Topoisomerase inhibitors
Topoisomerase inhibitors
Topoisomerase enzymes can unwind, cut and ligate DNA. Topoisomerase I is able to cleave one strand and is thus required for DNA replication and RNA transcription. In neoplastic cells, concentrations of this enzyme can be elevated. Topoisomerase II can break double strand DNA and helps DNA unwind when necessary. It has a crucial role in completion of mitosis, DNA replication and RNA transcription.
Doxorubicin (anthracyclin) intercalates with DNA and changes its spatial structure. By binding nuclear chromatin, it can form a complex between DNA and the topoisomerase II enzyme to produce strand cleavage. Inhibition of topoisomerase II enzyme results in decreased capacity for DNA repair. A second mechanism of DNA damaging is free radical formation, which causes many single- and double strand breaks. Because of its nature and its strand-breakage activities, doxorubicin and its isomere epirubicine can also be classified under the antitumor-antibiotics or strand-breakage agents (bleomycin).
The following tumors can be treated with doxorubicin: non-Hodgkin lymphomas, Hodgkin's disease, acute leukemias, carcinomas of breast, lung, stomach and sarcomas. The main toxicities of doxorubicin are myelosuppression, nausea, vomiting, alopecia, and cardiotoxicity.
Etoposide is a specific topoisomerase II inhibitor. The mechanism of action mainly involves the induction of double-strand DNA breaks by interaction with DNA topoisomerase II, by reversibly stabilizing the cleavage complex and the formation of free radicals. The result is arrest of the cell cycle in late S or early G2 phase or apoptosis. Indications for the use of etoposide are testis tumors, specific leukemias and bronchus carcinomas (second line and in combination with other cytostatics). Adverse effects include myelosuppression, nausea, vomiting, and alopecia.
Topotecan and irinotecan are specific topoisomerase I inhibitors. They stabilize the topoisomerase I -DNA complex, thereby causing DNA breaks and finally cell death. So, they inhibit DNA-strand religation. Indications for use are second line treatment of ovary carcinoma (topotecan) and colorectal carcinoma. The main toxicities involve bone marrow suppression resulting in severe neutropenia, diarrhea, cholinergic syndrome (irinotecan).
All of the following statements regarding doxorubicin are correct, EXCEPT:
