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an antineoplastic drug used to treat certain malignancies

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/02/12 09:25:34」(JST)

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N,N'N'-triethylenethiophosphoramide (ThioTEPA or thiotepa) is an alkylating agent used to treat cancer.

ThioTEPA is an organophosphorus compound with the formula SP(NC₂H₄)₃.^[1] It is an analogue of N,N',N''- triethylenephosphoramide (TEPA). This molecule features tetrahedral phosphorus and is structurally akin to phosphate. It is derived from aziridine and thiophosphoryl chloride.

History and use

ThioTEPA was first developed by American Cyanamid company in the early 1950s and was reported in 1953.^[2] ThioTEPA has been in use since the 1960s.

ThioTEPA has been designated as orphan drug by the European Medicines Agency on January 29, 2007, and by the United States Food and Drug Administration (FDA) on April 2, 2007, as a conditioning treatment prior to haematopoietic stem cell transplantation.^[3] The applicant for these orphan drug designations was the Italian company ADIENNE Pharma & Biotech, owner of the drug TEPADINA (INN: thiotepa).

Thiotepa is indicated, in combination with other chemotherapy medicinal products:

with or without total body irradiation (TBI), as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients;
when high dose chemotherapy with HPCT support is appropriate for the treatment of solid tumours in adult and paediatric patients.^[4]

Thiotepa has been previously used in the palliation of a wide variety of neoplastic diseases. The more consistent results have been seen in: adenocarcinoma of the breast, adenocarcinoma of the ovary, superficial papillary carcinoma of the urinary bladder and for controlling intracavitary effusions secondary to diffuse or localized neoplastic diseases of various serosal cavities.^[4]

Thiotepa is also used as intravesical chemotherapy in bladder cancer. Three patterns of usage is identified. 1) prophylactic - before taking cystoscopic biopsy, to prevent seeding of tumor cells; 2) adjunctive- at the time of biopsy; 3) therapeutic - to prevent recurrence after cystoscopic resection of bladder tumor (transurethral resection of bladder tumor - TURBT)

For therapeutic usage, thiotepa is given in 30 mg doses intravesically weekly for 4–6 weeks. Many studies have reported up to 55% of success rate. Main toxicity of intravesical therapy is due to systemic absorption causing myelosupression, which results in thrombocytopenia and leukopenia.

Thiotepa main toxicity is myelosuppression. The most serious complication of excessive therapy is bone marrow depression, causing leukopenia, thrombocytopenia, and anemia.^[5] Serious toxicity involving the hematologic, hepatic and respiratory system were considered as expected consequences of the conditioning regimen and transplant process.

Synthesis

Thiotepa synthesis: U.S. Patent 2,670,347 JP 55218

References

^ Maanen, M. J.; Smeets, C. J.; Beijnen, J. H. (2000). "Chemistry, pharmacology and pharmacokinetics of N,N',N" -triethylenethiophosphoramide (ThioTEPA)". Cancer Treatment Reviews 26 (4): 257–268. doi:10.1053/ctrv.2000.0170. PMID 10913381.
^ Sykes, M. P.; Karnofsky, D. A.; Philips, F. S.; Burchenal, J. H. (1953). "Clinical studies on triethylenephosphoramide and diethylenephosphoramide, compounds with nitrogen-mustard-like activity". Cancer 6 (1): 142–148. doi:10.1002/1097-0142(195301)6:1<142::AID-CNCR2820060114>3.0.CO;2-W.
^ "EMA Grants Adienne Marketing Rights for Tepadina". dddmag.com. Drug Discovery & Development. 19 March 2010. Retrieved 25 November 2011.
^ ^a ^b "URGENT – THIOTEPA UPDATE". Food and Drug Administration. ADIENNE Pharma & Biotech. 5 April 2011. Retrieved 25 November 2011.
^ Agnelli, G.; de Cunto, M.; Gresele, P.; del Favero, A. (1982). "Early onset life-threatening myelosuppression after low dose of intravesical thiotepa" (pdf). Postgraduate Medical Journal 58 (680): 380–381. doi:10.1136/pgmj.58.680.380. PMC 2426344. PMID 6812036.

External links

Thiotepa Official FDA information, side effects and uses on Drugs.com
Thiotepa on cancer.org

UpToDate Contents

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1. 筋層非浸潤性膀胱癌の治療 treatment of non muscle invasive bladder cancer
2. 軟髄膜転移の治療（癌性髄膜炎） treatment of leptomeningeal metastases carcinomatous meningitis
3. 非プラチナ製剤ベースの癌化学療法の神経学的合併症 neurologic complications of non platinum cancer chemotherapy
4. 造血細胞移植のための前処置療法 preparative regimens for hematopoietic cell transplantation
5. 従来の癌の化学療法による皮膚合併症 cutaneous complications of conventional chemotherapy agents

English Journal

T cell-depleted unrelated donor stem cell transplantation provides favorable disease-free survival for adults with hematologic malignancies.

