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Amrubicin (SM-5887), a third-generation synthetic 9-amino-anthracycline, is a potent DNA topoisomerase II inhibitor with antineoplastic activity. It can be used for the research of cancer. Amrubicin intercalates into DNA and inhibits the activity of topoisomerase II, resulting in inhibition of DNA replication, and RNA and protein synthesis, followed by cell growth inhibition and cell death. This agent has demonstrated a higher level of anti-tumor activity than conventional anthracycline drugs without exhibiting any indication of the cumulative cardiac toxicity common to this class of compounds. It is marketed in Japan since 2002 by Sumitomo Pharmaceuticals.
Amrubicin is a completely synthetic 9-aminoanthracycline derivative that functions as a potent DNA topoisomerase II inhibitor, exerting its cytotoxic effects by stabilizing the topoisomerase II-mediated cleavable complex and inducing DNA double-strand breaks . It is a prodrug that is converted in the body to its active 13-hydroxy metabolite, amrubicinol, which is 5 to 100 times more potent than the parent compound . Unlike many traditional anthracyclines such as doxorubicin, amrubicin is characterized by significantly reduced cardiotoxicity, while demonstrating high antitumor activity . It is administered intravenously at doses of 35-45 mg/m² on days 1-3 every 3-4 weeks . Amrubicin is approved in Japan for the treatment of small-cell lung cancer (SCLC) and non-small-cell lung cancer, and has been designated an orphan drug in the US for SCLC treatment . Common toxicities include hematological effects such as neutropenia, leukopenia, anemia, and thrombocytopenia, as well as non-hematological events like anorexia, nausea, and asthenia .| Targets |
Topoisomerase II (topo II) – stabilizes topoisomerase II-DNA cleavable complex, inhibits topoisomerase II activity [1][2][3]
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| ln Vitro |
Amrubicin (20 μM for 1 h) induced cell cycle arrest at G₂/M phase in human leukemia U937 cells, increased sub-G₁ phase cells (apoptotic population), and induced typical apoptosis with nuclear condensation, fragmentation (Hoechst 33258 staining), and internucleosomal DNA fragmentation (agarose gel electrophoresis). These effects were inhibited by the topoisomerase II catalytic inhibitor ICRF-193 (1 μM). [3]
Amrubicin induced apoptosis in U937 cells in a dose-dependent manner with IC50 of 5.6 μM (1 h exposure). [3] Amrubicin (20 μM for 1 h) induced reduction in mitochondrial membrane potential (ΔΨm) in U937 cells, with maximal reduction at 3-6 h. [3] Amrubicin (20 μM for 1 h) activated caspase-3/7 (DEVD-specific cleavage) in U937 cells at 2-4 h, but did not activate caspase-1 (YVAD-specific cleavage). [3] In A549 human lung adenocarcinoma cells, amrubicin (2.5 μg/ml for 3 h) enhanced radiosensitivity when administered prior to X-ray irradiation, reducing the shoulder-shaped portion of the survival curve (indicating inhibition of sublethal damage repair). The D₀ value for irradiation alone was 2.0 Gy; with amrubicin pre-treatment, D₀ was 1.7 Gy (enhancement ratio 1.38). [1] In A549 cells, amrubicin (2.5 μg/ml for 3 h) prior to fractionated irradiation (2 Gy × 4 fractions, 24 h intervals) reduced surviving fraction from 0.19 (irradiation alone) to 0.0093. [1] Amrubicin (20 μM for 1 h) induced DNA fragmentation in U937 cells, which was inhibited by ICRF-193 (1 μM). [3] In human cancer cell lines (LX-1, A431, BT-474, A549), amrubicin showed antiproliferative activity with IC50 values ranging from 0.61-3.0 μg/ml. [2] Amrubicin (SM-5887) is a DNA topozyme II. Amrubicin (SM-5887) (2.5 μg/mL) enhances radiation response in human lung adenocarcinoma A549 cells [1]. Amrubicin inhibits LX-1, A549, A431 and BT-474 cell lines at IC50s of 1.1, 2.4, 0.61, and 3.0 μg/mL, respectively [2]. Amrubicin tuff U937 cells exhibit cell cycle features with an IC50 of 5.6 μM. Amrubicin (SM-5887) (20 μM) causes duct induction in U937 cells, activates caspase-3/7, and lowers mitochondrial membrane potential (Δψm) [3]. |
| ln Vivo |
In human lung cancer xenograft models (athymic nude mice), amrubicin (25 mg/kg, i.v., single dose on day 0) significantly inhibited tumor growth in SCLC (Lu-24: T/C = 17%; Lu-134: T/C = 9%) and NSCLC (Lu-99: T/C = 29%; LC-6: T/C = 50%; L-27: T/C = 26%). Doxorubicin (12.5 mg/kg) was effective against Lu-24 but not Lu-134. Body weight decrease was within 10% in all treatment groups. [2]
In combination studies, amrubicin (25 mg/kg i.v.) enhanced the antitumor activity of cisplatin (10 mg/kg i.v.) against LX-1 tumors (T/C: amrubicin alone 57%, combination 31%); irinotecan (120 mg/kg i.v.) (T/C: amrubicin alone 41%, combination 24%); vinorelbine (16 mg/kg i.p.) against QG-56 tumors (T/C: amrubicin alone 43%, combination 27%); tegafur/uracil (28 mg/kg p.o., 5qd) against SC-6 tumors (T/C: amrubicin alone 8.5%, combination 3.7%); trastuzumab (100 mg/kg i.p., twice weekly × 2 weeks) against 4-1ST tumors (T/C: amrubicin alone 8.8%, combination 1.6%). Gemcitabine combination did not significantly enhance efficacy compared to amrubicin alone. [2] In A549 cells, amrubicin (2.5 μg/ml for 3 h) prior to X-ray irradiation enhanced radiosensitivity in a fractionated irradiation protocol (2 Gy × 4 fractions, 24 h intervals). [1] Amrubicin (SM-5887) (25 mg/kg, intravenous injection) demonstrates strong anticancer effect against SCLC tumors Lu-24 and Lu-134; T/C values (which compare the treatment group's mean tumor growth rate to Article 14 of those tumors) were 17% and 9%, respectively, for those tumors on a daily basis. Amrubicin (SM-5887) (25 mg/kg, iv) in combination with ciprofloxacin and irinotecan effectively decreased tumor formation in mice with produced LX-1 cells, as compared to Amrubicin alone. In human cancer xenograft models, amrubicin (SM-5887) either by itself or in conjunction with Tegaf and Urinary End Base suppresses tumor growth [2]. |
| Enzyme Assay |
Topoisomerase II-mediated DNA cleavage was inferred from cellular DNA fragmentation studies inhibited by ICRF-193. [2][3]
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| Cell Assay |
U937 human leukemia cells were cultured in RPMI-1640 with 10% FBS. Cells were treated with amrubicin (20 μM for 1 h), washed, and incubated in drug-free medium. Cell cycle analysis: fixed in 80% ethanol, stained with propidium iodide (50 μg/ml) with RNase A, analyzed by flow cytometry. Apoptosis detection: Hoechst 33258 staining for nuclear morphology; DNA fragmentation on 2% agarose gel electrophoresis. [3]
A549 human lung adenocarcinoma cells were cultured in Eagle's MEM with NCTC-135, lactalbumin hydrolysate, and 15% newborn calf serum. Cells were treated with amrubicin (2.5 μg/ml for 3 h) prior to X-ray irradiation (130 kVp, 5 mA, 0.5 mm Al filter, 1.0 Gy/min). Colony formation assay: cells plated, incubated for 7-10 days, stained with crystal violet, colonies >50 cells counted. [1] Human cancer cell lines (LX-1, A431, BT-474, A549) were cultured in appropriate media. Cell proliferation assay: cells plated in 96-well plates, treated with serial dilutions of amrubicin for 3 days, viable cells measured using WST-1 or AlamarBlue. IC50 values determined. [2] |
| Animal Protocol |
U937 human leukemia cells were cultured in RPMI-1640 with 10% FBS. Cells were treated with amrubicin (20 μM for 1 h), washed, and incubated in drug-free medium. Cell cycle analysis: fixed in 80% ethanol, stained with propidium iodide (50 μg/ml) with RNase A, analyzed by flow cytometry. Apoptosis detection: Hoechst 33258 staining for nuclear morphology; DNA fragmentation on 2% agarose gel electrophoresis. [3]
A549 human lung adenocarcinoma cells were cultured in Eagle's MEM with NCTC-135, lactalbumin hydrolysate, and 15% newborn calf serum. Cells were treated with amrubicin (2.5 μg/ml for 3 h) prior to X-ray irradiation (130 kVp, 5 mA, 0.5 mm Al filter, 1.0 Gy/min). Colony formation assay: cells plated, incubated for 7-10 days, stained with crystal violet, colonies >50 cells counted. [1] Human cancer cell lines (LX-1, A431, BT-474, A549) were cultured in appropriate media. Cell proliferation assay: cells plated in 96-well plates, treated with serial dilutions of amrubicin for 3 days, viable cells measured using WST-1 or AlamarBlue. IC50 values determined. [2] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Peak plasma concentrations of the active metabolite, amulbiscinol, were observed immediately to within 1 hour after administration of amulbiscin. Plasma concentrations of amulbiscinol were lower than those of amulbiscin. The area under