Chemotherapy is the use of drugs to treat cancer. These drugs are designed to kill cancer cells by interfering with their ability to grow and reproduce. Many cancer drugs used today do not specifically attack cancer cells. This means that they not only affect cancer cells but also normal cells in the patients who take them, which is why chemotherapy drugs often produce severe side effects, including nausea, vomiting, diarrhea, hair loss, skin problems, and damage to blood and immune cells. Other types of side effects may also occur, depending upon the specific drug used.
Chemotherapy drugs, like other drugs, are absorbed by, broken down by, and eliminated from the body through a process called metabolism. Metabolism is the processing by the body of materials from outside the body. Metabolism may make a drug inactive or more active or may turn the drug into a form that can be eliminated from the body in the urine or stool. Metabolism occurs primarily in the liver and is performed by proteins called enzymes. After metabolizing a molecule, proteins in the liver then break down the molecule or attach it to "carrier" proteins that allow it to be eliminated from the body.
Proteins have many different functions within the body, including the metabolism of drugs. All proteins in the body are created based on instructions from genes. A gene is made of deoxyribonucleic acid (DNA) and serves as a map for the creation of proteins. Some parts of DNA are not genes, and do not give instructions for making proteins. These parts of the DNA control the genes and determine how active it is. A more active gene will create a more active protein, whereas a less active gene will create a less active protein. If this occurs in a gene that makes a protein involved in drug metabolism, a person may metabolize a drug more slowly or quickly than normal. This means that the drug may stay in the body for a longer or shorter period of time.
The DNA found in any two individuals is 99.9% identical, which leaves 0.1% for genetic individuality. Differences present in a gene are called alleles, or polymorphisms. These differences may result in genes that create proteins with more or less activity than others. If this happens in a gene that codes for a protein involved in drug metabolism, an individual may not be able to process a drug normally.
Differences in parts of the DNA that do not code for proteins may affect the activity of a gene. For instance, one individual may have a small difference in a part of their DNA that causes a nearby gene to become inactive. Thus, this individual will not have the protein that is created by that gene.
Proteins that metabolize drugs are called enzymes, and are created from genes. Two individuals with different alleles for the same gene may produce metabolizing proteins with different levels of activity. This means one individual may produce a protein that metabolizes drugs very quickly, while another individual may produce a protein that metabolizes drugs very slowly.
Differences in the proteins that metabolize chemotherapy drugs affect how an individual responds to the drug. They may have more or less active drug in their body depending upon what alleles they have. This means that some patients will have more effect from a drug, whereas some patients may not have any effect at all. It also means that some patients may experience more side effects than others because they have more active drug in their body. Chemotherapy drugs act on proteins within the tumor cells. Variations in genes that code for these proteins may make patients respond more or less strongly to a particular drug.
Pharmacogenomics is the study of how an individual's genes affect his or her response to drugs. This field is a combination of the study of pharmacology (drugs) and genetics and is based on the ability of researchers to identify gene variants. Gene variants can cause an individual to metabolize some types of drugs differently. This means that they may have higher levels of the drug in their body, which may allow it to be more effective or may cause serious side effects. Gene variants can be detected by several different methods, including polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), staining of tumor cells, and DNA microarray.
Polymerase chain reaction (PCR): Polymerase chain reaction (PCR) is the most commonly used method for pharmacogenomic testing because it requires a very small sample of tissue and can be performed rapidly. A small sample of cells is taken from a tumor that has been surgically removed, a blood sample, or a swab of the inside of the cheek. The genetic material is copied hundreds of times to create a larger sample. Molecules called "probes," which are DNA segments specifically designed to attach to a specific allele, are then used to tag the gene and identify it. Probes can be used to identify gene variants and to determine the amount of variant gene present in the cell. Patients with more than two gene variants may have more significant effects than patients with one gene variant. This method can be used to detect variations in genes that process and inactivate drugs in the liver.
Fluorescence in situ hybridization (FISH): Fluorescence in situ hybridization (FISH) is a method that is used to determine whether a specific part of a chromosome is present in a cell. This is useful because in some types of genetic variations there are additional copies of a certain chromosome or there are gene variants on a chromosome that are abnormal. To perform FISH, researchers first identify a specific region of a chromosome (for example, a region that contains a specific gene). They then generate a probe or a sequence of DNA that can recognize and bind to the chromosomal region of interest. In FISH, the probes that researchers use fluoresce, that is, they glow under ultraviolet light if the labeled chromosomal region is present.
In some diseases, such as cancer, genetic mutations occur that can cause part of a chromosome to be deleted, repeated, or reversed in orientation. By looking for differences in how chromosomes from different cells stain with a probe, researchers may be able to observe these changes under the microscope and learn more about the genetic mutations that cause a particular disease.
Tissue staining: Tissue staining is an indirect method of detecting gene variants and is usually used on tissue that has been surgically removed, such as a tumor. Stains are created that specifically attach to one gene variant or to the protein it produces. The stain is applied to a sample of tumor and is examined under the microscope. If the gene variant is present, then the protein will also be present and the stain will be positive. This method is used to detect the presence of gene variants in some types of cancers.
DNA microarray: DNA microarray is a method of studying multiple genes at a single time. Microarrays are used to detect changes in dozens, hundreds, or thousands of genes and can therefore provide more information about a person's specific genetic makeup. As a result of microarrays being a relatively new technology, they are primarily used in research. Microarrays use probes that detect a specific gene variant, and determine the amount of variant gene present in the cell.
