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Sci Tech
Detecting cancer — try with a fly
CANCER IS a disease that results when cells in the body no longer stop dividing or proliferating beyond the normal limit, and go on an uncontrolled growth spree. The body has a well- regulated set of genetic programs that control the growth of cells into tissues and organs to specific sizes. These control signals are both positive in nature — coded by genes which instruct cells to divide and grow in to the desired sizes and shapes, and negative — through genes that contain messages asking growth to stop beyond the right point. When these growth- promoting genes are not controlled, they start promoting tumour growth in which case they are actually termed oncogenes (cancer promoters, onco meaning cancer); myc, jun and fos genes are examples of these. And there are other genes called tumour suppressor genes or antioncogenes — a famous example being the one termed p53. It is for this reason that cancer is increasingly identified as a disease of the genes. External agents such as intense radiation, smoke, tar and aromatic hydrocarbons, and excessive intake of steroids tend to put oncogenes on the overdrive, or to inhibit the controlling function of antioncogenes, either way leading to malignant growth or tumours.
How does one treat cancer? As the control genes get turned on or off, they set a whole sequence of cellular processes going. It costs energy and nutrition for cells to grow to cancerous proportions, which weakens and wastes the body. Specific drugs are used to stop the cells from dividing and proliferating. For example the drugs Mitomycin C and Cytoxan tend to predominantly target the DNA of the tumour cells and selectively stop them dead. Other drugs tend to collapse the blood flow pathway to cancers (e.g., Combrestatin A-4 and Dolastatin) or bind to the protein spindle which helps isolate and separate the daughter cell from the parent during the cell division process (Vinblastine, Vincristine, or Colchicine). Sadly though, these chemotherapeutics are not fine-tuned enough to target just the cancer cells and leave the normal ones alone. As a result, the cancer patient suffers painful and weakening side effects.
A major effort in cancer therapy is thus towards finding methods that tell apart rogue cells and hit at them. This becomes important even after a solid tumour is surgically removed, because some of these tumour cells can escape the surgeon's knife and escape to other parts of the body and initiate cancer growth (metastasis) there. Much effort is being put in by researchers to capture these secondary cells and kill them. One approach towards this goal is to look for specific differences that may exist on the outer cell surface of the metastatic cells and normal ones, and raise antibodies against the former in order to immobilise and remove them. The new generation drug called Herceptin is one such immunological device that seeks out metastasizing breast cancer cells. Her again, severe side reactions are seen in many patients. It is clear that in order to fight and win over cancer, a single or linear approach will not suffice, and a combination of methods and modes might be better. And if the propensity for cancer is detected through appropriate genetic and cell biological tests early enough, pro-active treatment becomes possible, enhancing the chances of success enormously.
Two new approaches, which have been published recently, appear to hold great promise in this connection. One of them is to try and look, way ahead of time, for tell-tale signs which indicate that cancer may be in the offing years from now, and take preventive action to ward it off. The other is to use a combination of therapies so that the treatment is multi-pronged and yet with fewer side effects. We shall discuss these two approaches in a two- part series. The first part described here talks about two methods to detect cancer years before it may show up. Such an early warning method lets us take pre-emptive action to ward off the disease before it can strike.
Cancer of the colon and rectal area is predominant in elderly males. It is characterised by small multiple polyps, or tiny bubbly protrusions in the large intestines and colon. This condition is often referred to as adenomatous polyposis. When these polyps proliferate in numbers, colorectal cancer, also called APC, results. The genes associated with such polyposis have been characterized and mutations in them documented. Fortunately, such APC cancers are slow in developing. Thus an early warning and detection system is of benefit in stopping full- blown cancer before it starts.
Dr. Bert Vogelstein at the Johns Hopkins University Medical School at Baltimore, MD, USA, has long concerned himself with devising methods to detect cancer and methods to fight it. His group has just come out with a DNA mutation analysis protocol which can offer such an early warning about APC decades before it strikes individuals. Writing in the 31 January issue of The New England Journal of Medicine, this group report on how they screened stool samples of over 70 men, isolated DNA from the colon cells that are discarded there, and looked for mutations in the APC gene. Like the p53 gene, APC is also a tumour suppressor gene, or a control element that keeps cell proliferation in check. Mutations in its DNA sequence will thus offer the clinician early warning and adequate time to institute a treatment regimen to the concerned individual so as to prevent the occurrence of APC cancer. Gratifyingly, of the many samples that they studied, none showed a false positive; in other words, no one tested positive for the errant mutation, who was not affected by APC. This is so because, in the test, the scientists extracted DNA from the cells and made it manufacture the protein it codes for (or studied the "expression" of the gene). Most mutations in the APC gene change its DNA programming or expression such that the protein made is shorter in length than normal, and that gives the first indication of possible colon cancer hitting the person later.
Along the same principle, but on a different note, is the recent paper by my former colleagues, Drs. Poonam Bhandari and L. S. Shashidhara of the CCMB at Hyderabad. This group has been studying the genetic blueprint of the tiny little fruit- fly called Drosophila. This insect has long been the favourite of biologists who wish to study and understand which genes are turned on or off, and when and how, during the course of the development of the fly from its egg and larval stage through its infancy all the way into adulthood.
Such studies have surprisingly revealed that the genes involved and the programming that they dictate for the development of tissues, organs, limbs and body parts in the fly are remarkably similar to, and indeed set the stage for the body part development of higher animals — mice or men! And the fruit- fly is a favourite for another reason. You can quite easily put in extra genes from elsewhere into its eggs or larvae through injection in the laboratory. The fly that comes out is therefore transgenic, and will display the characteristics of the property encoded in the added gene. Such display can be occasionally dramatic or even bizarre — an extra pair of wings, a leg on the antenna, or the details of its compound eye. Monitoring the expression of the transgene is thus convenient — look at the fly under the microscope live, or in vivo.
Poonam and Shashi decided to put in the APC gene from humans into the Drosophila larvae, and look into the eye of the fly for changes as it is born and grows into adulthood, which happens within weeks of hatching. Looking at the eye told them whether the APC gene is normal or mutated, and whether anticancer drugs against APC will work or not. They thus have come out with a mutation test and also a drug testing method in vivo, using the fruit- fly as the experimental animal; drug testing- try with a fly! Their paper has appeared in the October 18, 2001 issue of the journal called Oncogene (yes, there is a professional journal devoted to the study of cancer- causing genes alone).
The CCMB method is not only easier, but also can be patented and licensed to industry for diagnostic purposes. Being a simple method, it can be used by many pathology labs, and should not cost a fortune. Our appreciation and best wishes go to Poonam and Shashi, and we look forward to their method coming into use in the near future.
(To be concluded)
D. Balasubramanian
L. V. Prasad Eye Institute
Hyderabad
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