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Topotecan (trade name Hycamtin) is a chemotherapeutic agent that is a topoisomerase inhibitor. It is a synthetic, water-soluble analog of the natural chemical compound camptothecin. It is used in the form of its hydrochloride salt to treat ovarian cancer, lung cancer and other cancer types.

After GlaxoSmithKline received final FDA approval for Hycamtin Capsules on October 15, 2007, topotecan became the first topoisomerase I inhibitor for oral use.

Indications (approved uses)

Ovarian cancer (FDA May 1996).^[3]
Cervical cancer (FDA June 2006).^[4]^[5]
Small cell lung cancer (SCLC) (FDA Oct 2007).^[6]^[7]

Experimental use

As of 2016 experiments were under way for Neuroblastoma, Brainstem glioma, Ewing's sarcoma and Angelman's syndrome.

Angelman's syndrome

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 the ubiquitin protein ligase E3A.^[8] UBE3A is expressed in most body tissues. However, in neurons only the maternal copy of the gene is expressed. UBE3A is located on chromosome 15 and the paternal copy for the gene is genetically imprinted and is silenced by an antisense 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.^[9]

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 the proteasome.^[10]

16 topoisomerasesinhibitors unsilence paternal UBE3A. Topoisomerases are enzymes that regulate the unwinding of DNA.^[11] Of these 16 inhibitors, topotecan was found to induce the strongest upregulation of UBE3A.^[12] 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.^[9] When tested on mice in vivo, topotecan affected the hippocampus, striatum and cerebral cortex but not the cerebellum 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 by speech therapy, physical therapy and occupational therapy. Anti-seizure medication is often prescribed as seizures are a common symptom of Angelman’s syndrome.^[14] These treatments target only symptoms.

This drug has been administered to cancer patients. It was well-tolerated when administered to pediatric and adult patients.

Mechanism of action

Topotecan is a semi-synthetic derivative of camptothecin. Camptothecin is a natural product extracted from the bark of the tree Camptotheca acuminata. Topoisomerase-I is a nuclear enzyme that relieves torsional strain in DNA by opening single strand breaks.^[15] Once topoisomerase-I creates a single strand break, the DNA can rotate in front of the advancing replication fork. Topotecan intercalates between DNA bases in the topoisomerase-I clevage complex.^[16] The binding of topotecan in the cleavage complex prevents topoisomerase-I from religating the nicked DNA strand after relieving the strain.^[16] This intercalation therefore traps the topoisomerase-I in the cleavage complex bound to the DNA.^[16] When the replication-fork collides with the trapped topoisomerase-I, DNA damage occurs.^[16] The unbroken DNA strand breaks and mammalian cells cannot efficiently repair these double strand breaks.^[17] The accumulation of trapped topoisomerase-I complexes is a known response to apoptotic stimuli.^[18] This disruption prevents DNA replication and ultimately leads to cell death. This process leads to breaks in the DNA strand resulting in apoptosis.

Side effects

Myelosuppression
Diarrhea
Increased susceptibility to infections

Generic versions

Two generic versions have been approved in the European Union. In Nov 2010 the US FDA approved a generic version.^[19]^[20]

References

^ "Clinical Pharmacology & Therapeutics - Wiley Online Library".
^ "Abstracts".
^ "Archived copy". Archived from the original on January 19, 2009. Retrieved February 7, 2009.
^ "FDA Approval for Topotecan Hydrochloride". National Cancer Institute.
^ "Archived copy". Archived from the original on November 7, 2008. Retrieved February 7, 2009.
^ "Archived copy". Archived from the original on June 26, 2009. Retrieved February 7, 2009.
^ "GSK Receives Approval for Hycamtin (topotecan) Capsules for theTreatment of Relapsed Small Cell Lung Cancer".
^ (Huang et al)
^ ^a ^b Beaudet 2011.
^ (Malzac)
^ (Miller)
^ (Malpass)
^ (Huang)
^ (Aditi and Williams)
^ Pommier, Y., Leo, E., Zhang, H., Marchand, C. 2010. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem. Biol. 17: 421-433.
^ ^a ^b ^c ^d Pommier, Yves. "Topoisomerase I inhibitors: camptothecins and beyond". Nature Reviews Cancer. 6 (10): 789–802. doi:10.1038/nrc1977.
^ Staker, B.L.; et al. (2002). "The mechanism of topoisomerase I poisoning by a camptothecin analog". PNAS. 99 (24): 15387–15392. doi:10.1073/pnas.242259599.
^ Bertrand, Richard; Solary, Eric; O'Connor, Patrick; Kohn, Kurt W.; Pommier, Yves (1994-04-01). "Induction of a Common Pathway of Apoptosis by Staurosporine". Experimental Cell Research. 211 (2): 314–321. doi:10.1006/excr.1994.1093.
^ "FDA Rubber-Stamps APP Pharma's Generic Topotecan for Small Cell Lung and Cervical Cancers". 30 Nov 2010.
^ DNA Topoisomerases and Cancer, Yves Pommier Editor, Humana Press 2012

