. The immune stimulation affects observed with CpG-containing antisense oligonucleotides are being exploited as a novel therapeutic modality, with several CpG oligonucleotides being evaluated in clinical trials. A number of medicinal chemistry studies performed to date suggest that the immunomodulatory activity of CpG oligonucleotides can be fine-tuned by site-specific incorporation of chemical modifications in order to design disease-specific oligonucleotide therapeutics
[Back to top] Modification
of Alternative Splicing by Antisense Oligonucleotides as a Potential
Chemotherapy for Cancer and Other Diseases
D. R. Mercatante, P. Sazani and R. Kole
It has been estimated that greater than 35% of all human
genes undergo alternative splicing. The process of alternative splicing is
highly regulated and disruption of a splicing pattern can produce splice
variants that have different functions. Certain splice variants that are
associated with induction of cell death, regulation of cellular proliferation
and differentiation, cell signaling, and angiogenesis are present in a variety
of cancers. Several of these cancer-related alternatively spliced genes will be
discussed in this review. In addition, alternative splicing is associated with
several genetic disorders such as b-thalassemia, cystic fibrosis, and muscular
dystrophy. Control of pre-mRNA splicing patterns with antisense
oligonucleotides presents an attractive way to potentially treat and manage a
variety of diseases. This review will discuss potential gene targets for
antisense oligonucleotide induced modification of alternative splicing
patterns. Furthermore, the chemistries and delivery strategies of antisense
oligonucleotides will be discussed.
[Back to top] Targeting of
Cancer-Related Proteins with PNA Oligomers
Margus Pooga, and Ülo Langel
Aberrant gene expression is characteristic to all cancer cells and pathophysiology in general. Selective inhibition of constitutively elevated expression of oncogenes provides an opportunity to hinder the proliferation of malignant cells. Small synthetic molecules that specifically interfere with transcription and/or translation have great potential as anticancer drugs. Currently first-generation antisense oligonucleotides are widely used to inhibit the oncogene expression. The second generation of antisense agents have been studied mainly in vitro. One of these agents, peptide nucleic acid (PNA) is an oligonucleotide mimic with a non-charged achiral polyamide backbone to which the nucleobases are linked. PNA oligomers bind tightly to complementary DNA or RNA and are very stable in biological fluids. PNA can inhibit transcription and translation of target genes by specifically hybridizing to DNA or mRNA. The in vitro experiments showing inhibition of target protein expression by PNA have been followed by the first succes