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| Clinical data | |
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| Trade names | Hycamtin, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a610007 |
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| Routes of administration | Intravenous infusion,by mouth |
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| Pharmacokinetic data | |
| Bioavailability | 31.4 % in humans[4][5] |
| Protein binding | 35% |
| Metabolism | Liver |
| Eliminationhalf-life | 2–3 hours |
| Excretion | Kidney |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.213.372 |
| Chemical and physical data | |
| Formula | C23H23N3O5 |
| Molar mass | 421.453 g·mol−1 |
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Topotecan, sold under the brand nameHycamtin among others, is achemotherapeutic agent medication that is atopoisomerase inhibitor. It is a synthetic, water-solubleanalog of the natural chemical compoundcamptothecin. It is used in the form of itshydrochloridesalt to treatovarian cancer,lung cancer and other cancer types.
AfterGlaxoSmithKline received finalFDA approval for topotecan on 15 October 2007, it became the first topoisomerase I inhibitor for oral use.[6]
As of 2016, experiments were under way forneuroblastoma,brainstem glioma,Ewing's sarcoma andAngelman's syndrome. In addition, topotecan is experimentally treatingnon-small cell lung cancer,colorectal cancer-,breast cancer,non-Hodgkin lymphoma,endometrial cancer, andoligodendroglioma.[12]
Angelman's syndrome is a neuro-genetic disorder characterized by severe developmental delays, seizures, speech impairments and physical impairments. It is an epigenetic disease and other treatments focus on symptoms. It is caused by a deletion or mutation of the maternal allele for theubiquitin protein ligase E3A (UBE3A).[13] UBE3A is expressed in most body tissues. However, in neurons only the maternal copy of the gene is expressed. UBE3A is located onchromosome 15 and the paternal copy for the gene is genetically imprinted and is silenced by anantisense RNA transcript. The maternal copy control center of the gene is methylated, suppressing transcription in the antisense direction while the paternal copy control center is unmethylated.[14]
Treatment involves unsilencing the paternal allele allowing the normal paternal UBE3A allele to be transcribed. UBE3A, in normal function, adds ubiquitin chains to proteins to target unnecessary or damaged proteins for degradation by theproteasome.[15]
16 topoisomerase inhibitors unsilence paternal UBE3A. Topoisomerases are enzymes that regulate the unwinding of DNA.[16] Of these 16 inhibitors, topotecan was found to induce the strongest upregulation of UBE3A.[17] The enzymes bind to the DNA and cut the phosphate backbone, allowing the DNA to be unwound. Topotecan unsilences the paternal UBE2A allele by reducing the transcription of an antisense transcript. Topotecan inhibits topoisomerase I restoring UBE3A levels to wild-type range in cultured mince neurons.[13]
Transgenic mice with a fluorescently tagged UBE3A were used to test the effectiveness of unsilencing the paternal copy.[14] When tested on micein vivo, topotecan affected thehippocampus,striatum andcerebral cortex but not thecerebellum unless a higher dose was administered (21.6 micrograms/hour for five days). The study suggested that the topoisomerase inhibitors have the potential to produce a normally functioning UBE3A protein. Most symptoms due to Angelman's syndrome are traditionally treated byspeech therapy,physical therapy andoccupational therapy.Anti-seizure medication is often prescribed as seizures are a common symptom of Angelman's syndrome.[18] These treatments target only symptoms.
This drug has been administered to cancer patients. It was well tolerated when administered to pediatric and adult patients.
Topotecan is a semi-synthetic derivative ofcamptothecin. Camptothecin is a natural product extracted from the bark of the treeCamptotheca acuminata. Topoisomerase-I is a nuclear enzyme that relieves torsional strain inDNA by opening single strand breaks.[19] Once topoisomerase-I creates a single strand break, the DNA can rotate in front of the advancing replication fork. In physiological environments, topotecan is in equilibrium with its inactive carboxylate form.[20] Topotecan's active lactone formintercalates between DNA bases in the topoisomerase-I cleavage complex.[21] The binding of topotecan in the cleavage complex prevents topoisomerase-I from religating the nicked DNA strand after relieving the strain.[21] This intercalation therefore traps the topoisomerase-I in the cleavage complex bound to the DNA.[21] When the replication-fork collides with the trapped topoisomerase-I, DNA damage occurs.[21] The unbroken DNA strand breaks and mammalian cells cannot efficiently repair these double strand breaks.[22] The accumulation of trapped topoisomerase-I complexes is a known response to apoptotic stimuli.[23] This disruption prevents DNA replication and ultimately leads to cell death. This process leads to breaks in the DNA strand resulting inapoptosis. Administration of topotecan down-regulates its target, topoisomerase-I; therefore, it is dosed to maximize efficacy and minimize related toxicity.[20] Topotecan is often given in combination withpaclitaxel as first line treatment for extensive-stagesmall-cell lung cancer.[20]
Two generic versions have been approved in the European Union. In Nov 2010 the US FDA approved a generic version.[24][25]
