Triethylenethiophosphoramide

Description

Thiotepa, a tertiary aziridine, is less reactive than quaternary aziridinium compounds and is classified as a weak alkylator. It is possible for the nitrogen atoms to be protonate before reacting with DNA (a positively charged aziridine is more reactive than the un-ionized aziridine), but the electron-withdrawing effect of the sulfur atom decreases the pKa to approximately six, which keeps the percentage ionized at pH 7.4 relatively low. Thiotepa undergoes oxidative desulfuration, forming an active cytotoxic metabolite known as TEPA (triethylenephosphoramide).

Chemical properties

white crystals or powder

Chemical properties

Thiotepa is a crystalline substance.

Originator

Thio-Tepa,Lederle,US,1959

The Uses of Triethylenethiophosphoramide

Tri(1-aziridinyl)phosphine sulfide is useful for the treatment of cancers, especially cancers resistant to chemotherapy. Antineoplastic. Thio-TEPA (N,N?N?-triethylenethiophosphoramide) is used as a cancer chemotherapeutic, alkylating agent. It is used to treat various kinds of cancer such as breast, ovarian and bladder cancer. It is also used as conditioning treatment prior to hematopoietic progenitor cell transplantation (HPCT)

The Uses of Triethylenethiophosphoramide

This substance is listed as a known human carcinogen. It is useful for the treatment of cancers, especially cancers resistant to chemotherapy. Antineoplastic.

The Uses of Triethylenethiophosphoramide

suzuki reaction

The Uses of Triethylenethiophosphoramide

antiseborrheic, antipruritic

The Uses of Triethylenethiophosphoramide

Insect sterilant.

What are the applications of Application

Thio-TEPA is an alkylating agent

Indications

ThioTEPA is used a as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients. Also, when high dose chemotherapy with HPCT support it is appropriate for the treatment of solid tumours in adult and paediatric patients.

Background

N,N'N'-triethylenethiophosphoramide (ThioTEPA) is a cancer chemotherapeutic member of the alkylating agent group, now in use for over 50 years. It is a stable derivative of N,N',N''- triethylenephosphoramide (TEPA). It is mostly used to treat breast cancer, ovarian cancer and bladder cancer. It is also used as conditioning for Bone marrow transplantation. Its main toxicity is myelosuppression.

Indications

Although thiotepa is chemically less reactive than the nitrogen mustards, it is thought to act by similar mechanisms. Its oral absorption is erratic. After intravenous injection, the plasma half-life is less than 2 hours. Urinary excretion accounts for 60 to 80% of eliminated drug.
Thiotepa has antitumor activity against ovarian and breast cancers and lymphomas. However, it has been largely supplanted by cyclophosphamide and other nitrogen mustards for treatment of these diseases. It is used by direct instillation into the bladder for multifocal local bladder carcinoma.
Nausea and myelosuppression are the major toxicities of thiotepa. It is not a local vesicant and has been safely injected intramuscularly and even intrathecally.

Definition

ChEBI: Thiotepa is a member of aziridines.

Manufacturing Process

A solution of 30.3 parts of triethylamine and 12.9 parts of ethylenimine in 180 parts of dry benzene is treated with a solution of 16.9 parts of thiophosphoryl chloride in 90 parts of dry benzene at 5°C to 10°C. Triethylamine hydrochloride is filtered off. The benzene solvent is distilled from the filtrate under reduced pressure and the resulting crude product is recrystallized from petroleum ether. The N,N',N''-triethylenethiophosphoramide had a melting point of 51.5°C.

Therapeutic Function

Antineoplastic

General Description

Odorless white crystalline solid.

General Description

The early success of the nitrogen mustards led researchers toinvestigate other compounds that contained a preformed aziridinering, and thiotepa resulted from this work. Thiotepa containingthe thiophosphoramide functionality was found to bemore stable than the oxa-analog (TEPA) but is metabolicallyconverted to TEPA by desulfuration in vivo.Thiotepa incorporatesa less reactive aziridine ring compared with thatformed in mechlorethamine. The adjacent thiophosphoryl iselectron withdrawing and, therefore, reduces the reactivity ofthe aziridine ring system. Although thiotepa is less reactivethan many other alkylating agents, it has been shown to formcross-links.

