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Exatecan mesylate (DX8951)

Alias: DX-8951; DX 8951; DX8951
Cat No.:V20873 Purity: ≥98%
Exatecanmesylate (DX-8951) is the methylate of Exatecan, which is a semisynthetic analog of camptothecin with improved water solubility.
Exatecan mesylate (DX8951)
Exatecan mesylate (DX8951) Chemical Structure CAS No.: 169869-90-3
Product category: Topoisomerase
This product is for research use only, not for human use. We do not sell to patients.
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25mg
50mg
100mg
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Other Forms of Exatecan mesylate (DX8951):

  • Exatecan mesylate dihydrate (DX-8951 mesylate dihydrate)
  • Exatecan (DX 8951)
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Exatecan mesylate (DX-8951) is the methylate of Exatecan, which is a semisynthetic analog of camptothecin with improved water solubility. It has antineoplastic activity and is a potent inhibitor of DNA topoisomerase I, with an IC50 of 2.2 μM (0.975 μg/mL). By maintaining the cleavable complex between topoisomerase I and DNA and preventing the ligation of DNA breaks, exatecan mesylate inhibits topoisomerase I activity. This prevents DNA replication and causes apoptotic cell death. This substance is more potent than camptothecin and other camptothecin analogs and does not require enzymatic activation.

Biological Activity I Assay Protocols (From Reference)
Targets
Topoisomerase I ( IC50 = 0.975 μg/mL )
ln Vitro
Exatecan Mesylate exhibits potent inhibition of topoisomerase I along with potency against a battery of thirty-two malignant cell lines in vitro. Exatecan Mesylate exhibits anti-proliferative activity approximately 6 and 28 times higher than that of SN-38 or SK&F 10486-A, respectively. [1]
Exatecan has an IC50 of 0.975 μg/mL, making it a strong inhibitor of topoisomerase I. The proliferation of several cancer cell lines, including those from the breast, colon, stomach, and lung regions, is markedly inhibited by exatecan mesylate (DX-8951f) [1]. The cytotoxic action of exatecan mesylate (DX-8951f) against PC-6 and PC-6/SN2-5 cells is demonstrated by average GI50 values of 0.186 and 0.395 ng/mL, respectively. In PC-6 and PC-6/SN2-5 cells, exatecan mesylate (34 nM) stabilizes DNA-TopoI complexes [3].
ln Vivo
Three intravenous dosages of Exatecan Mesylate given at 4-day intervals have been shown to have more antitumor activity in mice than either CPT-11 or SK&F 10486-A when used against human gastric adenocarcinoma SC-6 xenografts. Additionally, it defeated P-glycoprotein-mediated multidrug resistance. These findings imply that Exatecan Mesylate is a promising therapeutic agent with strong antitumor activity.[1]
In a mouse model with tumor cells but no toxic mortality, exatecan mesylate (DX-8951f, 3.325-50 mg/kg, intravenous injection) showed anti-tumor efficacy [1]. In the MIA-PaCa-2 early model and the BxPC-3 early model, exatecan Mesylate (15, 25 mg/kg, iv) significantly suppresses the growth of MIA-PaCa and BxPC-3 primary tumors. In the BxPC-3 advanced cancer model, exatecan mesylate (15, 25 mg/kg, intravenous injection) totally eradicates lung metastasis and dramatically reduces BxPC-3 lymphatic metastasis [2].
Enzyme Assay
SDS buffer (10 mM HEPES, 2 mM orthovanadate, 10 mM NaF, 10 mM pyrophosphate, 1 mMPMSF, 10 µg/mL leupeptin, 10% 2-mercaptoethanol, 10% glycerol, 8% SDS, 42 mM Tris-HCl, 0.002% bromophenol blue, pH 7.4) is used to lyse cells (5×106). Protein from the lysates of the entire cell is separated using a 7.5% polyacrylamide gel and then blotted onto nitrocellulose membrane. First, horseradish peroxidase-conjugated protein A is applied to the membrane, followed by an anti-Topo I human antibody treatment. ECL reagents are used to detect the Topo I-specific band. In order to procure a nuclear extract, five hundred seventy-seven cells are cleaned using an ice-cold buffer (2 mM K2HPO4, 5 mM MgCl2, 150 mM NaCl, 1 mM EGTA, 0.1 mM dithiothreitol), reconstituted in a buffer that contains 0.35% Triton-X100 and PMSF, and subsequently placed on ice for ten minutes. The obtained lysates are centrifuged, and the precipitates are subsequently left to incubate for one hour at 4°C in a buffer containing 0.35 M NaCl. A protein assay kit is used to measure the protein concentration of the supernatant (nuclear extract) following centrifugation (18,000 g, 10 min). Western blotting analysis employing anti-Topo I antibody is used to analyze the same quantity of nuclear protein[3].
Cell Assay
MTT assay is used to measure the number of viable cells at the end of the incubation period in growth inhibition experiments, which are carried out in 96-well flat-bottomed microplates. After plating and growing 500–20,000000 cells/well in 150 μL of medium for 24 hours (P388, CCRF–CEM, and K562 cells for 4 hours), the drug (such as Exatecan Mesylate in 150 μL of medium/well) or the medium alone (as a control) is added, and the cells are cultured for an extra 3 days. The plates are incubated for 4 hours and centrifuged at 800 g for 5 minutes after adding MTT (20 μL/well, 5 mg/mL in phosphate-buffered saline). The medium is then removed, and the blue dye that forms is dissolved in 150 μL of DMSO. A Microplate Reader model 3550 is used to measure the absorbance at 540 nm[1].
Animal Protocol
For therapeutic purposes, mice are randomized into five groups of five at three weeks following orthotopic implantation of BxPC-3-GFP and MIA-PaCa-2-GFP. Group 1 is the negative control, getting no medical attention. Exatecan Mesylate is administered to Groups 2 and 3 at a dose of 25 and 15 mg/kg, respectively. LY 188011 treatments are administered to groups 4 and 5, at doses of 300 and 150 mg/kg, respectively. Mice are randomized into three groups of twenty at six weeks following BxPC-3-GFP orthotopic implantation in order to provide treatment. Group 1 is the negative control, getting no medical attention. Group 3 is administered 300 mg/kg/dose of LY 188011, while Group 2 is treated with 25 mg/kg/dose of Exatecan Mesylate. The dosage for both medications is taken once a week for three weeks, stopped for two weeks, and then resumed for an additional three weeks. Weekly measurements are made of the primary tumor size and body weights in both early and late cancer models. The formula for calculating tumor volumes is a × b2 × 0.5, in which a and b stand for the larger and smaller diameters, respectively. When the research is over, mice are killed and examined. We record the final tumor weights and the primary tumor and metastases' direct GFP images for every mouse. TWt and TWc are the mean tumor weights of the treated and control groups, respectively, and the formula for calculating the tumor growth index (IR) is IR (%) = (1 − TWt/TWc) × 100[2].
References

[1]. A new water-soluble camptothecin derivative, DX-8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Jpn J Cancer Res. 1995 Aug;86(8):776-82.

[2]. Efficacy of camptothecin analog DX-8951f (Exatecan Mesylate) on human pancreatic cancer in an orthotopic metastatic model. Cancer Res. 2003 Jan 1;63(1):80-5.

[3]. DX-8951f, a water-soluble camptothecin analog, exhibits potent antitumor activity against a human lung cancer cell line and its SN-38-resistant variant. Int J Cancer. 1997 Aug 7;72(4):680-6.

Additional Infomation
Exatecan Mesylate Anhydrous is the anhydrous, mesylate salt form of exatecan, a semisynthetic, water-soluble derivative of camptothecin, with antineoplastic activity. Upon administration, exatecan mesylate inhibits topoisomerase I activity by stabilizing the cleavable complex between topoisomerase I and DNA and inhibiting re-ligation of DNA breaks, thereby inhibiting DNA replication and triggering apoptotic cell death.
See also: Exatecan Mesylate (annotation moved to).
Exatecan is a pyranoindolizinoquinoline.
Exatecan has been used in trials studying the treatment of Sarcoma, Leukemia, Lymphoma, Lung Cancer, and Liver Cancer, among others.
CPT-11, a semisynthetic derivative of camptothecin, exhibited strong antitumor activity against lymphoma, lung cancer, colorectal cancer, gastric cancer, ovarian cancer, and cervical cancer. CPT-11 is a pro-drug that is converted to an active metabolite, SN-38, in vivo by enzymes such as carboxylesterase. We synthesized a water-soluble and non-pro-drug analog of camptothecin, DX-8951f. It showed both high in vitro potency against a series of 32 malignant cell lines and significant topoisomerase I inhibition. The anti-proliferative activity of DX-8951f, as indicated by the mean GI50 value, was about 6 and 28 times greater than that of SN-38 or SK&F 10486-A (Topotecan), respectively. These three derivatives of camptothecin showed similar patterns of differential response among 32 cell lines, that is, their spectra of in vitro cytotoxicity were almost the same. The antitumor activity of three doses of DX-8951f administered i.v. at 4-day intervals against human gastric adenocarcinoma SC-6 xenografts was greater than that of CPT-11 or SK&F 10486-A. Moreover, it overcame P-glycoprotein-mediated multi-drug resistance. These data suggest that DX-8951f has a high antitumor activity and is a potential therapeutic agent.[1]
We determined the antitumor and antimetastatic efficacy of the camptothecin analogue DX-8951f in an orthotopic metastatic mouse model of pancreatic cancer. DX-8951f showed efficacy against two human pancreatic tumor cell lines in this model. These cell lines were transduced with the green fluorescent protein, enabling high-resolution visualization of tumor and metastatic growth in vivo. The DX-8951f studies included both an early and advanced cancer model. In the early model, using the human pancreatic cancer lines MIA-PaCa-2 and BxPC-3, treatment began when the orthotopic primary tumor was approximately 7 mm in diameter. DX-8951f was significantly effective against both MIA-PaCa-2 and BxPC-3. In contrast, 2', 2'-difluorodeoxycytidine (gemcitabine), the standard treatment for pancreatic cancer, did not have significant efficacy against MIA-PaCa-2. Although gemcitabine showed significant activity against BxPC-3 primary tumor growth, it was not effective on metastasis. In the model of advanced disease, using BxPC-3, treatment started when the orthotopic primary tumor was 13 mm in diameter. DX-8951f was significantly effective in a dose-response manner on the BxPC-3 primary tumor. DX-8951f also demonstrated antimetastatic activity in the late-stage model, significantly reducing the incidence of lymph node metastasis while eliminating lung metastasis. In contrast, gemcitabine was only moderately effective against the primary tumor and ineffective against metastasis at both sites in the late-stage model. Therefore, DX-8951f was highly effective against primary and metastatic growth in this very difficult-to-treat disease and showed significantly higher efficacy than gemcitabine, the standard treatment of pancreatic cancer. DX-8951f, therefore, has important clinical promise and has more positive features than the currently used camptothecin analogue CPT-11, which requires metabolic activation and is toxic.[2]
We previously reported that DX-8951f, a novel water-soluble camptothecin analog, significantly inhibits the growth of various human and murine tumors in vitro and in vivo. The antitumor effects and topoisomerase I inhibitory activity of DX-8951f are stronger than those of other current camptothecin analogs. In this study, we established an SN-38-resistant cell line, PC-6/SN2-5, from the human oat cell carcinoma PC-6 cell line by a stepwise selection system, investigated the mechanism of resistance of this cell line and then compared the antitumor activity of camptothecin analogs against the cell line. PC-6/SN2-5 cells were resistant to SN-38 (32-fold) and SK&F 104864 (topotecan; 14-fold), but barely resistant to CPT-11 (3-fold) and DX-8951f (2-fold). Topoisomerase I protein levels and topoisomerase I activities of parental cells were similar to those of resistant cells. Determination of the cellular drug concentration by either flow cytometric analysis or the high-performance liquid chromatography method confirmed that the cellular accumulation of SN-38 and topotecan was significantly reduced in PC-6/SN2-5 cells, whereas that of DX-8951f was only slightly reduced. Furthermore, DX-8951f stabilized the cleavable complex formations in intact PC-6/SN2-5 cells as well as in parental cells, but SN-38 and topotecan did not in the resistant cells. Our data suggest that PC-6/SN2-5 cells may have acquired resistance to camptothecin analogs by a decrease in intracellular drug accumulation and that DX-8951f may have the potency to overcome such a type of resistance mechanism induced by camptothecin compounds.[3]
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C25H26FN3O7S
Molecular Weight
531.553248882294
Exact Mass
531.148
Elemental Analysis
C, 56.49; H, 4.93; F, 3.57; N, 7.91; O, 21.07; S, 6.03
CAS #
169869-90-3
Related CAS #
197720-53-9 (mesylate dihydrate); 169869-90-3 (mesylate); 171335-80-1; 144008-87-7 (HCl); 171335-80-1; 169869-90-3 (mesylate); 197720-53-9 (mesylate dihydrate); 144008-87-7 (HCl)
PubChem CID
6918249
Appearance
Yellow solid powder
LogP
3.758
Hydrogen Bond Donor Count
3
Hydrogen Bond Acceptor Count
10
Rotatable Bond Count
1
Heavy Atom Count
37
Complexity
1040
Defined Atom Stereocenter Count
2
SMILES
S(C)(=O)(=O)O.FC1C=C2C3=C(C=1C)CC[C@@H](C3=C1C(C3=CC4=C(COC([C@@]4(CC)O)=O)C(N3C1)=O)=N2)N([H])[H]
InChi Key
BICYDYDJHSBMFS-GRGFAMGGSA-N
InChi Code
InChI=1S/C24H22FN3O4.CH4O3S/c1-3-24(31)14-6-18-21-12(8-28(18)22(29)13(14)9-32-23(24)30)19-16(26)5-4-11-10(2)15(25)7-17(27-21)20(11)19;1-5(2,3)4/h6-7,16,31H,3-5,8-9,26H2,1-2H3;1H3,(H,2,3,4)/t16-,24-;/m0./s1
Chemical Name
(1S,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4'
Synonyms
DX-8951; DX 8951; DX8951
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

