Many pharmaceuticals currently in use have drastic side effects on the body. An example was a 2-year-old patient diagnosed with lymphoblastic acute leukemia, a rare type of cancer that usually occurs in children. The prognosis is good for certain patients treated with a chemotherapy drug cocktail. From the beginning of the treatment, the patient experienced severe side effects: the number of white and red blood cells and platelets was considerably reduced. Most patients undergoing this therapy do not have such severe side effects. However, doctors were not initially aware that the treatment was causing the low counts in the blood. Scientists at the Mayo Clinic, a hospital and one of the leading centers of medical research, located in Rochester, Minnesota, discovered that carriers of a mutant gene called thiopurine S-methyltransferase (TPMT) do not produce an enzyme essential for the body to rid itself of the chemotherapy drug 6-mercaptopurine (see Table 8-3). Individuals lacking the necessary enzyme accumulate toxic levels of the drug in their bodies. The lymphoblastic leukemia patient was a carrier of the TPMT gene, and in the battle with cancer the chemotherapy cocktail was doing more harm than good. After a DNA analysis, the defective gene was identified. The doctors prescribed a more appropriate chemotherapy treatment for the patient. The dose of 6-mercaptopurine was reduced in the cocktail, allowing a more effective treatment of the disease, without the side effects of the accumulated toxins.

The next generation of pharmaceuticals being developed takes into consideration the patient's genetic makeup, so the prescription of drugs will be tailored for each individual. Therefore, the treatments will be more efficient and less aggressive for one's body.

Do you realize that your medical doctor prescribes medicines just on the basis of your disease? What if he or she could decide on your prescription considering not only the illness, but your genetic makeup as well?

Genes in each human cell affect their response to drugs in two ways. Some genes code for receptors in cell membranes, which allows specific drugs to carry out their function. Other genes code for enzymes that affect the manner in which the individual is able to absorb, metabolize, and eliminate the drugs. In the former case the gene has a structural function, whereas in the latter it has a functional or metabolic role. With pharmacogenomics, the days of general-use medicines could be limited. Instead of treating breast cancer as it is done today, oncologists will determine the patient's genetic profile and establish a specially tailored therapy to maximize the efficiency of the drug in combating the disease, minimizing side effects. In other words, the medicines will become more personalized. It is likely to be many years, however, before this is commonplace in your local doctor's office.

Today, the pharmaceutical industry develops and the doctors prescribe therapies that are effective for most people, but not all. Pharmacogenomics promises to use information about the genetic differences among patients in the development of new drugs. Today, there are many deaths and complications associated with adverse reactions from medicines. Pharmacogenomics will clearly provide improvements in that area as well.

The β-2AR gene determines how well an asthmatic patient responds to albuterol, a medicine that opens the airway of the respiratory tract by relaxing the lung muscles. The gene has four or five different alleles (versions of the gene). One of them produces a high response to albuterol, whereas another reduces or prevents any response by the body. This explains why in about 25 percent of asthmatic patients, albuterol does not work properly. Knowing the patient's genetic profile, a doctor will have the ability to prescribe the right medicine, based on the disease and also on the patient. Many analysts estimate that within five years computer software will be available to help doctors prescribe drugs on the basis of their patients' genetic information. If scientific progress continues at the current pace, a genomic analysis, at an estimated cost of $500, would be the best investment one could make at a child's birth. The genomic sequence of a patient will allow a medical doctor to check genomic databases for possible side effects to medicines. Both effectiveness of the treatment and also its side effects could be foreseen prior to the beginning of a treatment. In this scenario, genes would be seen as factors that contribute to health and not only contributors to disease, as commonly portrayed.

Pharmacogenomics will eventually catalog all variations in the genome sequences across different populations. Most of those variations are single nucleotide changes from A to G or from C to T. This variation in a single base, or nucleotide, is called single nucleotide polymorphism (SNP). The current database of SNPs includes about 2 million of these variations, analyzed from individuals of several populations. Such variation is distributed in different parts of the human genome. In the studies underway, the function or association of those SNPs with an individual's susceptibility, resistance, or intolerance to medicines is being investigated. Therefore, the patient's genetic profile, composed of SNPs, might predict the response to different pharmaceuticals. With so many applications, the potential contribution of genomics for human health is still not completely fathomed by scientists in pharmacogenomics.

Although some skeptics do not agree with the potential of pharmacogenomics and the progress of medical genetics, many scientists believe that the impact of genetics in medicine will revolutionize the concept of human health. Some of the forecasts in medical genetics for the coming decades are summarized in Table 8-4.

The forecast by some scientists suggests that around 2040 the medicine practiced in many clinics will be based on the patients' own genomes. Others believe that this is much too optimistic. However, it is agreed that the scientific evolution in medical genetics is happening at a very fast pace. New discoveries occur every month. For example, recent studies at the NIH revealed the importance of some genes in the longevity of mice. Transgenic mice without one of these genes had a life span about 40 percent shorter than those carrying the gene. This specific gene is responsible for production of the enzyme methionine sulfoxide reductase (MrsA), which seems to be involved in mechanisms associated with protein repair. The NIH is carrying out other studies with the objective of understanding the effect of MrsA in the longevity of mice. If these results are promising, humans could be the next model for investigation.

Many people wonder why so much human health research is done in mice and pigs. No matter how incredible it seems, these animals are better models for these studies than monkeys. Their metabolic similarities to man are remarkable. Many growth hormones clinically used in humans were first developed and tested in mice. For obvious reasons, humans are not used in pharmacogenomics research until scientists have a certain degree of confidence of the safety and effectiveness of the new therapy.

Agrobiotechnology will also be contributing to the pharmaceutical industry. Beyond developing varieties that are high yielding, highly nutritious, and resistant to pests, agrobiotechnology will also be involved in pharmaceutical production. Companies such as Epicyte are focusing their efforts in agropharmacogenomics. Epicyte announced in 2001 the development of plants with antibodies for the treatment of herpes, respiratory diseases, and gastrointestinal diseases. The development of vaccines in plants, another contribution of agropharmacogenomics, is described in Chapter 13, “Bioterrorism.”

About 1.2 million Americans will be diagnosed with cancer in the next year. This is a fearful thing for many people. There is hope that the new drugs developed by pharmacogenomics and the new genetic tests will allow early diagnosis of this and many other diseases before they show any symptoms. Today, most children with cancer can be cured. If detected early, breast cancer can be treated without a mastectomy. Patients in chemotherapy or radiotherapy today possess an improved quality of life than those who underwent these treatments a decade ago. The hope for a cure today is substantially larger due to early detection and the existence of more efficient therapies. Clinical trials are currently in effect for various new drugs. For eligible patients these might be the best treatment available. A list of the clinical trials and other valuable information can be obtained on the Internet at http://www.cancertrialshelp.org.

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