Sources

Dagli, Aditi I.; Mueller, Jennifer; Williams, Charles A. (1993-01-01). Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora JH; Bird, Thomas D.; Fong, Chin-To; Mefford, Heather C., eds. Angelman Syndrome. Seattle (WA): University of Washington, Seattle. PMID 20301323.
Bailus, Barbara J.; Segal, David J. (2014-01-01). "The prospect of molecular therapy for Angelman syndrome and other monogenic neurologic disorders". BMC Neuroscience. 15: 76. doi:10.1186/1471-2202-15-76. ISSN 1471-2202. PMC 4069279. PMID 24946931.
Beaudet, Arthur L. (2011-12-21). "Drugs to awaken a paternal gene". Nature. 481 (7380): 150–152. doi:10.1038/nature10784. ISSN 0028-0836. PMC 3638729. PMID 22190038.

External links

NCI Drug Dictionary Definition of Topotecan
NCI Drug Information for Patients
Use for ovarian cancer

UpToDate Contents

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1. 成人における抗癌剤の投与 dosing of anticancer agents in adults
2. 難治性および再発性の小細胞肺癌の治療 treatment of refractory and relapsed small cell lung cancer
3. 上皮性卵巣癌、卵管癌、または腹膜癌の再発に対する薬物療法：プラチナ製剤抵抗性癌 medical treatment for relapsed epithelial ovarian fallopian tubal or peritoneal cancer platinum resistant disease
4. 進展型小細胞肺癌：初期マネージメント extensive stage small cell lung cancer initial management
5. High-grade gastroenteropancreatic neuroendocrine carcinoma

English Journal

Identification of compounds that modulate retinol signaling using a cell-based qHTS assay.

Chen Y1, Sakamuru S2, Huang R2, Reese DH3, Xia M2.
Toxicology in vitro : an international journal published in association with BIBRA.Toxicol In Vitro.2016 Apr;32:287-96. doi: 10.1016/j.tiv.2016.01.011. Epub 2016 Jan 25.
In vertebrates, the retinol (vitamin A) signaling pathway (RSP) controls the biosynthesis and catabolism of all-trans retinoic acid (atRA), which regulates transcription of genes essential for embryonic development. Chemicals that interfere with the RSP to cause abnormal intracellular levels of atRA
PMID 26820057

First case of type IV hypersensitivity to periocular topotecan.

Graham F1, Superstein R2, Carret AS3, Paradis L1, Hamel P2, Des Roches A4.
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.Ann Allergy Asthma Immunol.2016 Mar 25. pii: S1081-1206(16)30007-2. doi: 10.1016/j.anai.2016.03.001. [Epub ahead of print]
PMID 27021003

Pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinolines: Novel compounds that reverse ABCG2-mediated resistance in cancer cells.

Karthikeyan C1, Malla R2, Ashby CR Jr3, Amawi H4, Abbott KL5, Moore J6, Chen J4, Balch C4, Lee C6, Flannery PC5, Trivedi P1, Faridi J2, Pondugula SR5, Tiwari AK7.
Cancer letters.Cancer Lett.2016 Mar 21. pii: S0304-3835(16)30180-X. doi: 10.1016/j.canlet.2016.03.030. [Epub ahead of print]
Overexpression of ATP-binding cassette transporter (ABC) subfamily G2 in cancer cells is known to elicit a MDR phenotype, ultimately resulting in cancer chemotherapy failure. Here, we report, for the first time, the effect of eight novel pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline (IND) derivati
PMID 27012188

Japanese Journal

A phase II study of amrubicin and topotecan combination therapy in patients with relapsed or extensive-disease small-cell lung cancer: Okayama Lung Cancer Study Group Trial 0401

Nogami Naoyuki,Hotta Katsuyuki,Kuyama Shoichi,Kiura Katsuyuki,Takigawa Nagio,Chikamori Kenichi,Shibayama Takuo,Kishino Daizo,Hosokawa Shinobu,Tamaoki Akihiko,Harita Shingo,Tabata Masahiro,Ueoka Hiroshi,Shinkai Tetsu,Tanimoto Mitsune
Lung Cancer 74(1), 80-84, 2011-10
… We conducted a phase II trial of amrubicin (a topoisomerase II inhibitor) and topotecan (a topoisomerase I inhibitor) in chemotherapy-naïve and relapsed SCLC patients. … Methods: Amrubicin (35 mg/m(2)) and topotecan (0.75 mg/m(2)) were administered on days 3-5 and 1-5, respectively. … Conclusion: This phase II study showed the favorable efficacy and moderate safety profiles of a topotecan and amrubicin two-drug combination especially in relapsed patients with ED-SCLC. …
NAID 120003497042