Air & Water Reactions

Water soluble.

Reactivity Profile

Triethylenethiophosphoramide polymerizes readily upon exposure to heat or moisture, especially at acidic pH.

Hazard

Confirmed carcinogen.

Fire Hazard

Flash point data for Triethylenethiophosphoramide are not available. Triethylenethiophosphoramide is probably combustible.

Biochem/physiol Actions

The unstable nitrogen-carbon groups alkylate with DNA which causes irreversible DNA damage. They stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands, directly attacking DNA. The DNA strands are unable to uncoil and separate which halts cell division.

Mechanism of action

Thiotepa and the TEPA metabolite readily enter the CNS after systemic administration, leading to dizziness, blurred vision, and headaches. More critically, these agents also are severe myelosuppressants and can induce leukopenia, thrombocytopenia, and anemia. Patients treated with thiotepa are at high risk for infection and hemorrhage.

Pharmacokinetics

The unstable nitrogen-carbon groups alkylate with DNA causing irrepairable DNA damage. They stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically.

Clinical Use

This antineoplastic agent is most commonly employed in the treatment of ovarian and breast cancers, as well as papillary carcinoma of the bladder.

Side Effects

Patients have died from myelosuppression after intravesically administered thiotepa. The drug also causes damage to the hepatic and renal systems. Dose and/or administration frequency should be increased slowly, even if the initial response to the drug is sluggish, or unacceptable toxicity may result.

Safety Profile

Confirmed human carcinogen producing leukemia. Poison by ingestion, intraperitoneal, intravenous, and subcutaneous routes. Experimental teratogenic data. Human systemic effects by parenteral route: paresthesia, bone marrow changes, and leukemia. Experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits very toxic fumes of POx, SOx, and NOx.

Synthesis

Thiotepa, tris(1-aziridinyl)phosphine sulfate (30.2.2.1), is made by reacting ethylenimine with phosphorous sulfochloride .

Potential Exposure

Used in the treatment of cancers resistant to chemotherapy. Antineoplastic: thiotepa has been prescribed for a wide variety of neoplastic diseases: adenocarcinomas of the breast and the ovary; superficial carcinoma of the urinary bladder; controlling intracavitary or localized neoplastic disease; lymphomas, such aslymphosarcomas and Hodgkin’s disease; as well as bronchogenic carcinoma.

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid concomitant use with clozapine.
Avoid concomitant use with other myelosuppressive agents. Administration

Carcinogenicity

Thiotepa is known to be a human carcinogen based on sufficient evidence from studies in humans. Thiotepa was first listed in the Second Annual Report on Carcinogens in 1981 as reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals and insufficient evidenceof carcinogenicity from studies in humans. Thiotepa was reclassified as known to be a human carcinogen in the Eighth Report on Carcinogens in 1998.

Metabolism

Not Available

Metabolism

Thiotepa is extensively metabolised to triethylenephosphoramide (TEPA), the primary metabolite, and some of the other metabolites have cytotoxic activity and are eliminated more slowly than the parent compound. It is excreted in the urine: less than 2
% of a dose is reported to be present as unchanged drug or its primary metabolite.

Shipping

UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

Toxicity evaluation

One of the principal bond disruptions is initiated by alkylation of guanine at the N-7 position, which severs the linkage between the purine base and the sugar and liberates alkylated guanines. This causes DNA cross-linking and prevents the replication of rapidly dividing cells.

Incompatibilities

Tris(aziridinyl)phosphine sulfide polymerizes readily upon exposure to heat or moisture, especially at acidic pH. Incompatible with strong oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides.

Waste Disposal

It is inappropriate and possibly dangerous to the environment to dispose of expired or waste pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.