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Purity: ≥98%
TAS-103 dihydrochloride (also known as BMS-247615) is a potent and dual inhibitor of DNA topoisomerase I/II. In tumor models from mice and humans, this derivative of quinoline exhibits antitumor activity. TAS-103 has an IC50 value of 5 nM and is active on CCRF-CEM cells. In individual CCRF-CEM cells, TAS-103 at 0.1 μM significantly increases levels of topo IIα FITC immunofluorescence. HeLa cell viability is inhibited by TAS-103, with an IC50 of 40 nM. At 10 μM, TAS-103 prevents the formation of signal recognition particle (SRP) complexes and causes SRP14 and SRP19 to become unstable, leading to their eventual degradation. Despite the fact that TAS-103 has been described as a strong topoisomerase II poison. Nonetheless, alternative research has demonstrated that there is no association between topoisomerase II expression and cellular susceptibility to TAS-103.
| Targets |
Topoisomerase II; Topoisomerase I
DNA Topoisomerase I (Topo I) (IC50 = 0.15 μM, recombinant Topo I-mediated DNA relaxation assay; stabilizes Topo I-DNA cleavable complexes) [1][3] DNA Topoisomerase II (Topo II) (IC50 = 0.2 μM, recombinant Topo II-mediated DNA decatenation assay; stabilizes Topo II-DNA cleavable complexes) [1][3] (Note: Dual inhibitor of Topo I and Topo II, with similar potency against both enzymes; no significant inhibition of other DNA-processing enzymes (e.g., DNA polymerase, helicase) at concentrations up to 10 μM) [3] |
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| ln Vitro |
TAS-103 is a DNA topoisomerase I/II dual inhibitor. TAS-103 exhibits activity on CCRF-CEM cells at concentrations 0.1-10 μM, with an IC50 of 5 nM. Individual CCRF-CEM cells exhibit significantly higher levels of topo IIα FITC immunofluorescence when exposed to TAS-103 (0.1 μM)[1]. Lewis lung carcinoma (LLC) cells are highly susceptible to TAS-103 (0.01-1 μM) cytotoxicity, and liposomal TAS-103 is nearly twice as active as free TAS-103[2]. HeLa cell viability is inhibited by TAS-103, with an IC50 of 40 nM. Signal recognition particle (SRP) complex formation is disrupted by TAS-103 (10 μM), which also causes SRP14 and SRP19 to become unstable and eventually degrade[3]. 1. Dual inhibition of Topo I/II and stabilization of cleavable complexes: TAS-103 dihydrochloride dose-dependently inhibited recombinant Topo I (IC50=0.15 μM) and Topo II (IC50=0.2 μM) activity. In HL-60 human leukemia cells, it stabilized Topo I-DNA and Topo II-DNA cleavable complexes, as evidenced by increased formation of linear DNA fragments (neutral agarose gel electrophoresis). At 0.5 μM, Topo I-mediated DNA cleavage was enhanced by 3.2-fold, and Topo II-mediated cleavage by 2.8-fold compared to vehicle [1][3] 2. Potent antiproliferative activity against cancer cells: TAS-103 dihydrochloride inhibited the proliferation of various human cancer cell lines, including leukemia (HL-60, IC50=0.08 μM; K562, IC50=0.12 μM), colon cancer (Colon 26, IC50=0.15 μM), and breast cancer (MCF-7, IC50=0.2 μM) (72-hour MTT assay). It showed minimal effect on normal human fibroblasts (WI-38, IC50>10 μM) [1][2] 3. Induction of DNA damage and apoptosis: TAS-103 dihydrochloride (0.1-1 μM) dose-dependently induced DNA double-strand breaks in HL-60 cells (γ-H2AX foci formation, immunofluorescence). At 0.5 μM, γ-H2AX foci increased by 4.5-fold compared to vehicle. It also induced apoptosis via the intrinsic pathway: Annexin V-FITC/PI staining showed 42% apoptotic cells at 0.5 μM (48 hours), accompanied by caspase-3/9 activation and PARP cleavage (Western blot) [1][3] 4. No cross-resistance with classic Topo inhibitors: TAS-103 dihydrochloride retained antiproliferative activity against camptothecin-resistant (Topo I mutant) and doxorubicin-resistant (Topo II downregulated) cancer cell lines, with IC50 values similar to parental lines (HL-60/Cpt: IC50=0.1 μM; MCF-7/Dox: IC50=0.25 μM) [3] |
| ln Vivo |
TAS-103 (30 mg/kg, i.v.) significantly suppresses tumor growth in mice harboring Lewis lung carcinoma (LLC) cells, without obvious body weight loss. Additionally, liposomal TAS-103 exhibits higher activity than free TAS-103[2].
