DNA Alkylator

After being incubated, rat liver slices show alkylating activity for thio-TEPA. At all doses of 2, 5, and 10 mM, thio-TEPA does not accumulate in rat liver slices and has no effect on their viability[1].

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In precision-cut rat liver slice incubations, Thiotepa was metabolized to its oxo-analogue TEPA (N,N',N''-triethylenephosphoramide). The conversion followed first-order kinetics. [1]
Incubation of liver slices with Thiotepa (concentrations ranging from 5.2 to 104 µM) resulted in a 30%–50% increase in 4-(nitrobenzyl)-pyridine (NBP) alkylating activity in the buffer, which was independent of drug concentration. This increase showed a significant time-dependent correlation for Thiotepa but not for TEPA, suggesting the possible formation of unknown active metabolites beyond TEPA. [1]

During the first 10 weeks, donor-type blood chimerism is enhanced by thio-TEPA (20 mg/kg, i.p.) combined with total body irradiation (TBI), but it is not significantly higher than that of the TBI group alone. In mice, thio-TEPA alone enhances engraftment over the short and long terms[2].

Precision-cut rat-liver slices were used to study the metabolism of the alkylating agent N,N',N''-triethylenethiophosphoramide (thio-TEPA). Exposure to high concentrations (1-10 mM) of thio-TEPA for 6 h did not prove to be toxic to the liver slices as indicated by insignificant leakage of potassium from the cells. The time course of the disappearance of thio-TEPA (initial concentration, 5.2 microM) from the buffer during incubation followed first-order kinetics. Formation of N,N'N''-triethylenephosphoramide (TEPA) apparently accounted for the elimination of thio-TEPA. Pretreatment of the rats with phenobarbital significantly increased the reaction rate. Conversely, pretreatment with the cytochrome P-450 inhibitor allylisopropylacetamide significantly reduced the metabolic rate. The elimination of thio-TEPA and formation of TEPA occurred independently of thio-TEPA concentration, which ranged from 5.2 to 104 microM. Thio-TEPA's oxo-analogue TEPA, which was not further metabolized, was the only metabolite identified. However, a significantly time-related increase in 4-(nitrobenzyl)-pyridine (NBP) alkylating activity was observed following incubation of liver slices with thio-TEPA but not after their incubation with TEPA. This may possibly indicate the formation of unknown active metabolites[1].

Liver Slice Viability Assay (Potassium Leakage): Precision-cut rat liver slices were incubated with Thiotepa at concentrations of 1, 2, 5, and 10 mM for up to 24 hours. Intracellular potassium (K⁺) content was measured by flame photometry and expressed relative to DNA content. Viability was assessed by the extent of K⁺ leakage from cells. [1]
Drug Metabolism in Liver Slices: Liver slices were incubated with Thiotepa in Krebs-Henseleit buffer. Concentrations of Thiotepa and its metabolite TEPA in the incubation medium were measured at various time points using gas chromatography. The NBP alkylating activity in the medium was determined colorimetrically. [1]

Thiotepa (TT) has long been considered for inclusion in clinical bone marrow transplant (BMT) conditioning regimens in an attempt to prevent allograft rejection and leukemia relapse. These studies have been encouraged by initial murine experiments showing a clear improvement in allogeneic bone marrow engraftment with addition of TT to total body irradiation (TBI) where it was assumed that TT enhances donor-type chimerism via ablation of competing stem cells in the recipient. The aim of the present study was to re-evaluate the hematological toxicity of TT among different stem cell subsets that included primitive cells capable of long-term repopulation and to assess how the combination of TT with TBI influences the development of donor engraftment in both syngeneic (B6-Gpi-1a --> B6-Gpi-1b) and H-2 compatible allogeneic (BALB.B10 --> B6) BMT models. At 24 h after TT (20 mg/kg) the femoral content of different stem cell subsets was determined from the frequency of transient repopulating, and the more primitive cobblestone area-forming, cells (CAFCs) growing in stroma-supported cultures. This assay showed a large TT-induced depletion (2% survival) of early clones developing at day 7 in culture but survival recovered towards normal for later appearing clones developing from more primitive CAFC subsets. The sparing of these primitive stem cells was reflected as undetectable levels of donor marrow repopulation in recipients given TT followed by syngeneic BMT. Addition of TT to TBI did not significantly improve long-term engraftment of syngeneic marrow while this combination had a dramatic effect in allogeneic BMT by preventing allograft rejection. In this respect TT shares similar properties with cyclophosphamide and suggests that the large improvement of allogeneic stem cell engraftment is attributable to the immune suppressive properties of TT rather than to its toxicity against host primitive stem cells[2].