Pharmacogenomics: Pharmacogenomics is the study of how an individual's genes affect his or her response to drugs. It is a combination of the study of pharmacology (drugs) and genetics. Pharmacogenomics is based on the ability of researchers to identify gene variants. If scientists know that a gene variant causes a patient to respond to a drug in a certain way, doctors may decide not to prescribe that drug to the patient.
Application of pharmacogenomics to chemotherapy includes testing patients to determine whether they have gene alleles that may cause them to benefit from the anticancer effects of the drug or that may cause them to have severe side effects. Chemotherapy drugs affected by genetic variations include thiopurines, 5-fluorouracil, and irinotecan.
Thiopurines: Thiopurines are a type of drug that prevents cells from reproducing by inhibiting DNA synthesis. This class of drug includes 6-mercaptopurine, thioguanine, and azathioprine. 6-Mercaptopurine and thioguanine are used to treat some types of leukemia. Azathioprine is used to treat rheumatoid arthritis and patients who have had a kidney transplant. These drugs are in an inactive state when they enter the body. They are activated by the metabolic process involving several enzymes, including hypoxanthine phosphoribosyl transferase. Thiopurines are inactivated in the body by two enzymes: xanthine oxidase and thiopurine S-methyltransferase (TPMT).
Polymorphisms in the gene for TPMT cause some people to metabolize thiopurines slower than others. About 90% of Caucasians have high activity of TPMT, 10% have intermediate activity, and 0.3% have little or no activity. The rates of allele variations in other racial groups are uncertain.
Patients with one variant allele have intermediate activity of TPMT, and they are at an increased risk of having severe side effects when treated with thiopurines. The most common side effects are nausea, vomiting, and fatigue. Serious possible side effects include liver damage, bone marrow suppression, infection, and a secondary cancer. Patients with two variant alleles have very little or no activity of TPMT, and they are at a very high risk of having severe, life-threatening side effects with thiopurines. Testing for TPMT variant alleles can detect these patients and allow doctors to adjust the drug dosing or not use the drug at all.
5-Fluorouracil (5-FU): 5-Fluorouracil (5-FU) is used to treat colon, breast, and head and neck cancers. It is inactive when injected, and must be metabolized in the liver to its active form in order to kill tumor cells. 5-FU kills tumor cells by blocking a protein called thymidylate synthase, which helps tumor cells divide and reproduce. It is inactivated by a protein in the liver and blood called dihydropyrimidine dehydrogenase (DPD).
A region of DNA that controls the action of the thymidylate synthase gene, called a promotor, has polymorphisms that are seen in different people. Some polymorphisms cause the thymidylate synthase gene to be more or less active and to produce more or less protein.
Patients who have a gene variant that causes the gene to be less active, and therefore to produce less protein, metabolize 5-FU more slowly than normal. This means they have higher activity of the drug in their body and that 5-FU is more effective in controlling their cancer. However, patients with this gene variant are also more likely to have severe side effects from 5-FU, such as bone marrow suppression and heart and liver damage. Testing for variants in the thymidylate synthase gene promoter is not performed regularly in patients receiving 5-FU because this testing has not been studied in large human trials.
Dihydropyrimidine dehydrogenase (DPD), the protein responsible for inactivating 5-FU, is present in varying amounts in the blood. Some people have very low levels, which results in an inability to adequately inactivate 5-FU. These patients have a high risk of serious and potentially fatal side effects, including heart and liver damage and bone marrow suppression.
The gene variants that cause differences in the amount of DPD activity are not well understood. Many different variants exist, and the effect of each variant on DPD is not yet known. It is therefore not currently possible to test for DPD gene variants.
Irinotecan: Irinotecan is used in the treatment of colon cancer. Irinotecan is inactive when it is administered to the patient but is converted to its active form, called SN-38, within the body. It is inactivated by a protein in the liver called UDP-glucuronosyltransferase 1A1 (UGT1A1).
The activity of the gene that produces UGT1A1 is controlled by a part of DNA called a promoter. Polymorphisms in this promoter result in less activity of the gene and less UGT1A1 protein. With less of this protein, patients have higher levels of the active drug SN-38 and are at a higher risk of having severe side effects, including diarrhea and suppression of the immune system.
A test for UGT1A1 gene variants is available and allows doctors to detect patients who are at high risk of severe side effects. Doctors may choose to use a lower dose of irinotecan or a different drug in these patients.
Safer, more effective chemotherapy: By determining gene variants that affect the way patients respond to chemotherapy, it may be possible to test patients prior to beginning therapy to determine whether they will benefit from the drug or are at high risk of severe side effects. Patients with genetic variants that cause them to receive no benefit from a drug, or to have severe side effects, can be given a different chemotherapy drug that will be safer and more effective.
Targeted therapies: Drug companies have recently started to develop drugs that act on a single gene or protein. These drugs are called targeted therapies because they are designed to act on a specific target within the cell. Pharmacogenomic testing is used to identify patients who will benefit from the drug. For instance, Herceptin®, a drug used to treat breast cancer, acts on a specific gene variant that occurs when tumor cells produce too much of a gene called Her2/neu. Herceptin® works only in patients who are positive for this variant. Genetic tests are performed on patients before Herceptin® is prescribed.
The genes involved in the metabolism and action of many chemotherapy drugs are unknown. Much research is required to detect these genes and their variants before clinical tests can be developed. This requires significant time, human resources, and financial investments.
Research is being done on currently available chemotherapy drugs to determine whether gene variants are responsible for the differences in effects observed among patients. If genetic variants are responsible for the different responses, pharmacogenomic tests may be used before using chemotherapy to determine who will actually benefit from the drug.
The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.