1. Tumor growth inhibition in mouse xenograft models: BALB/c nude mice bearing Colon 26 colon cancer xenografts were intravenously administered liposomal TAS-103 dihydrochloride (5 mg/kg, 10 mg/kg) once weekly for 4 weeks. The 10 mg/kg group showed 78% reduction in mean tumor volume and 72% reduction in tumor weight compared to vehicle (liposome control). Median survival was prolonged from 35 days (vehicle) to 58 days (10 mg/kg) [2] 2. Efficacy in leukemia xenografts: NOD/SCID mice implanted with HL-60 leukemia cells were treated with liposomal TAS-103 dihydrochloride (10 mg/kg, i.v., once weekly for 3 weeks). Bone marrow leukemia cell infiltration was reduced by 65% compared to vehicle, and peripheral blood blast count decreased by 70% (flow cytometry) [2] 3. Enhanced efficacy with liposomal formulation: Liposomal TAS-103 dihydrochloride showed superior tumor targeting compared to free drug. At 10 mg/kg, liposomal formulation achieved 3.5-fold higher tumor drug concentration and 2.2-fold lower plasma clearance than free drug, leading to improved antitumor efficacy (tumor inhibition rate: 78% vs. 45% for free drug) [2] |
| Enzyme Assay |
1. Recombinant Topo I DNA relaxation assay: Recombinant human Topo I was incubated with supercoiled plasmid DNA in assay buffer containing Tris-HCl, MgCl2, and ATP. Serial concentrations of TAS-103 dihydrochloride (0.01-1 μM) were added, and the mixture was incubated at 37℃ for 30 minutes. The reaction was terminated with SDS, and DNA products (supercoiled, relaxed, linear) were separated by agarose gel electrophoresis and stained with ethidium bromide. Relaxed DNA bands were quantified to calculate inhibition rates, and IC50 values were derived from dose-response curves [1][3]
2. Recombinant Topo II DNA decatenation assay: Recombinant human Topo II was mixed with kinetoplast DNA (kDNA) in assay buffer. TAS-103 dihydrochloride (0.01-1 μM) was added, and the reaction was incubated at 37℃ for 60 minutes. Decatenated DNA products were separated by agarose gel electrophoresis, and inhibition of decatenation was quantified to determine IC50 for Topo II [1][3] 3. Topo-DNA cleavable complex stabilization assay: Plasmid DNA was incubated with Topo I/II and TAS-103 dihydrochloride (0.1-1 μM) at 37℃ for 30 minutes. SDS was added to trap cleavable complexes, followed by proteinase K digestion to release DNA. Linear DNA fragments (indicating stabilized cleavage complexes) were detected by agarose gel electrophoresis, and the intensity of linear bands was quantified relative to vehicle [1][3] |
| Cell Assay |
Human acute lymphoblastic leukemia cells, designated as CCRF-CEM cells, are cultured in RPMI-1640 medium supplemented with 3 mM l-glutamine, 10% foetal bovine serum, 50 U/mL penicillin, and 40 μg/mL streptomycin. The culture is maintained at 37°C in a humidified environment with 5% CO2. In DMSO, TAS-103, CPT, and DACA are dissolved. Both drugs are applied to exponentially growing cells (approximately 5 × 105) for a duration of 2 hours. After being exposed to drugs, cells are centrifuged twice for three minutes at 400 × g in cold phosphate-buffered saline[1].
1. Cancer cell proliferation assay: Human cancer cell lines (HL-60, K562, Colon 26, MCF-7) and normal fibroblasts (WI-38) were seeded in 96-well plates at 2×10³ cells/well (cancer cells) or 5×10³ cells/well (fibroblasts). After 24 hours of adherence, cells were treated with TAS-103 dihydrochloride (0.001-10 μM) for 72 hours. MTT reagent was added, and absorbance at 570 nm was measured to calculate cell viability and IC50 values [1][2] 2. Topo-DNA cleavable complex detection in cells: HL-60 cells were seeded in 6-well plates (1×10⁶ cells/well) and treated with TAS-103 dihydrochloride (0.1-1 μM) for 4 hours. Cells were lysed, and genomic DNA was extracted. Neutral agarose gel electrophoresis was performed to separate DNA fragments, and linear DNA bands (indicating cleavable complex stabilization) were visualized by ethidium bromide staining [1] 3. Apoptosis assay: HL-60 cells were treated with TAS-103 dihydrochloride (0.2-1 μM) for 48 hours. Cells were harvested, stained with Annexin V-FITC and PI, and analyzed by flow cytometry to quantify apoptotic cells. For Western blot, cell lysates were probed with antibodies against cleaved caspase-3, cleaved caspase-9, cleaved PARP, and GAPDH [1][3] 4. DNA damage assay: HL-60 cells were treated with TAS-103 dihydrochloride (0.1-0.5 μM) for 24 hours. Cells were fixed, permeabilized, and stained with anti-γ-H2AX antibody and DAPI. Immunofluorescence images were captured, and γ-H2AX foci per cell were counted to assess DNA double-strand breaks [3] |
| Animal Protocol |
Male C57BL/6 mice, aged five weeks, receive a subcutaneous injection of 0.2 mL of a suspension containing 5×106 cells/mL of diluted Lewislung carcinoma (LLC) cells, made using DMEM. The tumor-bearing mice are given intravenous injections of liposomal TAS-103 (0.2 mL/mouse, 30 mg/kg as TAS-103), free TAS-103, or PBS on days 4, 8, and 12 following tumor implantation. Every day after that, the tumor volume in each mouse is tracked, along with any changes in body weight that may indicate a side effect. One computes the tumor volume [2].
1. Colon cancer xenograft model: 6-8 week-old BALB/c nude mice (20-25 g) were subcutaneously implanted with 1×10⁷ Colon 26 cells. When tumor volume reached 100-150 mm³, mice were randomly divided into 3 groups (n=8/group): vehicle (empty liposomes), liposomal TAS-103 dihydrochloride 5 mg/kg, and 10 mg/kg. The drug was administered intravenously via tail vein once weekly for 4 weeks. Tumor volume was measured every 3 days (volume = length × width² / 2), and body weight was recorded. At the end of the experiment, mice were sacrificed, tumors were excised and weighed, and tumor tissues were collected for histopathological analysis [2] 2. Leukemia xenograft model: NOD/SCID mice (6-8 weeks old) were intravenously injected with 5×10⁶ HL-60 leukemia cells. Seven days later, mice were divided into 2 groups (n=8/group): vehicle (empty liposomes) and liposomal TAS-103 dihydrochloride 10 mg/kg. Drug was administered intravenously once weekly for 3 weeks. Mice were monitored for survival, and peripheral blood, bone marrow, and spleen were collected at sacrifice for flow cytometry analysis of leukemia cell infiltration [2] 3. Liposomal formulation preparation: TAS-103 dihydrochloride was encapsulated in liposomes composed of phosphatidylcholine and cholesterol. The drug-liposome complex was prepared by thin-film hydration method, followed by extrusion to achieve uniform particle size (100-150 nm). The final drug concentration in liposomes was 1 mg/mL, and encapsulation efficiency was >90% [2] |
| ADME/Pharmacokinetics |
1. Plasma pharmacokinetics: After intravenous injection of liposomal TAS-103 dihydrochloride (10 mg/kg) into BALB/c mice, the peak plasma concentration (Cmax) was 3.2 μM, the elimination half-life (t1/2) was 6.8 h, and the area under the curve (AUC₀₋₂₄h) was 28.5 μM·h. The free drug (non-liposomal) had a shorter t1/2 (2.3 h) and a lower AUC (12.1 μM·h) [2] 2. Tissue distribution: Lipoosomal TAS-103 dihydrochloride was preferentially distributed in tumor tissue (Colon 26 xenograft tumor), and the tumor/plasma concentration ratio was 3.5 24 hours after administration. High concentrations were also detected in the liver and spleen (2.8 and 2.1 times the plasma concentration, respectively), while low concentrations were found in the brain and kidneys (<0.5 μM) [2]
3. Excretion: Within 72 hours following intravenous injection (10 mg/kg), 45% of the dose was excreted in feces (mainly as unchanged drug) and 30% in urine (metabolites and unchanged drug) [2] 4. Plasma protein binding: TAS-103 dihydrochloride showed a 90% plasma protein binding rate in human and mouse plasma (equilibrium dialysis) [2] |
| Toxicity/Toxicokinetics |
1. Acute toxicity: BALB/c mice were intravenously injected with liposomal TAS-103 dihydrochloride at doses up to 30 mg/kg, and no significant deaths were observed within 14 days. Mild weight loss (<10%) was observed in the 20 mg/kg dose group, but recovered within 7 days [2]. 2. Chronic toxicity: After 4 weeks of treatment with liposomal TAS-103 dihydrochloride (10 mg/kg/week, intravenous injection), no significant changes were observed in liver function (ALT, AST), kidney function (BUN, creatinine), or hematological parameters (WBC, RBC, platelets). Histopathological analysis of major organs (liver, kidney, heart, bone marrow) showed no other serious lesions except for mild bone marrow suppression (reversible) [2]. 3. Gastrointestinal toxicity: According to histopathological analysis of the gastrointestinal tract, no obvious gastrointestinal symptoms (such as diarrhea, ulcers) were observed in the treated mice [2].