Jakubowski AA, Small TN, Kernan NA, Castro-Malaspina H, Collins N, Koehne G, Hsu KC, Perales MA, Papanicolaou G, van den Brink MR, O'Reilly RJ, Young JW, Papadopoulos EB.SourceAdult Allogeneic Bone Marrow Transplant Service, Division of Hematologic-Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, New York.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.Biol Blood Marrow Transplant.2011 Sep;17(9):1335-42. Epub 2011 Jan 11.
We report a prospective phase II clinical trial in 35 adult patients (median age 40.5 years) with hematologic malignancies who received T cell-depleted, hematopoietic stem cell transplants from HLA-compatible, unrelated donors. The cytoreductive regimen consisted of hyperfractionated total-body irra
PMID 21232623

Phase I study of tandem high-dose chemotherapy with autologous peripheral blood stem cell rescue for children with recurrent brain tumors: A pediatric blood and marrow transplant consortium study.

Gilman AL, Jacobsen C, Bunin N, Levine J, Goldman F, Bendel A, Joyce M, Anderson P, Rozans M, Wall DA, Macdonald TJ, Simon S, Kadota RP.SourceLevine Children's Hospital, Charlotte, North Carolina. andrew.gilman@carolinashealthcare.org.
Pediatric blood & cancer.Pediatr Blood Cancer.2011 Sep;57(3):506-13. doi: 10.1002/pbc.22899. Epub 2010 Dec 1.
BACKGROUND: High-dose chemotherapy with autologous stem cell rescue (HDC/SCR) has produced responses and prolonged survival for some children with recurrent brain tumors, but is associated with considerable morbidity and mortality. A Phase I trial of two cycles of HDC/SCR for recurrent brain tumors
PMID 21744474

Japanese Journal

難治性小児悪性固形腫瘍に対するチオテパ+ブスルファンまたはチオテパ+メルファランによる大量化学療法の検討

大嶋宏一,菊地陽,望月慎史,外山大輔,内坂直樹,北野良博,内田広夫,西本博,栗原淳,野澤久美子,小熊栄二,岸本宏志,花田良二
小児がん : 小児悪性腫瘍研究会記録 45(3), 256-263, 2008-09-25
チオテパ大量療法を行った難治性小児悪性固形腫瘍21例について検討した.移植適応を,再発のために経過中に大量化学療法の適応を決定した救済移植群と,治療当初からの計画的移植群とに分けた.対象疾患の悪性度が高いにも関わらず,計画的移植群では再発後死亡はみられていない.一方,救済移植群では移植時の状態が寛解以外の症例は全例が移植後再発し,再発後には1例を除いて全員が原病死した.再発固形腫瘍では移植前に寛解 …
NAID 110007170703

チオテパ点眼を用いた翼状片手術成績 (特集第61回日本臨床眼科学会講演集(2))

二階堂寛俊
臨床眼科 62(4), 513-515, 2008-04
NAID 40015997674

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★リンクテーブル★

リンク元	「チオテパ」「thioplex」

「チオテパ」

Thiotepa
Systematic (IUPAC) name
	1,1',1''-phosphorothioyltriaziridine
Clinical data
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a682821
Pregnancy; category	AU: D; US: D;
Legal status	UK: POM; US: ℞-only;
Routes	IV, intracavitary, intravesical
Pharmacokinetic data
Metabolism	Hepatic (CYP2B, CYP3A)
Half-life	1.5-4.1 hours
Excretion	Renal; 6 hours for ThioTEPA; 8 hours for TEPA
Identifiers
CAS number	52-24-4
ATC code	L01AC01
PubChem	CID 5453
DrugBank	DB04572
ChemSpider	5254
UNII	905Z5W3GKH
KEGG	D00583
ChEMBL	CHEMBL671
Chemical data
Formula	C6H12N3PS
Molecular mass	189.23 g/mol
	SMILES S=P(N1CC1)(N2CC2)N3CC3;
	InChI InChI=1S/C6H12N3PS/c11-10(7-1-2-7,8-3-4-8)9-5-6-9/h1-6H2 ; Key:FOCVUCIESVLUNU-UHFFFAOYSA-N ;
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