ThioTEPA

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Thiotepa
ThioTEPA.svg
Systematic (IUPAC) name
1,1',1''-phosphorothioyltriaziridine
Clinical data
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a682821
Pregnancy cat.
Legal status
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 YesY
ATC code L01AC01
PubChem CID 5453
DrugBank DB04572
ChemSpider 5254 YesY
UNII 905Z5W3GKH YesY
KEGG D00583 YesY
ChEMBL CHEMBL671 YesY
Chemical data
Formula C6H12N3PS 
Mol. mass 189.23 g/mol
 N (what is this?)  (verify)

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[edit]

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[edit]

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

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ "EMA Grants Adienne Marketing Rights for Tepadina". dddmag.com. Drug Discovery & Development. 19 March 2010. Retrieved 25 November 2011. 
  4. ^ a b "URGENT – THIOTEPA UPDATE". Food and Drug Administration. ADIENNE Pharma & Biotech. 5 April 2011. Retrieved 25 November 2011. 
  5. ^ 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[edit]