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Rat Pretreatment for Liver Slice Studies: Male Sprague-Dawley rats (250–350 g) were used. To induce cytochrome P-450 activity, rats received phenobarbital (80 mg/kg i.p.) daily for 3 days before sacrifice. To inhibit cytochrome P-450 activity, rats received allylisopropylacetamide (AIA, 100 mg/kg i.p.) 1 hour before sacrifice. Rats were killed by decapitation, and livers were immediately excised for slice preparation. [1]
Liver Slice Preparation and Incubation: Excised livers were placed in cold, aerated buffer. Precision-cut liver slices (dry weight 7.5–10 mg) were prepared using a mechanical slicer. Two slices were placed on a roller screen inside a 20-ml scintillation vial containing 1.7 ml of incubation medium (Krebs-Henseleit buffer or Waymouth's MB 752/1 medium) supplemented with Thiotepa. Vials were gassed with 95% O₂/5% CO₂, sealed, and rotated horizontally at 4 rpm at 37°C. A 30-minute preincubation in drug-free medium preceded transfer to drug-containing medium for experimental incubations. [1]

Absorption, Distribution and Excretion
In a 34-year-old patient with metastatic cecal cancer, urinary excretion was 63% following intravenous administration of 0.3 mg/kg of 14C-labeled thiotepa and its metabolites. [446 +/- 63 mL/min [Women aged 45 to 84 years with advanced ovarian cancer receiving intravenous infusions of 60 mg and 80 mg thiotepa every 4 weeks in subsequent treatment cycles] In humans, 50% of 14C-labeled thiotepa injected intravenously or locally into the tumor is excreted within the first 6 hours, with only low levels remaining after 48 hours. Oral absorption of (14)C-thiotepa varies: less than 1% of the injected dose recovered in the urine is unmetabolized.
...Five minutes after intravenous or arterial injection of labeled thiotepa in Sprague-Dawley rats, the levels of radioactivity in plasma, heart, kidneys, and lungs were slightly higher than in other organs; 94-98% of the intravenously injected radioactive material was excreted in urine within 8.5 hours. The majority of the radioactive material in urine was unmetabolized thiotepa. Tris(1-aziridinyl)phosphine oxide (tepa) accounted for approximately 30% of the radioactivity.
One hour after intraperitoneal injection of 9.3 mg/kg body weight of thiotepa in Sprague-Dawley rats, radioactivity was detected in plasma (5.4%), peritoneal fluid (26%), urine (1.9%), kidneys (0.7%), liver (3.8%), lungs (0.6%), and muscle (25.9%).
In patients with normal renal function, thiotepa, triethylenephosphoramide (TEPA), and unidentified metabolites with alkylating activity were all excreted in urine. Within 24–48 hours after administration, the urinary excretion of thiotepa, TEPA, and unidentified metabolites with alkylating activity was approximately 0.1–1.5%, 4%, and 13–24% of the administered dose, respectively. The parent drug was completely excreted in the urine within 6–8 hours after administration. Fecal excretion of the drug and its metabolites has not been studied. Following intravenous administration of high doses of thiotepa, the drug appears to be excreted in large quantities through sweat. For more complete data on absorption, distribution, and excretion of thiotepa (14 items), please visit the HSDB records page. Metabolites/Metabolites Following a single intravenous injection of (32) P-thiotepa in rats, rabbits, and dogs, the major metabolite in the urine was thiotepa, which is also an alkylating agent. However, most of the radioactive material in mouse urine was recovered as inorganic phosphate.
...In Sprague-Dawley rats, 5 minutes after intravenous or arterial injection of labeled thiotepa, the levels of radioactivity in plasma, heart, kidneys, and lungs were slightly higher compared to other organs; 94-98% of the intravenously injected radioactive material was excreted in urine within 8.5 hours. The majority of the radioactive material in urine was associated with unmetabolized thiotepa; tris(1-aziridinyl)phosphine oxide (tepa) accounted for approximately 30% of the radioactive material.
In mice, thiotepa is rapidly metabolized to tris(1-aziridinyl)phosphine oxide (tepa): after 30 minutes, only tepa and inorganic phosphate were detected in urine and plasma. Mice possess a unique ability to completely degrade the drug to inorganic phosphate.
