Antisense inhibition of survivin expression as a cancer. Antisense gene therapy using antikras and antitelomerase oligonucleotides in colorectal cancer. Antisense therapy the experimental drug, ionishttrx, is a type of drug called antisense oligonucleotides. These are small pieces of dna or rna that can bind to specific molecules of rna. Antisense inhibition of survivin expression as a cancer therapeutic rosa a. Antisense therapy is a form of treatment for genetic disorders or infections. This book summarizes and presents the best updates, therapeutic principles. Antisense therapy targeting mdm2 oncogene in prostate cancer.
The concept of gene therapy is older than the rnai technology and. Antisense therapy offers a comprehensive, stateofthe art perspective on the role of antisense therapy in the treatment of human disease, with a special focus on cancer. Antisense oligonucleotides offer one approach to target genes involved in cancer progression, especially those that are not amenable to small. Antisense antimdm2 oligonucleotides as a novel therapeutic. Antisense and nuclear medicine journal of nuclear medicine. The mdm2 gene is overexpressed in several human cancers, including breast, lung and colon cancer. The main obstacles that remained in cancer gene therapy and antisense therapy are the lack of delivery systems that successfully deliver an. Antisense oligonucleotide therapy for patients with. It is assumed that this is largely because of problems of target accessibility, which in turn may be because of the secondary or tertiary mrna structure andor to the proteins bound to the rna.
Studies combining antisense based technology with conventional cytotoxic drugs have shown that the antisense potentiates the antitumor effect with good overall tolerance because the toxicity profiles do not overlap 9, 11. Oligonucleotides hold promise as a cure for cancer chem sci j 8. In order to enhance the gene therapy and antisense therapy against a wide variety of cancers and cancer types in future, the development of next. The general mechanism underlying this is shown in the figure 2. Promise and problems of bcl2 antisense therapy jnci. Antiproliferative effects of cmyc antisense oligonucleotide in prostate cancer cells.
Nov 18, 2000 in a study with a different antisense drug designed to downregulate bcl2 in mice, miyake and colleagues found that antisense treatment selectively affected expression of the protein in a mouse model of prostate cancer without significantly affecting bcl2 expression or causing adverse effects in a various normal tissues and organs. This opportunity is being cashed on by the companies and are investing in. Recent technological advances now allowing both large scale data generation and its indepth analysis have opened new avenues to identify and target genes. In the development of rnaibased therapies, nanoparticles, which have distinctive size effects along with facile modification strategies and are capable of mediating effective rnai with targeting potential, are attracting extensive interest. Antisense therapy targeting mdm2 oncogene in prostate. Targets for antisense therapy in cancer cells recent years have seen an explosion in knowledge of the features whichdistinguish a cancercell fromits. The antisense approach is important in general in understanding gene function, and more specifically as a potential basis for new drugs, notably against cancer and viral genes.
Do antisense oligonucleotides hold promise as a cure for cancer chem sci j 8. Dec 14, 2017 antisense therapy the experimental drug, ionishttrx, is a type of drug called antisense oligonucleotides. Antisense oligonucleotides have been widely used in investigating gene functions and regulation. Antisense therapy delivers antisense molecules that target to mrna to the target cells with which they can hybridize and specifically inhibit the expression of target genes. In the present study, we investigated the functions of mdm2. A synergistic antitumoral effect of bcl2 antisense therapy combined with some anticancer agents has been demonstrated in leukemia and lung cancer cells overexpressing bcl2.
Colorectal cancer crc is the second leading cause of cancer related death in the u. In the present study, we investigated the functions of mdm2 oncogene in the. A and b antisense oligonucleotides were continuously infused for 2 weeks via infusion pump into the right lateral ventricle of normal rats at 100 mgd a or rhesus monkeys at 1 mgd b. Such an enhancement of sensitivity would suggest that combination therapy using antisense cyclin d1 and cisplatin would be an effective treatment modality for head and neck cancer. Antisense therapy is particularly promising when combined with traditional anticancer therapy. Antisense therapy an overview sciencedirect topics. Many pharmacologic advances involve creating compounds that bind and disable proteins. The specificity of hybridisation makes antisense treatment an attractive strategy to selectively modulate the expression of genes involved in. This study evaluated vegf production in pancreatic cancer cells and the effect of vegf antisense on growth and angiogenesis of human. Antisense therapy in canada and globally in the past, antisense therapy hasnt been widely used or adapted in canada. Gene therapy is being applied in i cancer diseases, involving the largest number of patients. In a study with a different antisense drug designed to downregulate bcl2 in mice, miyake and colleagues found that antisense treatment selectively affected expression of the protein in a mouse model of prostate cancer without significantly affecting bcl2 expression or causing adverse effects in a various normal tissues and organs. Cancer is a deadly disease and scientists are using many techniques to treat the cancerous cells and finding cure for this disease. But there are certain disorders cancer, viral and parasitic infections, and inflammatory diseases which result in an overproduction of certain normal proteins.
