Pharmacology
Summary
Topoisomerase inhibitors are a class of pharmacological agents that are widely used in cancer therapy. They target enzymes involved in DNA supercoiling, which is a crucial step in DNA replication.
Topoisomerases are enzymes that relieve the supercoiling produced during the unwinding and separation of DNA by helicase. Two medications that inhibit these enzymes are etoposide and podophyllin, which specifically target topoisomerase II. These inhibitors function by blocking the ability of topoisomerase II to seal the double-strand breaks it induces. This causes chromosomal breaks to accumulate, which eventually leads to cell death. The inhibitors also inhibit DNA synthesis and thus arrest cells in the S phase of the cell cycle.
Topoisomerase inhibitors are used to treat several types of cancer including testicular cancer, small cell lung cancer, and Hodgkin's and non-Hodgkin's lymphoma. However, etoposide treatment has potential side effects, including myelosuppression and increased vulnerability to infections. Other topoisomerase inhibitors include topotecan and irinotecan, which inhibit topoisomerase I and are used to treat ovarian cancer, small cell lung cancers, and colon cancer. The common side effects of these topoisomerase I inhibitors are myelosuppression and diarrhea.
Lesson Outline
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FAQs
Topoisomerases are enzymes that relieve the supercoiling produced during the unwinding and separation of DNA by helicase. Topoisomerase I inhibitors, such as topotecan and irinotecan, work by causing single-strand breaks to relieve supercoiling stress in DNA. Topoisomerase II inhibitors, such as etoposide and teniposide, cause double-stranded breaks to relieve supercoiling stress in DNA.
Topoisomerase inhibitors primarily interfere with the S and G2 phases of the cell cycle. During the S phase, DNA synthesis occurs. Here, topoisomerase inhibitors block the progression of the cell cycle by inhibiting topoisomerases, which leads to DNA damage. During the G2 phase, the cell checks and repairs any DNA damage before proceeding to mitosis (M phase). Again, these inhibitors can block this phase as well, preventing the cell from conducting necessary checks and repairs. This disruption can lead to cell death, particularly in cancer cells.
Etoposide and teniposide, both topoisomerase II inhibitors, have been proven effective in the treatment of many solid and hematological malignancies, such as testicular cancer, small cell lung cancer, and both Hodgkin and non-Hodgkin lymphomas.
While topoisomerase inhibitors can be effective in cancer treatment, they can also produce some adverse side effects. Some of these include myelosuppression (a decrease in bone marrow activity leading to fewer red and white blood cells and platelets), immunosuppression, and alopecia. Certain topoisomerase I inhibitors, such as topotecan and irinotecan, can also cause severe diarrhea.
Etoposide and teniposide are topoisomerase II inhibitors that blocking the ability of topoisomerase II to seal the double-strand breaks it induces. This causes chromosomal breaks to accumulate, which eventually leads to cell death.