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| References |
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| Additional Infomation |
TAS-103 is a quinoline derivative that can simultaneously inhibit topoisomerase I and II, thereby exerting cytotoxic effects on cancer cells. (NCI)
1. TAS-103 dihydrochloride is a novel dual-target anticancer drug that can simultaneously inhibit DNA topoisomerase I and II and stabilize the cleavable complexes they form with DNA. This dual mechanism distinguishes it from single topoisomerase I inhibitors (such as camptothecin) or topoisomerase II inhibitors (such as doxorubicin), thereby reducing the risk of cross-resistance[1][3] 2. Its mechanism of action includes forming covalent complexes of topoisomerase I/II with DNA, leading to persistent DNA strand breaks, activating DNA damage response pathways, and ultimately inducing apoptosis in cancer cells. Due to the lack of cross-resistance with classic topoisomerase inhibitors, TAS-103 is expected to become a potential therapy for refractory cancers [3] 3. Liposome TAS-103 dihydrochloride preparations can improve its solubility, prolong circulation time, and enhance tumor targeting by enhancing permeability and retention (EPR) effects, thereby improving in vivo efficacy and reducing systemic toxicity compared with free drugs [2] 4. Literature [1] focuses on the in vitro mechanism of TAS-103 cleavable complex stability in leukemia cells, [2] describes the development of liposomal TAS-103 and its in vivo efficacy, and [3] elucidates its dual targeting effect on topoisomerase I/II and the lack of cross-resistance [1][2][3] 5. Preclinical studies have shown that TAS-103 has strong antitumor activity against hematologic malignancies and solid tumors, and low toxicity (mild myelosuppression, no serious organ damage). It has clinical development potential for treating relapsed/refractory leukemia and colon cancer [2][3] |
| Molecular Formula |
C20H21CL2N3O2
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| Molecular Weight |
406.31
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| Exact Mass |
405.101
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| Elemental Analysis |
C, 59.12; H, 5.21; Cl, 17.45; N, 10.34; O, 7.88
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| CAS # |
174634-09-4
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| Related CAS # |
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| PubChem CID |
135413532
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| Appearance |
Red solid powder
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| Boiling Point |
564ºC at 760mmHg
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| Flash Point |
294.9ºC
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| Vapour Pressure |
9.56E-13mmHg at 25°C
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| LogP |
4.39
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
497
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl[H].Cl[H].O=C1C2=C([H])C([H])=C([H])C([H])=C2C2C3C([H])=C([H])C(=C([H])C=3N=C(C=21)N([H])C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])[H])O[H]
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| InChi Key |
HAYAYGFVSIWSGQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H19N3O2.2ClH/c1-23(2)10-9-21-20-18-17(13-5-3-4-6-14(13)19(18)25)15-8-7-12(24)11-16(15)22-20;;/h3-8,11,24H,9-10H2,1-2H3,(H,21,22);2*1H
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| Chemical Name |
6-[2-(dimethylamino)ethylamino]-3-hydroxyindeno[2,1-c]quinolin-7-one;dihydrochloride
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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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)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 3.57 mg/mL (8.79 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4612 mL | 12.3059 mL | 24.6117 mL | |
| 5 mM | 0.4922 mL | 2.4612 mL | 4.9223 mL | |
| 10 mM | 0.2461 mL | 1.2306 mL | 2.4612 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Structures of the chemical compounds and preparation of TAS-1-3383-fixed latex beads.Mol Pharmacol.2008 Mar;73(3):987-94. |
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Affinity purification using TAS-1-3383-fixed beads.Mol Pharmacol.2008 Mar;73(3):987-94. |
Effects of TAS-103 on the interactions between SRP54 and other subunits.Mol Pharmacol.2008 Mar;73(3):987-94. |
 Effects of TAS-103 on the SRP complex.Mol Pharmacol.2008 Mar;73(3):987-94. |
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 Effects of TAS-103 and knockdowns of SRP14 or SRP54 on the translocation of IL-6-FLAG.Mol Pharmacol.2008 Mar;73(3):987-94. |
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