The therapy is called a gene silencing technique because, instead of repairing the gene, it aims to silence the genes effect. In general, gene therapy is carried out by introducing a therapeutic gene to produce the defective or the lacking protein. Antisense oligonucleotides targeting angiogenic factors as. In this study, we investigate whether antisense cyclin d1 enhances the sensitivity of head and neck cancer cells to cisplatin. Antisense gene therapy hopes huntingtons disease information. Experimental therapy of human prostate cancer by inhibiting mdm2 expression with novel mixed. When the genetic sequence of a particular gene is known to be causative of a particular disease, it is possible to synthesize a strand of nucleic acid dna, rna or a chemical analogue that will bind to the messenger rna mrna produced by that gene and.
After initially observing antisense mediated rna regulation in nature, investigations using model systems to test the feasibility of using synthetic aos to reduce levels of. Colorectal cancer crc is the second leading cause of cancerrelated death in the u. E cotter and others published antisense therapy for cancer find, read and cite all the research you need on researchgate. Watanabegrowth inhibition of human pancreatic cancer cell lines by antisense oligonucleotides specific to mutated kras genes int j cancer, 80 1999, pp. Gene transfermediated overexpression of bcl2 in a wide. In practice, only a few complementary oligonucleotides can successfully hybridize to a targeted mrna. The concept underlying antisense technology is relatively straightforward. Therapeutic antisense oligonucleotides against cancer. The clinical potential of oligonucleotide therapeutics. Ruiwen zhang, hui wang, in novel anticancer agents, 2006.
There is a potential role for antisense oligonucleotides in the treatment of disease. Recall that people with huntingtons disease hd have two copies, or alleles, of the huntington gene. Antisense oligonucleotides asos may offer advantages over traditional therapies if an. The principle of antisense technology is the sequencespecific binding of an antisense. Definition of antisense therapy nci dictionary of cancer. Antisense therapy delivers exogenous antisense oligonucleotides to tumor cells to bind complementary sequences of target mrna, thereby blocking translation and sequestering target mrnas for subsequent degradation. When the genetic sequence of a particular gene is known to cause a particular disease, it is possible to synthesize a strand of nucleic acid dna, rna or a chemical analogue that will bind to the messenger rna mrna produced by that gene and inactivate it, effectively turning that gene off. Improvements in therapy have increased the survival of patients with crc from 10 months to two years, but for patients who stop responding to treatments, such as irinotecan, options for additional therapy are limited. Lesniak, in handbook of brain tumor chemotherapy, molecular therapeutics, and immunotherapy second edition, 2018. Ever since its implication in multidrug chemoresistance in tumors, the bcl2 gene also known as bcl2 has stood out among molecular targets in oncology 1. This approach is effective only if the antisense oligonucleotide antisense mrna specifically binds to the target mrna and blocks protein biosynthesis translation. A synergistic antitumoral effect of bcl2 antisense therapy combined with some anticancer agents has been demonstrated in leukemia and lung cancer cells overexpressing bcl2 zangemeisterwittke.
Stamm, eric marcusson, george sandusky, philip iversen and bharvin k. Our broad, diverse pipeline has more than 40 firstinclass andor bestinclass medicines designed to treat a broad range of diseases including cancer and cardiovascular, neurological, infectious and pulmonary diseases. Main function of this therapy so far is to stop the production of protein which progresses the growth of cancer by binding. Lemoine icrfoncology group, royalpostgraduate medicalschool, hammersmithhospital, ducaneroad, london w12onn, uk. Rna interference rnai, a newly developed method in which rna molecules inhibit gene expression, has recently received considerable research attention. Antisense rna molecules are more frequently used in cancer therapy. By effectively using this type of therapy to remove essential.
Vascular endothelial growth factor vegf, a key mediator of angiogenesis, is overexpressed in pancreatic cancer. Chemosensitisation of malignant melanoma by bcl2 antisense. Antisense therapy is an approach to fighting various forms of cancer using oligonucleotides as part of the basic strategy. Apr 25, 2020 antisense therapy is an approach to fighting various forms of cancer using oligonucleotides as part of the basic strategy. Antisense cyclin d1 enhances sensitivity of head and neck. Colorectal cancer is the second leading cause of death from cancer in the u.
