Topoisomerase II
DNA topoisomerase II [2][3]
MDM2 (indirect target, sensitized by miR-181b) [3]

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].

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In oral squamous cell carcinoma (OSCC) cells, Teniposide (VM-26) induced concentration-dependent antiproliferative activity, with significant cell viability reduction at concentrations ≥10 μM. It triggered apoptosis, characterized by caspase-3 activation, PARP cleavage, and DNA fragmentation. The drug also caused cell cycle arrest at G2/M phase in some OSCC cell lines and S phase in others [2]
- In glioma cells, Teniposide (VM-26) exhibited antitumor activity, and its efficacy was enhanced by miR-181b overexpression. miR-181b targeted MDM2, downregulating its expression and promoting p53 accumulation, which synergistically augmented teniposide-induced cell death [3]
- Teniposide (VM-26) trapped DNA topoisomerase II, stabilizing the enzyme-DNA cleavage complex and preventing DNA strand religation, leading to DNA double-strand breaks and subsequent cell cycle arrest or apoptosis [2][3]

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].

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In male mice, intraperitoneal administration of Teniposide (VM-26) induced aneugenic effects in both somatic (bone marrow) and germinal (spermatogonia) cells. It caused numerical chromosome abnormalities, including aneuploidy and polyploidy, in a dose-dependent manner. The frequency of chromosomal aberrations was significantly higher in treated groups compared to controls [1]

DNA topoisomerase II activity assay: Purified DNA topoisomerase II was incubated with supercoiled plasmid DNA in reaction buffer at 37°C. Teniposide (VM-26) was added at serial concentrations (1-20 μM), and the mixture was incubated for 45 minutes. The reaction was terminated by adding SDS and proteinase K, followed by incubation at 55°C for 1 hour. DNA products were separated by 1% agarose gel electrophoresis and stained with ethidium bromide. The inhibition of topoisomerase II-mediated DNA relaxation was quantified by measuring the intensity of supercoiled DNA bands, confirming the drug’s ability to stabilize the enzyme-DNA cleavage complex [2][3]

OSCC cell antiproliferation, apoptosis, and cell cycle assay: OSCC cells were seeded in 96-well plates at 4×10³ cells/well and treated with Teniposide (VM-26) at concentrations of 1, 5, 10, 20 μM for 24, 48, 72 hours. Cell viability was measured using a colorimetric assay. For apoptosis detection, cells treated with 10 and 20 μM of the drug for 48 hours were stained with annexin V-FITC/PI and analyzed by flow cytometry; caspase-3 and PARP expression were detected by western blot. Cell cycle distribution was assessed by propidium iodide staining and flow cytometry [2]
- Glioma cell sensitization assay: Glioma cells were transfected with miR-181b mimic or negative control mimic for 24 hours, then treated with Teniposide (VM-26) at 5-15 μM for 48 hours. Cell viability was measured by a tetrazolium-based assay. MDM2 and p53 protein levels were detected by western blot, and MDM2 mRNA expression was quantified by RT-PCR [3]

Aneugenic effect mouse model: Male ICR mice (8-10 weeks old) were randomly divided into control and treatment groups (n=6 per group). Teniposide (VM-26) was dissolved in a suitable solvent and administered intraperitoneally at doses of 5, 10, 20 mg/kg. Control mice received an equal volume of solvent. Mice were sacrificed 24 hours after a single dose for bone marrow sampling, and 35 days after dosing for spermatogonia sampling. Chromosomal preparations were made from bone marrow cells and spermatogonia, and numerical chromosome abnormalities were analyzed by microscopic observation [1]

Absorption, Distribution and Excretion
4% to 12% of the dose is excreted unchanged in the urine. Radioactive material is excreted in the feces within 72 hours after administration, accounting for 0% to 10% of the administered dose. 10.3 mL/min/m² In 11 patients who received teniposide at a dose of 100–150 mg/m², administered 1.5–3 hours before tumor resection, teniposide was detected in brain tumor tissue at concentrations of 0.05–1.12 μg/g tissue. In three patients, lower drug concentrations were observed in adjacent normal brain tissue (< 0.9 μg/g tissue), while in the remaining patients, it was undetectable (< 0.05 μg/g tissue). Teniposide was detected in one patient who died three days after receiving a cumulative intravenous dose of 576 mg teniposide. The highest concentrations of teniposide were found in the spleen, prostate, heart, large intestine, liver, and pancreas.
It is currently unclear whether teniposide is excreted into breast milk.
Excretion routes: Renal: 4% to 12% of the dose is excreted unchanged teniposide. In a study of tritium-labeled teniposide in adults, 44% of the radiolabeled substance (parent compound and metabolites) was recovered in urine within 120 hours after administration. Fecal excretion: 0% to 10% of the dose.
For more complete data on absorption, distribution, and excretion of teniposide (6 items in total), please visit the HSDB record page.
Metabolism/Metabolites
In isolated human liver formulations, cytochrome P450 mixed-function isoenzymes catalyze (side chain) E-ring metabolism to O-demethylated metabolites and catechol metabolites. This metabolism is subsequently attributed primarily to CYP3A4 activity, and secondarily to CYP3A5. Peroxidase-mediated O-demethylation of teniposide has also been reported.
It has been reported that in children taking teniposide, the main metabolites in serum and urine are hydroxy acids formed by the opening of the lactone ring; cis isomers have also been detected, possibly degradation products formed during storage. Aglycones formed from the partial loss of glucosinolates were not detected (Evans et al., 1982). In other studies using high doses of teniposide, no hydroxy acids were found in plasma or urine, and the concentration of teniposide did not change after incubation with glucuronidase in these samples, indicating that little or no formation of the proposed glucuronide metabolites was observed (Holthuis et al., 1987). However, in another study, 6% of teniposide was excreted unchanged in urine within 24 hours, and another 8% was excreted as an unidentified aglycone glucuronide.
In general, the effects of teniposide in mammalian cells in vitro occur without exogenous metabolic activation. Several teniposide metabolites have been identified, but their mutagenic properties have not been investigated.
The known metabolites of teniposide include teniposide catechol.
Biological half-life
5 hours
Terminal half-life: 5 hours. Note: Following intravenous infusion, plasma teniposide concentrations show a biexponential decrease.
Plasma clearance follows a multiphasic pattern. Half-lives of 4 hours and 10 to 40 hours were observed after distribution.

Drug Interactions
Intravenous administration of cyclosporine (5 mg/kg body weight, 2 hours later, followed by intravenous administration of 30 mg/kg body weight, 48 hours later) increased the AUC of teniposide by 50%, due to its reduced clearance. Conversely, concomitant administration of phenytoin increased the clearance of teniposide from 13 mL/min/m² in the control group to 32 mL/min/m².

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Genetic Toxicity: Teniposide (VM-26) exhibited dose-dependent aneuploidy toxicity in male mice, inducing chromosomal number abnormalities in somatic cells (bone marrow) and germ cells (spermatogonia). The highest dose (20 mg/kg) resulted in a significant increase in the incidence of aneuploidy and polyploidy [1]

[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.

According to state or federal labeling requirements, teniposide may cause developmental toxicity. Teniposide is a semi-synthetic derivative of podophyllotoxin with antitumor activity. Teniposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces double-strand DNA breaks and prevents topoisomerase II from binding for repair. The accumulation of DNA breaks prevents cells from entering the mitotic phase of the cell cycle, ultimately leading to cell death. Teniposide primarily acts on the G2 and S phases of the cell cycle. Teniposide is a topoisomerase inhibitor. The mechanism of action of teniposide is as a topoisomerase inhibitor. Teniposide is a semi-synthetic derivative of podophyllotoxin with antitumor activity. Teniposide forms a ternary complex with topoisomerase II and DNA, leading to dose-dependent DNA single-strand and double-strand breaks, DNA-protein crosslinking, inhibition of DNA strand reconnection, and cytotoxicity. This drug acts on late S phase or early G1 phase of the cell cycle. (NCI04)
Teniposide is a semi-synthetic derivative of podophyllotoxin with antitumor activity. Teniposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces double-strand DNA breaks and prevents topoisomerase II from binding for repair. The accumulation of DNA breaks prevents cells from entering the mitotic phase of the cell cycle, ultimately leading to cell death. Teniposide primarily acts on the G2 and S phases of the cell cycle.

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Drug Indications
Teniposide is used to treat refractory acute lymphoblastic leukemia.

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Mechanism of Action
The mechanism of action of teniposide appears to be related to the inhibition of type II topoisomerase activity, as teniposide does not intercalate into DNA or bind strongly to DNA. Teniposide binds to DNA topoisomerase II and inhibits its activity. The cytotoxic effect of teniposide is related to the relative number of double-strand DNA breaks generated intracellularly, reflecting the stability of the topoisomerase II-DNA intermediate. It is an inhibitor of DNA topoisomerase II: Teniposide is a DNA topoisomerase II poison that has been shown to promote DNA breaks, particularly with a strong affinity for the C or T at the -1 position. Most mutational events reported in mammalian cells, including point mutations, chromosomal deletions and crossing over, and aneuploidy, can be explained by this activity. Teniposide does not inhibit bacterial topoisomerases and therefore may not cause bacterial mutations through the same mechanisms as in mammalian cells. Unlike many other DNA topoisomerase II inhibitors, teniposide does not bind to DNA, either covalently or intercalally. Instead, it appears to interact directly with DNA topoisomerase II. …The drug appears to exert its cytotoxic effects by damaging DNA, thereby inhibiting or altering DNA synthesis. Studies have shown that teniposide can induce single-strand DNA breaks; the drug can also induce double-strand DNA breaks and DNA-protein crosslinks. …Teniposide appears to have cell cycle specificity, inducing G2 phase arrest and preferentially killing cells in the late G2 and S phases.

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Therapeutic Use
Antitumor drug; enzyme inhibitor; nucleic acid synthesis inhibitor
Teniposide, used in combination with other approved anticancer drugs, is indicated for induction therapy of refractory childhood acute lymphoblastic (lymphoblastic) leukemia. /Included in the US product label/
Teniposide can be used as monotherapy or in combination therapy for the treatment of refractory non-Hodgkin lymphoma. /Not included in the US product label/
Teniposide can be used as monotherapy or in combination therapy for the treatment of refractory neuroblastoma. /Not included in the US product label/

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Drug Warnings
Because patients with Down syndrome and leukemia may be particularly sensitive to myelosuppressive chemotherapy, the initial dose of teniposide should be reduced in such patients.
There is currently no experience with the use of teniposide in patients with impaired renal and/or hepatic function, therefore specific recommendations regarding dose adjustment cannot be made. However, the possibility of dose adjustment for such patients should be considered.
The major and dose-limiting adverse reaction of teniposide is hematologic toxicity. Myelosuppression is dose-related and can be severe when teniposide is used in combination with other chemotherapy drugs to treat acute lymphoblastic leukemia (ALL). When using the teniposide doses and dosing regimens required for treating refractory ALL, early and severe myelosuppression is expected, with delayed recovery, as myeloproliferation is the anticipated endpoint of treatment. Patients receiving this drug may experience severe myelosuppression, leading to infection and bleeding. In pediatric patients receiving teniposide monotherapy, infection and bleeding occurred in approximately 12% and 5%, respectively.
Pregnancy Risk Grade: D / Positive evidence of risk exists. Human studies, investigational data, or post-marketing data all indicate fetal risk. However, the potential benefits of using this drug may outweigh the potential risks. For example, this drug may be acceptable in life-threatening situations or when a patient has a serious illness for which safer drugs are unavailable or ineffective. /
For more complete data on drug warnings for teniposide (18 of them), please visit the HSDB record page.

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Pharmacodynamics
Teniposide is a phase-specific cytotoxic drug that acts on the late S phase or early G2 phase of the cell cycle. Teniposide inhibits cell mitosis by causing single-strand and double-strand DNA breaks and cross-linking between proteins and DNA.

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Teniposide (VM-26) is a semi-synthetic podophyllotoxin derivative with potent antitumor activity[2][3]
- Mechanism of action: It exerts its antitumor effect by capturing DNA topoisomerase II, stabilizing the enzyme-DNA cleavage complex, and inducing DNA double-strand breaks, thereby leading to cell cycle arrest (G2/M phase or S phase) and apoptosis[2][3]
- Sensitization pathway: miR-181b enhances the antitumor efficacy of teniposide (VM-26) in glioma cells by targeting MDM2, downregulating its expression, and promoting p53-mediated cell death[3]
- Clinical application: It is used to treat a variety of cancers, including childhood acute lymphoblastic leukemia, glioma, and oral squamous cell carcinoma[2][3]
- Genetic toxicity risk: The aneuploidy effect of germ cells suggests a potential genetic risk, which needs to be taken seriously in clinical applications[1]

C32H32O13S

656.65

656.156

C, 58.53; H, 4.91; O, 31.67; S, 4.88

29767-20-2

452548

White to off-white solid powder

1.6±0.1 g/cm3

864.3±65.0 °C at 760 mmHg

274 - 277ºC

476.5±34.3 °C

0.0±0.3 mmHg at 25°C

1.697

1.71

3

14

6

46

1090

10

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

NRUKOCRGYNPUPR-QBPJDGROSA-N

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

(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

VM26; NSC-122819; VM-26; HSDB 6546; NSC 122819; VM 26; HSDB-6546; NSC122819; HSDB6546; CCRIS 2058. Trade name: Vumon; Vehem. Abbreviations: EPT; PTG

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)

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.

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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.

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