Topoisomerase inhibitors
Topoisomerase inhibitors are a class of anticancer drugs that target topoisomerases, which are crucial enzymes involved in the unwinding and relaxation of DNA, facilitating DNA replication necessary for cell division. By interfering with the normal functioning of these enzymes, topoisomerase inhibitors effectively hinder tumor growth, particularly in rapidly dividing cancer cells. These medications are often used in combination with other chemotherapy treatments and can be administered orally or intravenously. They are commonly employed to treat various cancers, including advanced colorectal cancer, testicular tumors, small-cell lung cancer, and certain leukemias and lymphomas, especially when first-line therapies fail.
The two main subclasses of topoisomerase inhibitors are epipodophyllotoxins, such as etoposide, which target topoisomerase II, and camptothecin analogs, like topotecan and irinotecan, which inhibit topoisomerase I. While generally well tolerated, these drugs can cause significant side effects, primarily myelosuppression, leading to decreased white blood cells and platelets, thus increasing infection and bleeding risks. Other side effects may include gastrointestinal issues and hair loss; however, most are reversible post-treatment. Rarely, their use has been linked to secondary cancers, highlighting the importance of careful monitoring during therapy. Despite the risks, topoisomerase inhibitors remain essential in the fight against various malignancies and can also have applications in treating HIV and certain sexually transmitted diseases.
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Topoisomerase inhibitors
ATC CODE: 101XX, 101CB
DEFINITION: Topoisomerase inhibitors are a group of anticancer chemotherapeutic drugs. Topoisomerases are important in changing the topology of deoxyribonucleic acid (DNA), allowing for efficient DNA replication and subsequent cell proliferation. Inhibitors of topoisomerases primarily kill tumors by interfering with DNA replication, which results in both a decrease in tumor cell division and an increase in tumor cell death. Because tumors comprise rapidly dividing cells, cancer cells are particularly susceptible to the inhibitory actions of topoisomerase inhibitors. These drugs are often administered in combination with other chemotherapy agents but may also be given as a single-agent therapy.
Cancers treated: Advanced colorectal cancer, testicular tumors, small-cell lung cancer, and acute lymphocytic leukemia, germ cell tumors, and lymphomas; many other cancers that are refractory to first-line therapies
Subclasses of this group: Epipodophyllotoxins, camptothecin, and related analogs
Delivery routes: Topoisomerase inhibitors are generally administered orally or intravenously (IV). The topoisomerase inhibitors are administered orally or intravenously (IV). The two main oral formulations are a solution and a soft gelatin capsule. Many of the topoisomerase inhibitors are not water-soluble. Therefore, IV must be dissolved in a special chemical solution, including alcohol, polyethylene glycol, and polysorbate 80. This solution is responsible for the hypersensitivity reactions induced in some patients (less than 5 percent) following infusion, such as vasomotor changes in the gastrointestinal and pulmonary systems. Slowing the rate of infusion, as well as administration of steroids or antihistamines can diminish these hypersensitivity reactions.
How these drugs work: As a cell prepares for division, the DNA must be replicated to provide a copy of DNA for each resulting cell. Double-stranded DNA is normally tightly coiled in the nucleus of non-dividing cells. The supercoiled topology of the DNA strands makes it difficult for the replication protein complexes necessary to copy the DNA to localize on the DNA strand properly. Therefore, properly duplicating the DNA must first be “unwound,” relaxing the structural topology and allowing access for the replication protein complexes. Topoisomerases are proteins located in the cell nucleus that can act to unwind the DNA. These proteins are enzymes, meaning they have an intrinsic catalytic activity that allows them to perform a certain function in the cell. Topoisomerases relax the supercoiled DNA by making transient breaks within the DNA strand, allowing it to unwind. Once the topoisomerase cleaves and relieves the DNA topology, the enzyme reseals the breakage.
Two topoisomerases have been identified, mainly differentiated by how they cleave double-stranded DNA. Type I topoisomerases alter DNA supercoiling by cleaving only one DNA strand. Type II enzymes are capable of cleaving both DNA strands. The current model of both types I and II topoisomerase activity predicts that the enzyme breaks the DNA phosphate backbone. In an intermediate reaction step, a covalent linkage is formed between the DNA and the enzyme. For type I topoisomerases, the nicked DNA strand can rotate around the unnicked strand, relieving the DNA supercoil. Type II topoisomerases relax the DNA by cleaving the entire DNA strand, inducing the passage of one DNA double-strand through a loop in another DNA double-strand. Without the action of topoisomerases, normal cell division would not be possible. However, these enzymes also play a major role in the growth of cancer cells.
Many natural compounds act to poison topoisomerases. Inhibitors to both types of topoisomerases have shown clinical activity against tumors. The primary mechanism of action of topoisomerase inhibitors is the stabilization of the enzyme while it is bound to the cleaved DNA. The topoisomerase enzyme cannot religate the DNA back together by stabilizing this complex, resulting in cleaved DNA strands. Prolonged DNA cleavage induces apoptosis or cell death. These drugs, therefore, are thought to kill cells either by increasing the rate of DNA breakage or by decreasing the rate of DNA religation. Although some drugs may also intercolate between DNA bases, DNA binding is not a critical component of topoisomerase activity inhibition, as neither camptothecin nor etoposide binds DNA.
Two main groups of topoisomerase inhibitors are in clinical use—epipodophyllotoxins and camptothecin analogs. Epipodophyllotoxins, which target topoisomerase II, were synthesized to chemically improve the efficacy of the antimicrotubule drug podophyllotoxin isolated from the mandrake plant. The epipodophyllotoxins include etoposide and teniposide. Camptothecin, an inhibitor of topoisomerase I, was discovered in an extract from the Chinese tree Camptotheca acuminate. The extreme side effects of camptothecin induced the creation of two main derivatives that cause fewer side effects—topotecan and irinotecan.
Resistance to topoisomerase inhibitors can occur through many mechanisms, including changes in the accumulation of these drugs, changes in the topoisomerase enzyme, and changes in the cellular response to the damage induced by these drugs. Because many topoisomerase inhibitors are naturally occurring substances, they are susceptible to natural cellular efflux mechanisms. Cellular efflux results in a “pumping out” of the drugs, causing less total drug concentration inside the cell. Using in vitro laboratory techniques, several cancer cell lines display resistance to topoisomerase inhibitors. One mechanism of this resistance is the development of point mutations within the topoisomerase enzyme. These genetic alterations may change the target binding site where these drugs bind to the enzyme, inhibiting the drug's ability to bind. Another way cells evade the effects of topoisomerase inhibitors is by increasing the expression of DNA repair enzymes, which can repair the cleavage induced by the topoisomerases.
Side effects: Topoisomerase inhibitors are generally well tolerated in most patients. The primary toxicity of topoisomerase inhibitors is bone marrow suppression, also called myelosuppression. This primarily manifests as leukopenia—a decrease in circulating white blood cells—and thrombocytopenia—a decrease in blood platelets. The decrease in white blood cells increases the risk of patients developing infections, while the decrease in blood platelets may increase the risk of bleeding. Typically, the onset of myelosuppression occurs within five to seven days after the initiation of therapy, peaks within the next week, and is returned to normal approximately twenty-one to twenty-eight days after the original administration. Because of the potential seriousness of myelosuppression, patients receiving topoisomerase inhibitor therapy are required to be closely monitored by a clinician. Patients can effectively manage myelosuppression by avoiding interaction with infected people and by minimizing the risk of cuts and bruises.
Other side effects that result from drug administration mainly involve the gastrointestinal system, including diarrhea, nausea, constipation, heartburn, and vomiting. Many patients also experience hair loss, headache, mouth sores, back pain, and anemia. Side effects can be controlled by reducing the dosage of therapy administered and by administering drugs to control them, such as antinausea agents. Most of these side effects are reversible after drug therapy ends.
Despite the powerful effects that these drugs have in inducing tumor cell death, the use of topoisomerase inhibitors has also been linked with the development of secondary cancers in rare cases. For example, the use of epipodophyllotoxins such as etoposide has been associated with an increased risk of developing secondary leukemia, at an incidence ranging from 0.7 to 3.2 percent. The reason for this increase is unknown. Conversely, some topoisomerase inhibitors effectively treat
HIV and some sexually transmitted diseases.
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