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Gene silencing offers hope

Normal and disease states are expressions of normal and abnormal gene activities. Genes are genetic DNA codes that tell the body how to make a certain protein, just as a recipe tells a chef how to make a dish.

The human body consists of billions of cells. Each cell is a unit; the nucleus is the command center of the cell. Here lie the chromosomes on which reside the genes.

The planning and messages emanate from here but the execution occurs in the cytoplasm. There is no barrier between the cytoplasm and nucleus in lower-order organisms such as the e-coli (Procaryocytes.) However, in humans, the nuclear membrane separates the two. Therefore, a complex mechanism of transport exists that involves the transfer of DNA sequences from double-stranded DNA to a single strand of RNA. This transports the code, which is further translated into the destined protein.

Whereas the code is relatively closed in the DNA, some short segments (oligonucleotides) are exposed in the M-RNA. These contain anywhere from eight to 500 base pairs of DNA and are available for therapeutic blockade by synthetically constructed DNA sequences that are the exact reverse of the original sequence.

Whereas this text is written in English, the genetic code is written in, say, "Genetish," a language that consists of only four letters, ATCG, which are repeated in different combinations.

If a DNA sequence is written as, say, AAATCGGGAT, its reverse (anti-sense) can be designed as TAGGGCTAAA, which will block the message. If this message were to make a protein that promotes cancer, a blocking anti-sense would essentially block the promotion of cancer.

In the past, the selection of the right anti-sense used to be a formidable task. But with the advent of the "Microarray" technology, this has become relatively simple. In this technique, a large selection of possible anti-senses are arranged onto a microchip, which is then treated with a radio-labeled M-RNA. The anti-sense that attracts the largest amount of radioactivity will be the best fitting anti-sense. A second problem used to be the destruction of anti-sense by certain enzymes (neucleases.) This is largely overcome by changing the chemical structure (from phosphodiester to phosphothioate)

The anti-sense treatment has been successfully employed in cell culture and mouse models of human cancer in blocking a gene called Bcl-2. In the treated mice there was an 82 percent complete remission by PCR (Polymerase chain reaction, which detects even minute amounts of cancer.) In normal health there is a balance between cell production and destruction (apoptosis.)

At the Royal Marsdon Hospital in London, Bcl-2 anti-sense treatment had measured success in all grades of B-Cell non-Hodgkins lymphomas with minimal improvable side effects. Gene silencing by anti-sense oligoneucleotides may play an important role in cancer treatment in the future.

_ V. Upender Rao M.D., FACP, practices at the Cancer and Blood Disease Center in Lecanto.

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