Thiotepa appears to be extensively metabolized in the liver primarily via the cytochrome P-450 microsomal enzyme system, mainly through oxidative desulfurization to triethylenephosphamide (TEPA). Although TEPA is the only metabolite detected and identified in plasma, there is evidence that other unidentified metabolites are also generated. In adults with normal renal and hepatic function, plasma drug concentrations decreased biphasically after rapid intravenous injection of thiotepa, with an initial half-life of approximately 6–12 minutes and a terminal half-life of 1.2–2.9 hours. The plasma elimination half-life of TEPA was approximately 10–21 hours. This study measured the urinary excretion of N,N',N"-triethylenethiophosphoramide (thiotepa) and its metabolites N,N',N"-triethylenephosphoramide (TEPA), N,N'-diethylene,N"-2-chloroethylphosphoramide (monochlorotepa), and thiotepa-mercaptourate in patients receiving high-dose chemotherapy regimens with thiotepa in combination with cyclophosphamide and carboplatin. The dose of thiotepa was 40 or 60 mg/L. mg/m², short-term intravenous infusion, twice daily for 4 days. During the administration period, urine samples were collected after each daily urination until 24–48 hours after the last thiotEPA infusion. The concentrations of thiotEPA, TEPA, and monochlorotEPA were determined by gas chromatography, and the concentration of thiotEPA-thiourate was determined by liquid chromatography-mass spectrometry. A direct injection method was used. ThiotEPA was detectable in urine 30 minutes after infusion and was still excreted 18 hours after the last infusion. All metabolites were detected in urine 1 hour after infusion. Patients with creatinine clearance greater than 140 mL/min had higher TEPA excretion rates than those with creatinine clearance less than 140 mL/min (12.8% vs. 4.9%, p=0.01). The lower the urine pH, the higher the proportion of monochlorotEPA excreted relative to TEPA excreted. (The text abruptly ends here, likely due to an incomplete sentence or missing information.) Patients treated with a mg/m² dose had a higher proportion of thiotepa-mercapturate excreted as a percentage of the dose. Thiotepa and monochlorotepa were excreted at only 0.5% of the dose, while TEPA and thiotepa-mercapturate were excreted at 11.1% of the dose.
Excretion route: Urinary excretion. A 34-year-old patient with metastatic cecal cancer received 0.3 mg/m² of thiotepa-mercapturate. The detection rate of 14C-labeled thiotepa and its metabolites in vivo was 63% after intravenous injection of mg/kg. Half-life: 1.5 to 4.1 hours. In a phase I study, 15 patients with residual ovarian cancer confined to the peritoneal cavity after first-line systemic chemotherapy received thiotepa treatment. A total of 50 cycles of intraperitoneal injection of thiotepa were administered, with doses ranging from 30 to 80 mg/m². …Peritoneal fluid concentration decreased rapidly with first-order kinetics, with a half-life of 0.96 ± 0.1 hours. …In the first few hours after intravenous injection of thiotepa, plasma thiotepa concentration decreased exponentially. In Swiss-Webster mice, at 5… After injection of thiotepa at mg/kg body weight, the first phase half-life was 0.21 minutes and the second phase half-life was 9.62 minutes. In adults with normal renal and hepatic function, plasma concentrations of the drug decreased in a biphasic manner after rapid intravenous injection of thiotepa, with an initial phase half-life of approximately 6-12 minutes and a terminal phase half-life of 1.2-2.9 hours. The plasma elimination half-life of triethylenephosphoramide (TEPA) was approximately 10-21 hours. In rat liver incubation experiments, using untreated rat liver slices, the elimination half-life (t₁/₂) of thiotepa from buffer was 2.23 ± 0.15 hours. Phenobarbital pretreatment significantly shortened the half-life to 0.91 ± 0.05 hours, while pretreatment with allyl isopropyl acetamide (AIA) significantly prolonged its duration of action to 3.23 ± 0.27 hours. [1] In the tested concentration range (5.2 Within 104 µM, the conversion of thiotepa to TEPA followed first-order kinetics. [1]
The metabolite TEPA was not further metabolized in the liver slice system. [1]
This study did not provide systemic pharmacokinetic parameters (absorption, distribution, excretion, in vivo half-life, bioavailability) for thiotepa. [1]

