Topotecan

• (S )-9 -dimethylaminomethyl -10 - hydroxycamptothecin
• (S) -10 - [( dimethylamino) methyl ]-4 -ethyl- 4 ,9 -dihydroxy -1H- pyrano [3, 4: 6,7? ?] Indolizino [1,2- b] quinolin -3, 14 - ( 4H, 12H )-dione
• TOPO, TPT, TTC, NSC - 609 699, SKF -S 104864, SKF 104864

L01XX17

Cytostatic

Topoisomerase I inhibitors

213-218 ° C ( topotecan · hydrochloride)

1 mg · ml - 1 in water

Hydrochloride Hydrate

Attention

Template: Infobox chemical / molecular formula search available

Topotecan (INN, trade name Hycamtin ®; manufacturer GlaxoSmithKline) is a drug, as a descendant of the semi-synthetic ( derivative ) of the plant component camptothecin is made. Camptothecin is an alkaloid and is obtained from the plant Camptotheca acuminata.

Topotecan is light yellowish to greenish powder and used as a chemotherapeutic agent for the treatment of cancer. Topotecan belongs to the cytostatic group of topoisomerase inhibitors.

Mechanism of action

Topotecan (as camptothecin ) is an inhibitor of DNA topoisomerase I. The DNA topoisomerase I did reduce the physiological function, Shear stress of the DNA duplex by causing DNA single strand breaks. Topotecan is deposited on the complex of DNA topoisomerase I and preventing the reocclusion of previously made ​​single-stranded DNA breakage. According to current knowledge, the replication of DNA caused by the appropriate enzymes, such as DNA polymerases, in contact with the complex of topotecan, DNA, and DNA topoisomerase I has a double-strand break of the DNA and hence discontinuation of the DNA replication. Mammalian cells do not have sufficiently efficient DNA repair mechanisms to repair such DNA double-strand breaks. Measured at cell cycle is topotecan effective only in the S phase of the cell cycle (DNA synthesis). Quiescent cells (normal and pathological ), which do not synthesize DNA and thus are not in the S phase of the cell cycle are not damaged by topotecan. Related substances with the same mechanism of action are irinotecan and camptothecin. Etoposide ( VP16 ) and teniposide ( VM26 ) are even topoisomerase inhibitors; but they inhibit DNA topoisomerase II

Metabolism

Topotecan is as irinotecan water. Unlike irinotecan, topotecan, however, is not a prodrug.

Indication (s )

Ovarian cancer, metastatic and refractory to treatment

In the Federal Republic of Germany Topotecan is used to treat metastatic ( scattered ) ovarian cancer ( ovarian cancer), when the ovarian cancer has not or only responded to a primary (1st line ) treatment insufficient ( literally: failure of first - line or subsequent therapy ).

Lung cancer, small cell, refractory to treatment

In the USA Topotecan is used to treat small cell lung cancer (SCLC; small cell lung carcinoma ) admitted who have not responded to a primary (1st line ) treatment and compared with topotecan are sensitive. In the Federal Republic of Germany Topotecan is approved for ( quote) " patients with relapsed small cell lung cancer ( SCLC), which are not suitable for re- treatment with the treatment regimen used in the first-line therapy. " (SPC Hycamtin ® 1 mg of 01 /2006)

Children and young people

In children and adolescents topotecan is currently being tested in clinical trials.

• In combination with cyclophosphamide and etoposide: neuroblastoma
• In combination with cyclophosphamide, etoposide, and carboplatin: Rhabdomyosarcoma

Within the present state of knowledge Topotecan is no standard treatment for the tumors mentioned above.

Contraindications

Topotecan can be administered under any circumstances to:

• Hypersensitivity to topotecan, irinotecan, camptothecin or
• Severe bone marrow depression
• During pregnancy and lactation

An indication in the strictest benefit- risk ratio is given by:

• Severe renal impairment
• Severe hepatic insufficiency (due to cirrhosis with serum bilirubin > 10 mg / dl )
• Mäßiggradiger bone marrow depression

Topotecan is not adequately tested in children and consequently also not approved for children and adolescents. The treatment of children with cancer with the use of topotecan in the context of chemotherapy should - if ever - made ​​exclusively in the context of studies.

Side effects

• Myelosuppression (bone marrow toxicity): yourself Manifested neutropenia, anemia and thrombocytopenia. Blood counts are required in the application of topotecan. Administration of G-CSF can be, but need not.
• Alopecia possible
• Hepatotoxicity ( liver damage ) manifested as elevated transaminases, hyperbilirubinemia (jaundice) to liver failure.
• Nephrotoxicity ( kidney damage ) manifested as creatinine, but sometimes kidney failure, particularly if accompanied by fluid loss through diarrhea.
• Hypersensitivity (hypersensitivity, allergic reaction)
• Carcinogenicity ( causing cancer): Within the present state of knowledge, there are indications that the use of or use of topoisomerase I inhibitors such as topotecan can favor the occurrence of leukemia. What is certain is that the use of topoisomerase II inhibitors such as etoposide when it exceeds certain threshold doses favors the occurrence of leukemia.