the plasma curve (AUC) of amulbiscinol was approximately one-tenth that of amulbiscin in plasma. Amulbiscinol concentrations in erythrocytes were higher than in plasma. The AUC of amulbiscinol in erythrocytes was 2.5 to 57.9 times higher than in plasma. Because amulbiscinol distributes more readily into erythrocytes than amulbiscin, the concentrations of amulbiscinol and amulbiscin in erythrocytes were very similar. The AUC of amulbiscinol in erythrocytes was approximately half that of amulbiscin in erythrocytes. In one study, accumulation of amulbiscinol was observed in plasma and erythrocytes following repeated daily administration of amulbiscin. On day 3, the AUC of amulbiscinol in plasma was 1.2 to 6 times higher than on day 1; the AUC of amulbiscinol in erythrocytes was 1.2 to 1.7 times higher than on day 1. After 5 consecutive days of administration, the AUC of amulbiscinol in plasma and erythrocytes was 1.2 to 2.0 times higher than on day 1. In another study, after oral administration of amulbiscin, the excretion of amulbiscin and amulbiscinol in urine accounted for 2.7% to 19.6% of the administered dose. The amount of amulbiscinol excreted was approximately 10 times that excreted from amulbiscin. The excretion of amulbiscin and its metabolites is primarily via the hepatobiliary route. Enterohepatic circulation was confirmed in rats. The volume of distribution is moderate (1.4 times the total body fluid volume). The pharmacokinetic characteristics of amulbiscin in the plasma of cancer patients are low total clearance (22% of total hepatic blood flow). Metabolism/Metabolites In rats and dogs, the major metabolite (amrubicinol) is the product of cytoplasmic carbonyl reductase reduction at the C-13 carbonyl group. Other enzymes involved in the metabolism of amulubixin and amulubixinol include reduced nicotinamide adenine dinucleotide phosphate (NADPH)-P450 reductase and nicotinamide adenine dinucleotide phosphate (NAD[P]H)-quinone oxidoreductase. One study detected an additional 12 metabolites in vivo and in vitro. Peak plasma concentrations of the active metabolite amulubixinol appeared immediately after administration to within 1 hour after administration. These metabolites included four aglycone metabolites, two amulubixinol glucuronides, deaminoamrubixin, and five highly polar unknown metabolites. The in vitro cell growth inhibitory activity of the minor metabolites was significantly lower than that of amulubixinol. Amulubixin and its metabolites are primarily excreted via the hepatobiliary pathway. Enterohepatic circulation has been confirmed in rats. Biological half-life 20-30 hours. In a canine study, amrubicin plasma concentrations exhibited a biphasic pattern, reaching peak concentration immediately after administration, followed by α and β half-lives (t1/2) ± standard deviations of 0.06 ± 0.01 hours and 2.0 ± 0.3 hours, respectively. Amrubicin is metabolized to its active 13-hydroxy metabolite, amrubicinol, mainly by carbonyl reductases. In tumor-bearing mice treated with amrubicin, amrubicinol was found to be a major metabolite in tumor tissue, with levels higher than those of doxorubicin in mice treated with doxorubicin. In contrast, levels of amrubicin and amrubicinol were lower than those of doxorubicin in several normal tissues, including the heart. A good correlation was found between the level of amrubicinol in the tumor and the efficacy of amrubicin in vivo. [2][3] In rats and dogs, the concentrations of amrubicin or amrubicinol in the heart after amrubicin administration were lower than those of doxorubicin after doxorubicin administration. [2] |
| Toxicity/Toxicokinetics |
Protein Binding
A study investigated the protein binding rate of amurubicin in the plasma of patients with impaired liver function and those with normal liver function. The results showed that the plasma protein binding rate was 91.3%–97.1% in patients with impaired liver function, compared to 82.0%–85.3% in patients with normal liver function. Amrubicin showed much less cardiotoxicity than doxorubicin in chronic experimental models using rabbits and dogs. [2] In A549 cells, amrubicin (2.5 μg/ml) alone for 3 h had minimal cytotoxicity (surviving fraction ~0.9). [1] In human leukemia U937 cells, amrubicin (20 μM for 1 h) induced apoptosis as measured by sub-G₁ population increase. [3] In vivo, amrubicin (25 mg/kg i.v.) was well tolerated with body weight decrease within 10% in all treatment groups. [2] |
| References |
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| Additional Infomation |
Amrubicin (amrubicin hydrochloride) is a completely synthetic 9-aminoanthracycline derivative characterized by a 9-amino group and a simple sugar moiety. It was developed to reduce cardiotoxicity while maintaining antitumor efficacy. Amrubicin is currently approved in Japan for the treatment of small-cell lung cancer and non-small-cell lung cancer. Its active metabolite, amrubicinol (13-hydroxy metabolite), is 5-100 times more active than amrubicin in inhibiting human tumor cell growth. The selective distribution of amrubicinol in tumors (higher than in normal tissues including heart) contributes to the greater efficacy and lower cardiotoxicity of amrubicin compared to doxorubicin. [2][3]
Amrubicin is a synthetic anthracycline antibiotic with the molecular formula C25H25NO9. It is a topoisomerase II specific inhibitor, primarily used to treat cancer, especially lung cancer. In lung cancer treatment, it is a prodrug of the active metabolite ambruciclovir. Amrubicin has multiple functions as a topoisomerase II inhibitor, an antitumor drug, and a prodrug. It is a quinone compound belonging to the tetrabenzocyclohexane class, methyl ketone class, anthracycline antibiotics, and primary amino compounds. Amrubicin is a third-generation synthetic anthracycline antibiotic currently under development for the treatment of small cell lung cancer. Pharmion acquired the rights to amrubicin in November 2006. Based on Phase II efficacy data in small cell lung cancer and non-small cell lung cancer, amrubicin was approved for marketing in Japan in 2002. Since January 2005, amrubicin has been marketed by Nippon Kayaku, a Japanese pharmaceutical company focused on oncology treatment. Nippon Kayaku Co., Ltd. has acquired the Japanese sales rights for amphobacin from Dainippon Sumitomo Co., Ltd., the original developer of amphobacin. Amphobacin is a synthetic 9-aminoanthracycline antitumor drug. Amphobacin intercalates into DNA and inhibits the activity of topoisomerase II, thereby inhibiting DNA replication and the synthesis of RNA and proteins, ultimately leading to cell growth inhibition and cell death. Compared with traditional anthracyclines, amphobacin exhibits higher antitumor activity and does not show the cumulative cardiotoxicity common in this class of compounds. Indications: It has been investigated for the treatment of lung cancer. Mechanism of Action: As an anthracycline, amphobacin exerts its antimitotic and cytotoxic effects through multiple mechanisms of action. Amphobacin forms a complex with DNA by intercalating between base pairs and inhibits the activity of topoisomerase II by stabilizing the DNA-topoisomerase II complex, thereby preventing the rejoining portion of the ligation-rejoining reaction that topoisomerase II typically catalyzes. Topoisomerase II is a nucleus enzyme that regulates DNA structure through double-strand breaks and rejoining, thereby controlling DNA replication and transcription. Inhibition of this enzyme leads to DNA replication arrest, cell growth cessation, and cell cycle arrest at the G2/M phase. The mechanism by which amrubicin inhibits DNA topoisomerase II is believed to be the stabilization of the cleavable DNA-topoisomerase II complex, ultimately resulting in rejoining failure and DNA strand breaks. DNA damage triggers the activation of caspase-3 and -7 and the cleavage of PARP (poly-ADP-ribose polymerase), leading to apoptosis and loss of mitochondrial membrane potential. Like all anthracycline drugs, amrubicin can intercalate into DNA and cause cell damage by interacting with NADPH to generate reactive oxygen species. Compared to doxorubicin, another anthracycline drug, amrubicin has a 7-fold lower affinity for DNA, thus requiring higher concentrations to promote DNA unwinding. Pharmacodynamics Anthracycline antibiotics, including amorubicin, are a class of potent anticancer drugs with significant activity against solid tumors and hematologic malignancies. They are the subject of extensive research in the treatment of cancer in adults and children. Amorubicin is a 9-aminoanthracycline derivative that inhibits cell growth by stabilizing protein-DNA complexes, leading to double-strand DNA breaks, a process mediated by topoisomerase II. Anthracyclines have been observed to have various molecular effects (e.g., DNA intercalation, inhibition of topoisomerase II, and stabilization of topoisomerase IIα-cleavable complexes). Compared to doxorubicin, amorubicin has reduced DNA intercalation capacity. This reduced DNA interaction may affect the intracellular distribution of amorubicin and its metabolite amorubicinol. Amorubicin has a nuclear distribution of 20% in P388 cells, while doxorubicin (another anthracycline) has a nuclear distribution of 80%. The cell growth inhibitory effect of amorubicin appears to be primarily attributed to its inhibition of topoisomerase II. |
| Molecular Formula |
C₂₅H₂₅NO₉
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| Molecular Weight |
483.47
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| Exact Mass |
483.152
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| Elemental Analysis |
C, 62.11; H, 5.21; N, 2.90; O, 29.78
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| CAS # |
110267-81-7
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| Related CAS # |
92395-36-3 (HCl);110267-81-7;110311-30-3;
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| PubChem CID |
3035016
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| Appearance |
Pink to red solid powder
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| Density |
1.6±0.1 g/cm3
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| Boiling Point |
717.8±60.0 °C at 760 mmHg
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| Melting Point |
172-174ºC
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| Flash Point |
387.9±32.9 °C
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| Vapour Pressure |
0.0±2.4 mmHg at 25°C
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| Index of Refraction |
1.720
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| LogP |
2.64
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
35
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| Complexity |
881
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| Defined Atom Stereocenter Count |
5
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| SMILES |
CC(=O)[C@]1(C[C@@H](C2=C(C1)C(=C3C(=C2O)C(=O)C4=CC=CC=C4C3=O)O)O[C@H]5C[C@@H]([C@@H](CO5)O)O)N
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| InChi Key |
VJZITPJGSQKZMX-XDPRQOKASA-N
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| InChi Code |
InChI=1S/C25H25NO9/c1-10(27)25(26)7-13-18(16(8-25)35-17-6-14(28)15(29)9-34-17)24(33)20-19(23(13)32)21(30)11-4-2-3-5-12(11)22(20)31/h2-5,14-17,28-29,32-33H,6-9,26H2,1H3/t14-,15+,16-,17-,25-/m0/s1
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| Chemical Name |
(7S,9S)-9-acetyl-9-amino-7-[(2S,4S,5R)-4,5-dihydroxyoxan-2-yl]oxy-6,11-dihydroxy-8,10-dihydro-7H-tetracene-5,12-dione
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| Synonyms |
SM-5887; AMR; SM-5887; Amrubicin; 110267-81-7; amrubicina; amrubicine; amrubicinum; SM5887; SM 5887; Amirubicin Hydrochloride; Foreign brand name: Calsed
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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 |
| 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) |
DMSO : ≥ 30 mg/mL (~62.05 mM)
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| 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
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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 : PEG300 ：Tween 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). View More
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)] 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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0684 mL | 10.3419 mL | 20.6838 mL | |
| 5 mM | 0.4137 mL | 2.0684 mL | 4.1368 mL | |
| 10 mM | 0.2068 mL | 1.0342 mL | 2.0684 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.
Phase II trial of amrubicin and cisplatin chemotherapy for invasive thymoma
CTID: UMIN000003933
Phase: Phase II Status: Complete: follow-up complete
Date: 2010-08-01
Products are for research use only; We do not sell to patients
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