Pharmacogenomics: Decreasing Drug Toxicity Through Personalized Medicine EHA Congress 2007

Pharmacogenomics offers the promise of individualized drug therapies based on a patient’s genetic make-up and that of the tumor cells. Such tailor-made drug regimes hold the promise to further increase survival rates for cancer. They could also decrease the sometimes lethal side effects of the powerful drugs used in cancer therapy, experts reported at the 12th Congress of the European Hematology Association in Vienna.

The role of pharmacogenomics in the treatment of childhood acute lymphoblastic leukemia (ALL) was addressed today by Dr Leo Kager from St Anna Children’s Hospital in Vienna at the European Hematology Association congress in Vienna (Austria) from 7 to 10 June 2007. Pharmacogenomics is a new technique for investigating the influence of variations in genetic make-up on an individual’s response to a particular drug. Tests are carried out on patients’ blood or bone marrow cells to look at the expression of genes which affect drug metabolism and activity. These laboratory tests are then correlated with the actual response of patients to the same drugs both with respect to effectiveness and toxicty.

Dr Kager says he has seen patients die because of toxic reactions to drugs used in leukemia treatments. In those patients where severe toxicity is exhibited, reactions can include such consequences as convulsions, severe infections or bleeding due to hemato-toxicity, liver failure, thrombosis, and mucositis.

Toxic drug reactions are very individual. For example, 1 in 300 people may have a severe toxic reaction to a drug, while 10 percent of a sample of patients may exhibit low toxic reactions and 90% full tolerance of the same medication. “The great difficulty for physicians is that they must prescribe medication without being able to assess which patient will response with severe toxic reactions”, Dr Kager says.

Genetic tests to prevent toxicity

Pharmacogenomics effectively means it may be possible to develop genetic tests that utilize a patient’s genetic profile to prevent toxicity. Simple as this may sound, Dr Kager says the difficulties should not be minimized: “Estimating appropriate drug dosages is a complicating factor. Administering too little of a drug can be dangerous, if poor results are achieved in the tumor cells targeted. What doctors need to know is what a particular drug will do in tumor cells.”

The latest research in pharmacogenomics examines the genetics of both normal and tumor cells, addressing the need to balance requirements to protect healthy tissue as much as possible while destroying the tumor.

At the moment, ALL patients are stratified according to certain risk factors (e.g., age, cytogenetic changes in tumor cells, in vivo response to chemotherapy) to receive either very intensive treatment (so called ‘high-risk’ patients, which means based on their prognostic factors these patients have a high risk of relapse), or less intensive treatment (standard risk and low risk patients). Within a risk group all patients receive the same course of treatment of drugs, at the same dosage. It has been established empirically that these dosages represent the range of best available treatment. Dr Kager: “But this is clearly not the best for each individual patient, as is amply demonstrated by the fact that in patients with a high risk ALL, many patients survive, while in patients with a low risk ALL, a few patients die. The fact is that a patient may die because too low or too high dose of these very powerful drugs is administered.” In treating childhood ALL, a physician is normally working with a range of up to eight different drugs. Childhood ALL remains a rare disease, fortunately. But there is a slight increase in incidence.

Promising approach to tailor therapy

Pharmacogenomics is of course relevant beyond the treatment of leukemia. Good success has already been achieved in the treatment of gastro-intestinal tumors. In fact these methods to assess drug effectiveness and toxicity begin to be applied in all fields. As a further example of the growing importance of pharmacogenomics, essential literature on hematology increasingly dedicates space to the field. In the use of oral anti-coagulants in treatment of thrombosis patients, which affects vastly more patients than leukemia, pharmacogenomics is a promising approach to tailor therapy.

Front line research being conducted at the moment in pharmacogenomics has shown that cellular pathways targeted by antileukemic medications differ considerably in ALL subtypes. A powerful tool to analyze the expression of thousands of genes in one experiment are microarray gene chips. In such experiments, the expression of about 20,000 genes can be measured, and ground breaking work testing patients samples and cell lines is being done to ascertain the interplay between a drug and particular genes to understand better why some leukemia patients are resistant, for example, to cortisone treatment.

Dr Kager: “While pharmacogenomics won’t perhaps explain all differences in individual patient reactions to drugs it can certainly further improve a physician’s ability to accurately prescribe.”

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