Survivin, a family member of the inhibitor of apoptosis proteins that is expressed during mitosis in a cell cycledependent manner and localized to different components of the mitotic apparatus, plays an important role in both cell division and inhibition of apoptosis. Antisense therapy is one of the methods for treating cancer. The most promising for antisense therapy are those targets that become upregulated during and are causally related to cancer progression and. Antisense therapy is a relatively new way of attacking cancer cells. This blocks the cells ability to use the rna to make a protein or work in other ways. Antisense oligonucleotides are used for the treatment of myeloid leukemia in as early as 1991. In vitro and in vivo activities and mechanisms hui wang department of pharmacology and toxicology, division of clinical pharmacology, comprehensive cancer center, and gene therapy center, university of alabama at. Antisense agents in cancer research and therapeutics. The antisense approach involves a specific drug that inhibits the expression of a cancer causing gene known as mdm2. Antisense therapy shows promise in breast cancer treatment. Antisense therapy is an approach to fighting diseases using dnalike molecules aos. Antisense targets in cancer elucidation of the pathogenic role of target genes associated with tumour progression continues to produce a growing list of antisense gene candidates. Pdf vegf antisense therapy inhibits tumor growth and.
However, although antisense oligonucleotides are commonly. Figure 1, by cmello labs figure 2, by teri platt, courtesy of fred hutchinson cancer research center protein formation proteins are constantly being produced in the body. Phase ii trials of another antisense dna for the treatment of. The mouse double minute 2 mdm2 oncogene has been suggested as a target for cancer therapy. Antisense inhibition of methylenetetrahydrofolate reductase. Read this article to learn about the antigene and antisense therapy. Antisense technology is supposed toprevent protein production from a targeted gene. Aug 02, 20 antisense therapy is an approach to fighting diseases using short dnalike molecules called antisense oligonucleotides. Asx is an australian publicly traded biopharmaceutical drug discovery and development company whose mission is to create, develop and commercialize novel antisense therapeutics for a variety of drug candidates including duchenne muscular dystrophy dmd, multiple sclerosis ms, and acromegaly. As a result, there is still a large unmet medical need to identify and develop better therapeutics for the treatment of cancer. Ccr researchers are investigating antisense oligonucleotides as potential treatments for this cancer. Current cancer therapy involves a combination of different approaches, including surgery, chemotherapy, radiotherapy, immunotherapy, targeted. The goal of the present study was to evaluate an antipka antisense oligonucleotide mixedbackbone oligonucleotide as a therapeutic approach to human cancer treatment. Our antisense technology platform has served as a springboard for drug discovery and realized hope for patients with unmet needs.
The aim of antisense oligonucleotide therapy is to control, and in some cases prevent, the absorption or translation of proteins that are believed to be playing a role in the development of the malignancy. A number of gene therapy clinical trials are being carried out the world over. Distribution of antisense oligonucleotides after infusion into the right lateral ventricle in rats and rhesus monkeys. When the genetic sequence of a particular gene is known to be causative of a particular disease, it is possible to synthesize a strand of nucleic acid dna, rna or a chemical analogue that will bind to the messenger rna mrna produced by that. Survivin is expressed in a vast majority of human cancers, but not in normal adult tissues. However canada has been interested in the research being done in relation to this new form of technology but has only recently taken part in the research as well. Development ofagents to target oncogenes and the intracel lular signalling pathways in which their products participate is already underway. Antisense oligonucleotides offer one approach to target genes involved in cancer progression, especially those that are not amenable to smallmolecule or antibody inhibition. Now, just over 20 years later, the first antisense product for cancer treatment has reached the clinical trial stage. Use of antisense oligonucleotides is a growing field of pharmaceutical and biotech companies and research programs for treatment of several diseases. Antisense oligonucleotides are being studied in the treatment of many types of cancer. Antisense technology provides the opportunity to manipulate the gene expression and this is being considered as an effective treatment for various diseases. Specific inhibition of kras expression and tumorigenicity of lung cancer cells by antisense rna.
Antisense oligonucleotidebased therapeutics for cancer nature. The principle of antisense technology is the sequencespecific binding of an antisense oligonucleotide to target mrna, resulting in the prevention of gene translation. Protein production is triggered by various stimuli, such as hormones. The most promising for antisense therapy are those targets that become upregulated during and are causally related to. Cancer, gene therapy, antisense therapy, antisense oligonucleotides, small interfering rna. Experimental therapy of human prostate cancer by inhibiting. Antisense definition of antisense by medical dictionary. Target dependence of antisense oligodeoxynucleotide inhibition of charas p21 expression and focus formation in t24transformed nih3t3 cells. Antisense gene therapy is a gene silencing technique similar to rna interference, but uses a slightly different mechanism. Nanobased delivery of rnai in cancer therapy molecular. There now has been a large body of evidence from preclinical and.
417 965 1532 7 1222 1524 1152 630 197 241 1070 1378 1533 180 1504 1183 1620 9 693 1588 1268 1569 601 792 242 1047 1286 1586 151 155 358 939 524 869 1494 554 1266 682 1321 1442