Toxicity Summary
Identification and Uses: Thiotepah forms crystals or small white crystalline flakes. Thiotepah is widely used in high-dose chemotherapy. Human Exposure and Toxicity: Based on sufficient evidence from human studies, thiotepah has been proven to be a human carcinogen. The main adverse reaction of thiotepah is hematologic toxicity, which is usually dose-related and cumulative. Adverse hematopoietic effects include leukopenia, anemia, thrombocytopenia, and pancytopenia, the latter of which can sometimes be fatal. Patients receiving thiotepah treatment must be closely monitored for hematologic status. Although the lowest white blood cell count may occur 10–14 days after weekly intravenous thiotepah, the initial effects on bone marrow may not appear until up to 30 days later. Because thiotepah can be absorbed through the serous membranes, intracavitary and intravesical instillation of thiotepah can produce varying degrees of systemic adverse reactions; there have been cases of death due to bone marrow suppression caused by systemic absorption of the drug following intravesical instillation of thiotepah. In high-dose thiotepa combined with autologous bone marrow transplantation, serious central nervous system disorders, liver damage, infection, nausea, vomiting, diarrhea, mucositis, rash, hemorrhagic cystitis, and cardiomyopathy may occur. Overdose can lead to hematopoietic toxicity, manifested as a decrease in white blood cell count and/or platelet count. Red blood cell count is not an accurate indicator of thiotepa toxicity. Patients may experience bleeding symptoms, be more susceptible to infection, and have decreased resistance to infection. Even at or slightly above the recommended therapeutic dose, thiotepa can cause life-threatening hematopoietic toxicity. Thiotepa has dose-dependent toxic effects on the hematopoietic system. Treatment of cultured human lymphocytes with thiotepa significantly increases the frequency of chromosomal aberrations. Thiotepa may cause fetal harm when used in pregnant women. Animal studies: Intravitreal injection of thiotepa at a concentration of 8 mg/mL in rabbit eyes has been reported to have no excessive inflammation or electroretinogram changes and was well tolerated. Corneal vascularization and cataracts developed in weaned rats treated with 1:445 or 1:1000 thiotepa eye drops for six consecutive weeks. Rats were injected weekly with thiotepa at a dose of 1 mg/kg body weight for 52 weeks. Malignant tumors appeared in 30% of the treated animals and in 6% of the control group. In pregnant mice, intraperitoneal injection of a single dose of 0.5–30 mg/kg body weight of thiotepa caused malformations. The minimum teratogenic dose was 1 mg/kg body weight; after injection of 10 mg/kg body weight, all fetuses showed malformations. In rats, injection of 5 mg/kg body weight of thiotepa resulted in significant developmental abnormalities and skeletal defects in the fetuses. Thiotepa interfered with spermatogenesis in hamsters and mice. In vivo, thiotepa induced dominant lethal mutations, chromosomal aberrations, micronuclei, and sister chromatid exchanges in rodents. In vitro, thiotepa induced sister chromatid exchanges and chromosomal aberrations in rodent cells. In vitro, thiotepa is mutagenic in both Chinese hamster cells and host-mediated mouse lymphoma cells. Thiotepa induces sex-linked recessive lethal mutations in Drosophila, causes sister chromatid exchange and chromosomal aberrations in plant cells, and is mutagenic to fungi and bacteria in both in vitro and host-mediated assays. Alkyl groups are linked to guanine bases in DNA, located at the 7th nitrogen atom of the imidazole ring. They inhibit tumor growth by cross-linking guanine nucleobases in the DNA double helix, directly attacking the DNA. This prevents the DNA strand from unwinding and dissociating. Since DNA replication requires unwinding and dissociation, cells cannot divide. The effects of these drugs are nonspecific. Hepatotoxicity: Elevated serum enzymes are common during thiotepa treatment, but are usually mild and resolve spontaneously without dose adjustment. Rare clinically significant acute liver injury has been reported with thiotepa, especially at high doses. In most cases, thiotepa is used in combination with other drugs known to cause liver injury; the specific role of thiotepa remains unclear. Thiotepa is often used in combination with other alkylating agents in pretreatment regimens for myeloablation in preparation for hematopoietic stem cell transplantation, and is therefore associated with the development of hepatic sinusoidal obstruction syndrome. Hepatic sinusoidal obstruction syndrome typically develops within 1 to 3 weeks after myeloablative or high-dose therapy, characterized by sudden onset of abdominal pain, hepatomegaly, weight gain, and ascites, followed by jaundice. Serum enzyme elevations are usually hepatocellular, with significantly elevated levels of serum transaminases and lactate dehydrogenase, while alkaline phosphatase elevations are less pronounced. In severe cases, prothrombin time is prolonged, and progressive liver failure occurs. Immune hypersensitivity and autoimmune features are uncommon. Mortality is high. Liver biopsy shows centrilobular necrosis and congestion, venous obstruction, and erythrocytes within the sinusoids. Probability score: D (Possibly a rare cause of clinically significant liver injury).