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: 11.8~12.5 mg/mL (22.1~23.5 mM)
Water: ~12.5 mg/mL
Solubility (In Vivo)
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

Injection Formulations
(e.g. IP/IV/IM/SC)
Injection Formulation 1: DMSO : Tween 80: Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution 50 μL Tween 80 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO 400 μLPEG300 50 μL Tween 80 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).
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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO 100 μLPEG300 200 μL castor oil 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10: 10 : 80 (i.e. 100 μL Ethanol 100 μL Cremophor 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH 400 μLPEG300 50 μL Tween 80 450 μL Saline)


Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).
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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders


Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.8813 mL 9.4065 mL 18.8129 mL
5 mM 0.3763 mL 1.8813 mL 3.7626 mL
10 mM 0.1881 mL 0.9406 mL 1.8813 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.

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Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:
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In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)
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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.

Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00055939 Completed Drug: exatecan mesylate Sarcoma Daiichi Sankyo, Inc. January 2003 Phase 2
NCT00055952 Completed Drug: exatecan mesylate Sarcoma Daiichi Sankyo, Inc. January 2003 Phase 2
NCT00041236 Completed Drug: exatecan mesylate Sarcoma European Organisation for Research
and Treatment of Cancer - EORTC
May 2002 Phase 2
NCT00017212 Completed Drug: exatecan mesylate Esophageal Cancer
Gastric Cancer
Daiichi Sankyo, Inc. April 2001 Phase 2
NCT00004108 Completed Drug: exatecan mesylate Liver Cancer Daiichi Sankyo, Inc. September 1999 Phase 2
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