Antineoplastic agents inhibitors of topoisomerases
One distinguishes two DNA topoisomerases: topoisomerase I which cuts and seals one DNA strand, and topoisomerase II, also called DNA-gyrase, which cuts the two DNA strands and seals them in a different conformation after torsion.
Among inhibitors of topoisomerase I, are camptothecins having antineoplastic effects, but also severe adverse effects. Derivatives of camptothecins better tolerated such as irinotecan have been obtained.
Irinotecan is a semisynthetic derivative of campothecins which is, itself and especially one of its metabolites, a potent inhibitor of topoisomerase I. It binds to the complex of cleavage constituted by topoisomerase I and DNA and inhibits the ligature of the DNA fragments. Irinotecan, (Campto*, Camptosar*) is used in the treatment of colorectal cancer refractory to the combination 5-fluoro-uracil / folinic acid. It is administered by intravenous infusion every three weeks. During and after the perfusion, a cholinergic syndrome preventable by atropine administration can be observed. Its main adverse effects are diarrhea and myelosuppression.
Topotecan, inhibitor of the DNA topoisomerase I, prevents the ligature of the cleaved DNA strand and replication. It is prescribed in the treatment of the metastatic cancer of the ovary and of small cell lung cancer. Its main adverse effects are hematologic (neutropenia, thrombocytopenia, anemia) and digestive.
Inhibitors of topoisomerase II having an antineoplastic effect can be divided in two groups, those which have, moreover, an intercalating effect, like amsacrine and anthracyclines, which we saw previously, and those without this additional effect like etoposide and teniposide.
Etoposide and teniposide are semisynthetic derivatives of podophyllotoxin and are used in combination in many protocols of chemotherapy (leukemia, malignant lymphoma).
Etoposide
Etoposide (Etopophos*, Vepeside*) prevents the entry in mitosis of the cancerous cells by inhibiting topoisomerase II, which leads to a modification of the conformation of DNA. It is used in the treatment of testicular cancer in combination with bleomycin and platinum, in acute leukemia and small cell lung cancer. Its adverse effects are primarily hematologic: leukopenia, trombocytopenia.
Teniposide
Teniposide (Vumon*) has properties close to those of etoposide. Its main clinical uses are Hodgkin's disease, brain tumors and bladder tumors.
Notice: Telomerase inhibitors
The chromosomes are finished by particular structures called telomeres, made of repetitive sequences of DNA (TTAGGG), synthesized under the influence of an enzyme constituted of RNA and a protein, called telomerase. It is a reverse transcriptase. The telomeres protect the chromosomes from destruction and take part in their binding to the nuclear matrix. In certain cancerous cells telomerases are particularly active. Telomerase inhibitors could be used in oncology for preventing formation of telomeres, protective shields of the chromosomes of cancerous cells.
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