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Effects of Pregnancy and Lactation
◉ Overview of Medication Use During Lactation
Most sources suggest that mothers should avoid breastfeeding while receiving anti-tumor drug treatment, especially when using alkylating agents such as thiotepa. Drug instructions recommend that mothers should not breastfeed during treatment and for one week after their last dose of thiotepa. Chemotherapy may adversely affect the normal microbiota and chemical composition of breast milk. Women receiving chemotherapy during pregnancy are more likely to experience breastfeeding difficulties.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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Interactions
Methylxanthine drugs can enhance the killing effect of alkylating agents on human cancer cells; this phenomenon is attributed to their inhibition of DNA repair. Pentoxoxobromine is a non-toxic methylxanthine drug used clinically to treat intermittent claudication. This study investigated the efficacy of combined treatment with alkylating agents and other methylxanthines using in vitro cultured human cancer cells or mouse xenograft models. In in vitro cultured human bladder cancer cells, posttreatment with pentoxifylline, its major clinical metabolite, or caffeine increased the cytotoxicity of thiotepa by up to 10-fold (p<0.01); the required pentoxifylline concentrations (0.4–1.0 mM) achieved clinically achievable concentrations in the bladder after a non-toxic oral dose. In a modified subcapsular xenograft model using human bladder or breast cancer xenografts, posttreatment with pentoxifylline also enhanced the efficacy of thiotepa in vivo. Conversely, these combined treatments did not increase toxicity to normal tissues in animals, whether assessed by body weight, mortality, or histological changes in normal bladder urothelial tissue. ...
In cultured human lymphocytes, 2 mM vitamin C enhanced the sister chromatid exchange frequency induced by thiotepa or L-ethionine. However, vitamin C concentrations of 0.02 mM and 0.2 mM showed a protective effect against sister chromatid exchange rate induced by thiotepa or L-ethionine. 2 mM vitamin C caused delayed cell division in cell cultures treated with thiotepa or L-ethionine. The delayed cell division induced by thiotepa or L-ethionine was reversed in the presence of 0.02 mM or 0.2 mM vitamin C. The mitotic index was persistently inhibited in cell cultures treated with thiotepa or L-ethionine in the presence of 2 mM vitamin C. However, 0.02 mM vitamin C reversed the inhibition of the mitotic index induced by L-ethionine or thiotepa. These findings reveal the complexity of vitamin C interactions in biological systems and demonstrate that different concentrations of vitamin C can both induce and inhibit genotoxicity. Researchers tested the antimutagenic activity of dietary components chlorophyll, β-carotene, and alpha-linolenic acid (in its methyl ester form) against the potent mutagen thiotepa in Chinese hamsters. Each natural protective compound inhibited 70-85% of the mutagen-induced chromosome breakage. No additive effect was observed when two or three antimutagens were used simultaneously. Under the experimental conditions, methyl alpha-linolenic acid was the most effective antimutagen. Five women with metastatic breast cancer developed hyperpigmentation localized to skin covered with adhesive materials after receiving intravenous injections of N,N',N"-triethylenethiophosphoramide (thiotepa) and cyclophosphamide. Researchers measured thiotepa concentrations in covered and uncovered skin, plasma, adhesive bandages, and sweat-soaked gauze. The results showed that this alkylating agent is secreted to the skin surface via sweat, accumulates under adhesive bandages and ECG electrode pads, and produces local toxicity, leading to hyperpigmentation.

