Fludarabine is a cytostatic drug used for the therapy of malignant diseases. For this purpose, it is applied intravenously as an infusion.
What is fludarabine?
Fludarabine is a cytostatic drug used for the therapy of malignant diseases. For this purpose, it is applied intravenously as an infusion. Fludarabine, also known as fludara or fludarabine-5-dihydrogen phosphate, is a drug belonging to the group of purine analogues. The substance is a so-called fluorinated nucleotide analog of vidarabine. Nucleotide analogs have structural and/or functional similarities to nucleotides. Nucleotides are the basic building blocks of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Purines are also important building blocks of nucleic acids. Unlike most nucleotides, fludarabine does not contain β-D-ribofuranose, but rather β-D-arabinofuranose. In addition, fluorine replaces adenine in the 2-position. Fludarabine is predominantly used for the treatment of low-malignant non-Hodgkin’s lymphoma. Furthermore, it is used for the treatment of acute leukemias. Chronic lymphocytic leukemia (CLL) is also treated with fludarabine.
Pharmacologic action
Fludarabine is administered intravenously. The drug reaches the cells through the bloodstream. In the cells, fludarabine becomes an active metabolite. A metabolite is an intermediate in a biochemical pathway. In this case, the metabolite is referred to as fludarabine ATP. The conversion occurs through phosphorylation. In phosphorylation, a phosphate group is attached to an organic molecule. This results in the formation of a phosphoroprotein. Fludarabine ATP is the actual active form of fludarabine. The drug interferes with DNA synthesis and inhibits ribonucleotide reductase. This enzyme forms the last link in the synthesis of DNA building blocks. Without ribonucleotide reductase, the organism cannot produce DNA building blocks. Whenever a cell divides or needs to repair DNA damage, it relies on ribonucleotide reductase. Many cancer cells increase the turnover rate of ribonucleotide reductase through modifications. This allows them to divide more quickly. Fludarabine addresses this issue. Ribonucleotide reductase allows the cells to divide more slowly or not at all. Since cancer cells usually divide very frequently, they are particularly affected by the drug’s action. However, fludarabine inhibits not only ribonucleotide reductase but also DNA polymerase. Just like ribonucleotide reductase, DNA polymerase is an enzyme. It catalyzes DNA synthesis from deoxyribonucleotides and thus plays an important role in DNA replication. When DNA polymerase is inhibited, genetic information can no longer be copied correctly. Furthermore, the fludarabine nucleotide is incorporated into the DNA of the affected cell. This leads to apoptosis of the cell. Apoptosis is also known as programmed cell death. By damaging the genetic material, the cell triggers its own death and perishes.
Medical application and use
Fludarabine is used to treat low-malignant non-Hodgkin’s lymphoma. ‘Non-Hodgkin’s lymphoma‘ is a collective term for all malignancies of the lymphatic system except Hodgkin’s disease. Non-painful enlargement of the lymph nodes is typical of the disease, as is a tendency and susceptibility to infection. Patients may also suffer from fever, night sweats, weight loss, and fatigue. Fludarabine is also used to treat acute leukemias. Leukemias are also known colloquially as blood cancers. They are malignancies of the hematopoietic or lymphatic systems. In a broader sense, leukemias can be classified as cancers. Acute leukemias include acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Both are treated with fludarabine. Chronic leukemias can also be distinguished between a myeloid and a lymphoid variant. Fludarabine is only used in the treatment of chronic lymphocytic leukemia. CLL is a low-malignant, leukemic non-Hodgkin’s lymphoma of B cells. It is the form of leukemia that is most common in the Western world.
Risks and side effects
The main side effect of fludarabine is marked myelosuppression. Myelosuppression is bone marrow inhibition.The depression of the bone marrow causes blood formation to stop. This leads to a deficiency of red blood cells (erythrocytes), white blood cells (leukocytes) and platelets (thrombocytes) in the organism. The lack of red blood cells leads to anemia. This is manifested by susceptibility to infections, fatigue and hair loss. The lack of white blood cells, leukopenia, also results in a strong susceptibility to infections. Thrombocytopenia, the lack of platelets, leads to an increased tendency to bleed. Myelosuppression is life-threatening. The combination of myelosuppression and immunosuppression is particularly dangerous. Fludarabine reduces CD4 helper cells, CD8 suppressor cells, and natural killer cells. Antibodies also decrease. This can lead to severe infections that are fatal in the worst cases. As with other cytostatic drugs, patients taking fludarabine may experience nausea, weakness, fever, and loss of appetite. An overdose can also cause severe neurological symptoms. Overdose can have fatal consequences. Fludarabine must not be used in cases of hypersensitivity to purine analogues. Furthermore, renal insufficiency must not be present when the drug is administered. Decompensated hemolytic anemia is also a contraindication. Due to severe side effects and cytotoxic effects, fludarabine must not be used during pregnancy and lactation. Interactions exist with pentostatin, dipyridamole, inhibitors of adenosine uptake, and with various vaccines.
