Abstract:
It is now clear that, in living cells in vitro, appropriately modified antisense DNA molecules can decrease the amount or translatability of mRNAs from both cells and infectious organisms. Such decreases in mRNA lead directly to a decrease in the protein coded by that mRNA or to the destruction of an RNA form or critical RNA from a pathogenic organism. Development of antisense agents for use against pathogenic and other diseases is discussed, including antisense pharmacology, advantages of antisense (true rational drug design), disease targets, safety studies (toxicity, pharmacokinetics, genetic toxicity), antisense patents, delivery formulation of antisense drugs, and manufacture of antisense drugs. Only about 15 bases are necessary to bind with absolute precision to any given unique mRNA produced by the human genome. An antisense DNA drug should precisely inhibit the synthesis of a targeted protein without disrupting the synthesis of any other protein. Major viral targets for antisense agents include HIV, herpes simplex, influenza, and human T-cell leukemia virus. For cancer therapy, antisense agents can be designed that can downregulate the expression of oncogenes known to be important in the transformation of a cell line or tumor. For example, expression of the c-fos gene in H-ras-transformed NIH-3T3 cells has been downregulated by using an antisense fos construct, causing tumorigenic cells to lose many of their tumorigenic properties. A potential antisense approach to cancer therapeutics that would be extremely selective for transformed cells is based on the fact that some malignant cells have specific activating mutations in certain oncogenes such as ras or translocations as in myc or bcl-2. These mutations provide a therapeutic window that permits the destruction of cells containing only those specific mutations. Polymerase chain reaction diagnosis of mutations in tumors may provide the necessary genetic information to support this type of therapy. Antisense therapeutics are poised to bring a revolution to the pharmaceutical industry. Although unproven, this new technology has the potential to bring to market new drugs with fewer side effects. Novel treatments may be devised that utilize gene regulatory circuits to create totally new classes of pharmaceutical agonists that have never been seen before in human therapy. (19 Refs)
Keywords: Drug Design DNA, Antisense/PHARMACOLOGY/*THERAPEUTIC USE Neoplasms/DRUG THERAPY Patents RNA, Antisense/PHARMACOLOGY/*THERAPEUTIC USE MONOGRAPH 930330
M9331095
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Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.