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Non-human toxicity values
Mouse intravenous LD50: 14,500 μg/kg
Mouse subcutaneous LD50: 19,500 μg/kg
Mouse oral LD50: 38 mg/kg
Rat intravenous LD50: 9400 ug/kg
Rat intraperitoneal LD50: 8 At concentrations up to 10 mM, thiotepa did not induce significant potassium (K⁺) leakage in rat liver sections during a 6-hour incubation period, indicating no acute cytotoxicity under these conditions. [1] After 12 hours of incubation, significant K⁺ leakage was observed at the highest concentration (10 mM). Concentration-dependent K⁺ leakage was observed after 24 hours. However, at a concentration of 1 mM (far higher than the concentration used in metabolic studies), K⁺ leakage was not significantly different from the control group throughout the incubation period. [1] This study did not report the classic in vivo toxicity parameters of thiotepa (LD50, organ toxicity, protein binding, drug interactions). [1]

[1]. Metabolism and alkylating activity of thio-TEPA in rat liver slice incubation. Cancer Chemother Pharmacol. 1991;28(6):441-7.

[2]. Thiotepa improves allogeneic bone marrow engraftment without enhancing stem cell depletion in irradiated mice. Bone Marrow Transplant. 1998 Feb;21(4):327-30.

Therapeutic Uses
Anti-tumor drugs, alkylating agents; myeloablative agonists. ClinicalTrials.gov is a registry and results database that indexes human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, action, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for patient health information) and PubMed (for citations and abstracts of academic articles in the medical field). Thiotepa is indexed in the database. Thiotepa (USP) for injection has been tried in the palliative treatment of various oncological diseases, but with mixed results. However, the most stable efficacy has been observed in the following tumors: 1. Breast adenocarcinoma; 2. Ovarian adenocarcinoma; 3. For the control of effusions caused by various diffuse or localized neoplastic diseases of the serous cavities; 4. For the treatment of superficial papillary carcinoma of the bladder. Although thiotepa has been largely superseded by other therapies, it is also effective against other lymphomas such as lymphosarcoma and Hodgkin's lymphoma. /Included on US product label/
Thiotepa has been used as an ophthalmic drop to prevent recurrence after surgical resection of pterygium; however, postoperative beta-ray irradiation is generally preferred as a prophylactic treatment due to its low recurrence rate and relative ease of administration. Many clinicians recommend limiting the use of thiotepa to the treatment of pterygium recurrence after postoperative beta-ray irradiation. /Not included on US product label/
For more complete data on the therapeutic uses of thiotepa (6 types), please visit the HSDB record page.

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Drug Warnings
Intraocular instillation of thiotepa may occasionally cause irritation or periorbital depigmentation; depigmentation usually occurs 6 months or longer after discontinuation of the drug. Intrathecal thiotepa injection has been associated with lower extremity weakness, pain, and spinal cord demyelination in some patients; transient lower extremity paresthesia has also been reported after intrathecal injection of hypertonic solutions of the drug.
Other reported adverse reactions to thiotepa include injection site pain, headache, dizziness, blurred vision, conjunctivitis, dysuria, urinary retention, amenorrhea, and a feeling of tightness in the throat. Some symptoms, such as hyperuricemia or febrile reactions and subcutaneous lesion exudation, may be due to tumor tissue breakdown. Lower abdominal pain, bladder irritation, and hematuria have been reported in some patients after intravesical injection of thiotepa; in rare cases, hemorrhagic chemical cystitis has also occurred.
Hypersensitivity reactions, including anaphylactic reactions, rash, urticaria, laryngeal edema, asthma, anaphylactic shock, and wheezing, have been reported in patients receiving thiotepa. In addition, there have been reports of contact dermatitis and hair loss. There have been reports of skin depigmentation after topical use of this drug. Nausea, vomiting, abdominal pain and anorexia have occasionally occurred after administration of thiotepa. There have also been reports of stomatitis and intestinal mucosal ulcers. For more complete data on thiotepa (15 in total), please visit the HSDB record page. Pharmacodynamics Unstable nitrogen-carbon groups alkylate DNA, causing irreparable DNA damage. They inhibit tumor growth by crosslinking guanine nucleobases in the DNA double helix, directly attacking DNA. This prevents the DNA strand from unwinding and separating. Since DNA replication requires unwinding and separation, cells will not be able to divide. The action of these drugs is nonspecific. Thiotepa is an alkylating agent. [1] Its main metabolite is TEPA, which is produced by an oxidative desulfurization reaction catalyzed by hepatic cytochrome P-450 enzymes (especially phenobarbital-inducible enzymes). [1]
The increased NBP alkylation activity observed after incubation of liver sections with thiotepa exceeded the range that could be explained by thiotepa and TEPA, suggesting the possible generation of other unidentified active metabolites. [1]
The liver section model maintained tissue integrity and could be used to study the metabolism of thiotepa under experimental conditions, without the observation of significant drug toxicity. [1]

C6H12N3PS

189.2183

189.048

C, 38.09; H, 6.39; N, 22.21; P, 16.37; S, 16.95

52-24-4

55-98-1 (Busulfan); 299-75-2 (Treosulfan)

5453

White to off-white solid powder

1.5±0.1 g/cm3

270.2±23.0 °C at 760 mmHg

54-57 °C

117.2±22.6 °C

0.0±0.6 mmHg at 25°C

1.709

0.52

0

4

3

11

194

0

S=P(N1C([H])([H])C1([H])[H])(N1C([H])([H])C1([H])[H])N1C([H])([H])C1([H])[H]

FOCVUCIESVLUNU-UHFFFAOYSA-N

InChI=1S/C6H12N3PS/c11-10(7-1-2-7,8-3-4-8)9-5-6-9/h1-6H2

tri(aziridin-1-yl)phosphine sulfide

NSC-6396; AI3 24916; WR45312; NSC 6396; AI324916; WR 45312; NSC6396; AI3-24916; Girostan; thiophosphoramide; thiophosphamide; THIO-TEPA; Triethylenethiophosphoramide; Thiophosphamide; Thiofozil; Tiofosfamid; triethylene thiophosphoramide. trade names: Girostan; STEPA; TESPA; Thiofozil; Thioplex; Tifosyl. Foreign brand names: Ledertepa; Oncotiotepa; Onco Tiotepa; Tespamin; Tespamine; Thiotef; TioTEF; TSPA; WR45312.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 50~100 mg/mL ( 264.24 ~528.48 mM )
Water : ~100 mg/mL
Ethanol : ~100 mg/mL

Solubility in Formulation 1: 2.5 mg/mL (13.21 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (13.21 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (13.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)