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Teniposide (VM-26; HSDB-6546; NSC-122819; CCRIS-2058; Vumon; Vehem; EPT; PTG) is a semisynthetic podophyllotoxin derivative and chemotherapeutic agent mainly used in the treatment of childhood acute lymphocytic leukemia (ALL). It functions by combining with DNA and the enzyme topoisomerase II to form a ternary complex. This complex causes dose-dependent breaks in DNA, both single and double stranded, as well as protein cross-links, inhibition of DNA strand religation, and cytotoxicity. Teniposide acts during the cell cycle's late S or early G phases.
Physicochemical Properties
| Molecular Formula | C32H32O13S | |
| Molecular Weight | 656.65 | |
| Exact Mass | 656.156 | |
| Elemental Analysis | C, 58.53; H, 4.91; O, 31.67; S, 4.88 | |
| CAS # | 29767-20-2 | |
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| PubChem CID | 452548 | |
| Appearance | White to off-white solid powder | |
| Density | 1.6±0.1 g/cm3 | |
| Boiling Point | 864.3±65.0 °C at 760 mmHg | |
| Melting Point | 274 - 277ºC | |
| Flash Point | 476.5±34.3 °C | |
| Vapour Pressure | 0.0±0.3 mmHg at 25°C | |
| Index of Refraction | 1.697 | |
| LogP | 1.71 | |
| Hydrogen Bond Donor Count | 3 | |
| Hydrogen Bond Acceptor Count | 14 | |
| Rotatable Bond Count | 6 | |
| Heavy Atom Count | 46 | |
| Complexity | 1090 | |
| Defined Atom Stereocenter Count | 10 | |
| SMILES | S1C([H])=C([H])C([H])=C1C1([H])OC([H])([H])[C@]2([H])[C@]([H])([C@@]([H])([C@]([H])([C@@]([H])(O2)OC2([H])C3=C([H])C4=C(C([H])=C3[C@@]([H])(C3C([H])=C(C(=C(C=3[H])OC([H])([H])[H])O[H])OC([H])([H])[H])[C@@]3([H])C(=O)OC([H])([H])C32[H])OC([H])([H])O4)O[H])O[H])O1 |
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| InChi Key | NRUKOCRGYNPUPR-QBPJDGROSA-N | |
| InChi Code | InChI=1S/C32H32O13S/c1-37-19-6-13(7-20(38-2)25(19)33)23-14-8-17-18(42-12-41-17)9-15(14)28(16-10-39-30(36)24(16)23)44-32-27(35)26(34)29-21(43-32)11-40-31(45-29)22-4-3-5-46-22/h3-9,16,21,23-24,26-29,31-35H,10-12H2,1-2H3/t16-,21+,23+,24-,26+,27+,28+,29+,31+,32-/m0/s1 | |
| Chemical Name | (5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2-yl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one | |
| Synonyms | VM26; NSC-122819; VM-26; HSDB 6546; NSC 122819; VM 26; HSDB-6546; NSC122819; HSDB6546; CCRIS 2058. Trade name: Vumon; Vehem. Abbreviations: EPT; PTG | |
| HS Tariff Code | 2934.99.9001 | |
| Storage |
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. |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Topoisomerase II |
| ln Vitro | Teniposide is a topoisomerase II inhibitor. Teniposide (VM-26, 0.15–45 mg/L) has an IC50 of 0.35 mg/L and inhibits Tca8113 cell proliferation in a dose-dependent manner. Tca8113 cells undergo apoptosis when exposed to 5 mg/L of Teniposide. Cells in Tca8113 cells are arrested at the G2/M phase by Teniposide (5.0 mg/L)[2]. With an IC50 of 1.3?±?0.34 μg/mL, Teniposide is active on patient-derived primary cultured glioma cells when the cells have a high level of miR-181b. In comparison to control cells, Teniposide-treated cells exhibit reduced viability, and when MDM2 is suppressed, the IC50 drops from 5.86?±?0.36 μg/mL to 2.90?±?0.35 μg/mL. Via the mediation of MDM2, Teniposide also reduces the viability of glioma cells expressing high levels of miR-181b[3]. |
| ln Vivo | Teniposide (0.5 mg/kg, i.p.) profoundly raises the frequencies of micronucleated polychromatic erythrocytes (MNPCEs), a finding that is directly linked to bone marrow toxicity due to the significant suppression of bone marrow. The frequencies of BrdU-labeled sperm are significantly reduced by Teniposide (24 mg/kg, i.p.). Additionally, Teniposide (12, 24 mg/kg, i.p.) significantly induces disomic sperm in male mouse germ cells[1]. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the dose. 10.3 mL/min/m2 Teniposide was detected in intracerebral tumors at concentrations of 0.05-1.12 ug/g tissue in 11 patients given 100-150 mg/sq m teniposide 1.5-3 hr before tumor resection. The concentrations in adjacent normal brain tissue were low (< 0.9 ug/g tissue) in three patients and undetectable (< 0.05 ug/g tissue) in the others Teniposide was detected in one patient who died three days after a cumulative intravenous dose of 576 mg, the highest concentrations occurring in the spleen, prostate, heart, large bowel, liver and pancreas. It is not known whether teniposide is distributed into breast milk. Elimination: Renal: 4 to 12% of a dose as unchanged teniposide. In a study of tritium-labeled teniposide in adults, 44% of the radiolabel (parent compound and metabolites) was recovered in urine within 120 hours after dosing. Fecal: 0 to 10% of a dose. For more Absorption, Distribution and Excretion (Complete) data for TENIPOSIDE (6 total), please visit the HSDB record page. Metabolism / Metabolites In isolated human liver preparations, cytochrome P450 mixed-function isozymes catalysed metabolism of the (pendant) E-ring to O-demethylated and catechol metabolites. This metabolism was subsequently attributed primarily to CYP3A4 activity and to a lesser degree to CYP3A5. Peroxidase-mediated O-demethylation of teniposide has also been reported. In children given teniposide, the main metabolite in serum and urine was reported to be the hydroxy acid, formed by opening of the lactone ring; the cis-isomer, which may be a degradation product formed during storage, was also detected. The aglycone, formed by loss of the glucopyranoside moiety, was not detected (Evans et al., 1982). The hydroxy acid has not been found in plasma or urine in other studies with high doses of teniposide, and no changes in the measured concentration of teniposide in these samples was found after incubation with glucuronidase, indicating formation of little or none of the proposed glucuronide metabolites (Holthuis et al., 1987). In another study, however, 6% of the administered dose of teniposide was excreted in the urine as parent drug over 24 h, and a further 8% as a proposed aglycone glucuronide, which was not formally identified. In general, the effects of teniposide in mammalian cells in vitro occurred in the absence of exogenous metabolic activation. Various metabolic species of teniposide have been identified, but their mutagenic properties have not been studied. Teniposide has known human metabolites that include Teniposide catechol. Biological Half-Life 5 hours Terminal half life: 5 hours. NOTE: Plasma teniposide concentrations decline biexponentially following intravenous infusion. It has a multiphasic pattern of clearance from plasma. After distribution, half lives of 4 hours and 10 to 40 hours are observed. |
| Toxicity/Toxicokinetics |
Interactions Concurrent administration of ciclosporin at 5 mg/kg bw over 2 h, followed by 30 mg/kg bw over 48 h intravenously, increased the AUC for teniposide by 50%, due to a reduction in clearance. Conversely, concurrent administration of phenytoin increased the clearance rate of teniposide to 32 mL/min per m2 from 13 mL/min per m2 for control patients. |
| References |
[1]. Molecular cytogenetic evaluation of the aneugenic effects of teniposide in somatic and germinal cells of male mice. Mutagenesis. 2012 Jan;27(1):31-9. [2]. Topoisomerase II trapping agent teniposide induces apoptosis and G2/M or S phase arrest of oral squamous cell carcinoma. World J Surg Oncol. 2006 Jul 6;4:41. [3]. MiR-181b sensitizes glioma cells to teniposide by targeting MDM2. BMC Cancer. 2014 Aug 25;14:611. |
| Additional Infomation |
Teniposide can cause developmental toxicity according to state or federal government labeling requirements. Teniposide is a semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Teniposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent cells from entering into the mitotic phase of the cell cycle, and lead to cell death. Teniposide acts primarily in the G2 and S phases of the cycle. Teniposide is a Topoisomerase Inhibitor. The mechanism of action of teniposide is as a Topoisomerase Inhibitor. Teniposide is a semisynthetic derivative of podophyllotoxin with antineoplastic activity. Teniposide forms a ternary complex with the enzyme topoisomerase II and DNA, resulting in dose-dependent single- and double-stranded breaks in DNA, DNA: protein cross-links, inhibition of DNA strand religation, and cytotoxicity. This agent acts in the late S or early G phase of the cell cycle. (NCI04) A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Teniposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent cells from entering into the mitotic phase of the cell cycle, and lead to cell death. Teniposide acts primarily in the G2 and S phases of the cycle. Drug Indication Teniposide is used for the treatment of refractory acute lymphoblastic leukaemia Mechanism of Action The mechanism of action appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. Teniposide binds to and inhibits DNA topoisomerase II. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate. It is an inhibitor of DNA topoisomerase II enzymes: Teniposide is a DNA topoisomerase II poison that has been shown to promote DNA cleavage, with a strong preference for a C or T at position -1. Most of the mutational events reported in mammalian cells, including point mutations, chromosomal deletions and exchanges and aneuploidy, can be explained by this activity. Teniposide does not inhibit bacterial topoisomerases and may not mutate bacterial cells by the same mechanism as mammalian cells. Unlike many other DNA topoisomerase II poisons, teniposide does not bind to DNA, either covalently or by intercalation. Instead, it appears to interact directly with the DNA topoisomerase II enzyme. ... The drug appears to produce its cytotoxic effects by damaging DNA and thereby inhibiting or altering DNA synthesis. Teniposide has been shown to induce single-stranded DNA breaks; the drug also induces double-stranded DNA breaks and DNA-protein cross links. ... Teniposide appears to be cell cycle specific, inducing G2-phase arrest and preferentially killing cells in the G2 and late S phases. Therapeutic Uses Antineoplastic Agents; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors Teniposide is indicated, in combination with other approved anticancer agents, for induction therapy of refractory childhood acute lymphocytic (lymphoblastic) leukemia. /Included in US product labeling/ Teniposide is indicated as a single agent or in combination for therapy of refractory non-Hodgkin's lymphoma. /NOT included in US product labeling/ Teniposide is indicated as a single agent or in combination for therapy of refractory neuroblastoma. /NOT included in US product labeling/ Drug Warnings Since patients with Down's syndrome and leukemia may be particularly sensitive to myelosuppressive chemotherapy, initial dosage of teniposide should be reduced in such patients. There currently is insufficient experience with teniposide therapy in patients with impaired renal and/or hepatic function to make specific recommendations for dosage adjustment. However, the possibility that adjustment in teniposide dosage may be necessary in such patients should be considered. The major and dose-limiting adverse effect of teniposide is hematologic toxicity. Myelosuppression, which is dose related, can be severe when teniposide is used in combination with other chemotherapeutic agents for the treatment of acute lymphocytic leukemia (ALL). Early onset of profound myelosuppression with delayed recovery can be expected when using the doses and schedules of teniposide necessary for the treatment of refractory ALL, since bone marrow hypoplasia is a desired endpoint of therapy. Severe myelosuppression with resulting infection and bleeding may occur in patients receiving the drug. Infection and bleeding have occurred in about 12 and 5%, respectively, of pediatric patients receiving teniposide monotherapy. Pregnancy risk category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./ For more Drug Warnings (Complete) data for TENIPOSIDE (18 total), please visit the HSDB record page. Pharmacodynamics Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G 2 phase of the cell cycle. Teniposide prevents cell mitosis by causing single and double stranded DNA breaks as well as cross linking between protein and DNA. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.81 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.81 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5229 mL | 7.6144 mL | 15.2288 mL | |
| 5 mM | 0.3046 mL | 1.5229 mL | 3.0458 mL | |
| 10 mM | 0.1523 mL | 0.7614 mL | 1.5229 mL |