研究奨励賞受賞論文白金製剤耐性卵巣癌におけるAkt/VEGFをターゲットとした分子標的薬としてのトポテカンの機能解析

恒遠啓示
大阪医科大学雑誌 70(2), 100-106, 2011-09
NAID 40019018765

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★リンクテーブル★

リンク元	「イリノテカン」「トポテカン」

「イリノテカン」

Topotecan
Systematic (IUPAC) name
	(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione monohydrochloride
Clinical data
Trade names	Hycamtin
AHFS/Drugs.com	Monograph
MedlinePlus	a610007
Pregnancy; category	AU: D; US: D (Evidence of risk); ;
Routes of; administration	Intravenous infusion, oral (capsules)
Legal status
Legal status	UK: POM (Prescription only); US: ℞-only;
Pharmacokinetic data
Bioavailability	31.4 % in humans
Protein binding	35%
Metabolism	Hepatic
Biological half-life	2–3 hours
Excretion	Renal
Identifiers
CAS Number	123948-87-8 119413-54-6 (hydrochloride)
ATC code	L01XX17 (WHO)
PubChem	CID 60700
IUPHAR/BPS	7101
DrugBank	DB01030
ChemSpider	54705
UNII	7M7YKX2N15
KEGG	D08618
ChEMBL	CHEMBL84
Chemical data
Formula	C23H23N3O5 •HCl
Molar mass	457.9 g/mol
	SMILES O=C\1N4\C(=C/C2=C/1COC(=O)[C@]2(O)CC)c3nc5c(cc3C4)c(c(O)cc5)CN(C)C ;
	InChI InChI=1S/C23H23N3O5/c1-4-23(30)16-8-18-20-12(9-26(18)21(28)15(16)11-31-22(23)29)7-13-14(10-25(2)3)19(27)6-5-17(13)24-20/h5-8,27,30H,4,9-11H2,1-3H3/t23-/m0/s1 ; Key:UCFGDBYHRUNTLO-QHCPKHFHSA-N ;
(what is this?) (verify)

　　[★]

英: irinotecan IRT, CPT-11
同: 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin]
化: 塩酸イリノテカン irinotecan hydrochloride、イリノテカン塩酸塩
商: カンプト、トポテシン
関: 抗悪性腫瘍薬; 抗腫瘍性植物成分製剤

概念

抗悪性腫瘍薬の一種。
camptothecinのアナログ

作用機序

トポイソメラーゼの機能を阻害してDNA合成を阻害する

block topoisomerase function

同じグループの薬剤

camptothecins

「トポテカン」

　　[★]

英: topotecan
関: ノギテカン、抗悪性腫瘍薬

[1] "Clinical Pharmacology & Therapeutics - Wiley Online Library".

[2] "Abstracts".

[3] "Archived copy". Archived from the original on January 19, 2009. Retrieved February 7, 2009.

[4] "FDA Approval for Topotecan Hydrochloride". National Cancer Institute.

[5] "Archived copy". Archived from the original on November 7, 2008. Retrieved February 7, 2009.

[6] "Archived copy". Archived from the original on June 26, 2009. Retrieved February 7, 2009.

[7] "GSK Receives Approval for Hycamtin (topotecan) Capsules for theTreatment of Relapsed Small Cell Lung Cancer".

[8] (Huang et al)

[FOOTNOTEBeaudet2011-9] Beaudet 2011.

[10] (Malzac)

[11] (Miller)

[12] (Malpass)

[13] (Huang)

[14] (Aditi and Williams)

[15] Pommier, Y., Leo, E., Zhang, H., Marchand, C. 2010. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem. Biol. 17: 421-433.

[:0-16] Pommier, Yves. "Topoisomerase I inhibitors: camptothecins and beyond". Nature Reviews Cancer. 6 (10): 789–802. doi:10.1038/nrc1977.

[17] Staker, B.L.; et al. (2002). "The mechanism of topoisomerase I poisoning by a camptothecin analog". PNAS. 99 (24): 15387–15392. doi:10.1073/pnas.242259599.

[18] Bertrand, Richard; Solary, Eric; O'Connor, Patrick; Kohn, Kurt W.; Pommier, Yves (1994-04-01). "Induction of a Common Pathway of Apoptosis by Staurosporine". Experimental Cell Research. 211 (2): 314–321. doi:10.1006/excr.1994.1093.

[19] "FDA Rubber-Stamps APP Pharma's Generic Topotecan for Small Cell Lung and Cervical Cancers". 30 Nov 2010.

[20] DNA Topoisomerases and Cancer, Yves Pommier Editor, Humana Press 2012

匿名

検索

案内

案内

topotecan