Topotecan

Structural formula
General
Non-proprietary name	Topotecan
other names	( S ) -9-Dimethylaminomethyl-10-hydroxycamptothecin ( S ) -10 - [(Dimethylamino) methyl] -4-ethyl-4,9-dihydroxy-1 H -pyrano [3 ', 4': 6.7] indolizino [1,2- b ] quinoline-3, 14- (4 H , 12 H ) -dione TOPO, TPT, TTC, NSC-609699, SKF-S 104864, SKF 104864
Molecular formula	C 23 H 23 N 3 O 5
External identifiers / databases
CAS number 123948-87-8 (topotecan) 119413-54-6 (topotecan hydrochloride ) PubChem 60700 DrugBank DB01030 Wikidata Q419953
Drug information
ATC code	L01 XX17
Drug class	Cytostatic
Mechanism of action	Topoisomerase I inhibitors
properties
Molar mass	421.45 g · mol -1
Physical state	firmly
Melting point	213–218 ° C (topotecan hydrochloride )
solubility	1 mg ml −1 in water
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Hydrochloride hydrate Caution H and P phrases H: 341 P: 281
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Topotecan (INN; trade name Hycamtin ^® ; manufacturer Novartis ) is a medicinal substance that is produced semi-synthetically as a derivative ( derivative ) of the phytonutrient camptothecin . Camptothecin is an alkaloid and is obtained from the plant Camptotheca acuminata .

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

Mechanism of action

Topotecan (like camptothecin) is an inhibitor of DNA topoisomerase I. DNA topoisomerase I has the physiological function of breaking down the shear stress of the DNA double strand by causing DNA single strand breaks. Topotecan attaches itself to the complex of topoisomerase I and DNA and prevents the reclosure of the previously made DNA single strand break . According to current knowledge, the cause replication of DNA by the corresponding 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 DNA replication . Mammalian cells do not have sufficiently efficient DNA repair mechanisms to repair such DNA double-strand breaks.
In terms of the cell cycle , topotecan is only effective in the S phase of the cell cycle ( DNA synthesis ). Dormant cells (healthy and diseased), which do not synthesize DNA and are therefore 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 also topoisomerase inhibitors; however, they inhibit DNA topoisomerase II.

Metabolism

Like irinotecan, topotecan is water-soluble. However, unlike irinotecan, topotecan is not a prodrug .

Application areas)

Ovarian cancer, metastatic and refractory to therapy

In the Federal Republic of Germany, topotecan is approved for the treatment of metastatic (spread) ovarian carcinoma (ovarian cancer) if the ovarian carcinoma did not respond or responded only insufficiently to primary (1st line) treatment (literally: failure of primary or subsequent therapy ).

Lung carcinoma, small-cell, therapy-refractory

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

Children and young people

Topotecan is currently being tested in clinical studies in children and adolescents.

• in combination with cyclophosphamide and etoposide : neuroblastoma
• in combination with cyclophosphamide , etoposide and carboplatin : rhabdomyosarcoma

According to the current state of knowledge, topotecan is not a standard therapy for the aforementioned tumor diseases .

Contraindications

Topotecan must not be given under any circumstances if:

• Hypersensitivity to topotecan, irinotecan or campothecin
• Existing severe bone marrow depression
• During pregnancy and breastfeeding

An indication under the strictest risk-benefit assessment is given for:

• severely impaired kidney function
• severely impaired liver function (due to liver cirrhosis with serum bilirubin values> 10 mg / dl)
• moderate bone marrow depression

Topotecan has not been adequately tested in children and is consequently not approved for children and adolescents. The treatment of children with cancer with the use of topotecan in the context of chemotherapy should - if at all - only be carried out in the context of studies .

Side effects

• Myelosuppression ( bone marrow toxicity ): Is neutropenia , anemia, and thrombopenia manifest . Blood counts are required when using topotecan. The administration of G-CSF can take place, but does not have to be.
• Alopecia possible
• Liver toxicity (liver damage): manifested as an increase in transaminases , hyperbilirubinemia ( jaundice ) up to liver failure .
• Kidney toxicity (kidney damage): manifested as an increase in creatinine , but sometimes also kidney failure, especially with simultaneous fluid loss due to diarrhea.
• Hypersensitivity ( hypersensitivity , allergic reaction)
• Carcinogenicity (causing cancer ): According to the current state of knowledge, there are indications that the use of topoisomerase I inhibitors such as topotecan can promote the occurrence of leukemia . It is certain that the use of topoisomerase II inhibitors such as etoposide favors the occurrence of leukemia when certain threshold doses are exceeded.

Individual evidence

1. ↑ Entry on topotecan. In: Römpp Online . Georg Thieme Verlag, accessed on October 1, 2014.
2. ^ Entry on topotecan in the DrugBank of the University of Alberta .
3. ↑ ^{a b} Data sheet Topotecan hydrochloride hydrate from Sigma-Aldrich , accessed on April 24, 2011 ( PDF ).

Web links

• Public Assessment Report (EPAR) of the European Medicines Agency (EMA) for: Topotecan
• Drug Prescription Information at FDA (PDF; 267 kB) US package insert for topotecan (Hycamtin ^® ). As of March 26, 2010, freely accessible.

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !