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Identification
NameDactinomycin
Accession NumberDB00970  (APRD00124)
TypeSmall Molecule
GroupsApproved
Description

A compound composed of a two cyclic peptides attached to a phenoxazine that is derived from streptomyces parvullus. It binds to DNA and inhibits RNA synthesis (transcription), with chain elongation more sensitive than initiation, termination, or release. As a result of impaired mRNA production, protein synthesis also declines after dactinomycin therapy. (From AMA Drug Evaluations Annual, 1993, p2015)

Structure
Thumb
Synonyms
2-amino-N,N'-bis(hexadecahydro-2,5,9-trimethyl-6,13-bis(1-methylethyl)-1,4,7,11,14-pentaoxo-1H-pyrrolo(2,1-I)(1,4,7,10,13)oxatetra-azacyclohexadecin-10-yl)-4,6-dimethyl-3-oxo-3H-phenoxazine-1,9-dicarboxamide
ActD
Actinomycin C1
Actinomycin D
Actinomycin iv
Dactinomicina
Dactinomycin
Dactinomycine
Dactinomycinum
Meractinomycin
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Cosmegeninjection, powder, lyophilized, for solution.5 mg/mLintravenousRECORDATI RARE DISEASES, INC.1964-12-10Not applicableUs
Cosmegenpowder for solution0.5 mgintravenousRecordati Rare Diseases Inc1963-12-31Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
Lyovac CosmegenLundbeck
Brand mixturesNot Available
SaltsNot Available
Categories
UNII1CC1JFE158
CAS number50-76-0
WeightAverage: 1255.417
Monoisotopic: 1254.628474764
Chemical FormulaC62H86N12O16
InChI KeyInChIKey=RJURFGZVJUQBHK-IIXSONLDSA-N
InChI
InChI=1S/C62H86N12O16/c1-27(2)42-59(84)73-23-17-19-36(73)57(82)69(13)25-38(75)71(15)48(29(5)6)61(86)88-33(11)44(55(80)65-42)67-53(78)35-22-21-31(9)51-46(35)64-47-40(41(63)50(77)32(10)52(47)90-51)54(79)68-45-34(12)89-62(87)49(30(7)8)72(16)39(76)26-70(14)58(83)37-20-18-24-74(37)60(85)43(28(3)4)66-56(45)81/h21-22,27-30,33-34,36-37,42-45,48-49H,17-20,23-26,63H2,1-16H3,(H,65,80)(H,66,81)(H,67,78)(H,68,79)/t33-,34-,36+,37+,42-,43-,44+,45+,48+,49+/m1/s1
IUPAC Name
N1,N9-bis[(6S,9R,10S,13R,18aS)-2,5,9-trimethyl-1,4,7,11,14-pentaoxo-6,13-bis(propan-2-yl)-hexadecahydro-1H-pyrrolo[2,1-i]1-oxa-4,7,10,13-tetraazacyclohexadecan-10-yl]-2-amino-4,6-dimethyl-3-oxo-3H-phenoxazine-1,9-dicarboxamide
SMILES
[H][C@@]12CCCN1C(=O)[[email protected]](NC(=O)[C@@H](NC(=O)C1=C3N=C4C(OC3=C(C)C=C1)=C(C)C(=O)C(N)=C4C(=O)N[[email protected]]1[C@@H](C)OC(=O)[[email protected]](C(C)C)N(C)C(=O)CN(C)C(=O)[C@]3([H])CCCN3C(=O)[[email protected]](NC1=O)C(C)C)[C@@H](C)OC(=O)[[email protected]](C(C)C)N(C)C(=O)CN(C)C2=O)C(C)C
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as cyclic depsipeptides. These are natural or synthetic compounds having sequences of amino and hydroxy carboxylic acid residues (usually α-amino and α-hydroxy acids) connected in a ring. The residues are commonly but not necessarily regularly alternating.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentCyclic depsipeptides
Alternative Parents
Substituents
  • Cyclic depsipeptide
  • Phenoxazine
  • Macrolide lactam
  • N-acyl-alpha amino acid or derivatives
  • Macrolactam
  • Alpha-amino acid ester
  • 2-aminobenzamide
  • Aminobenzoic acid or derivatives
  • Benzamide
  • Aminobenzamide
  • Benzoyl
  • Benzenoid
  • Primary aromatic amine
  • Dicarboxylic acid or derivatives
  • Heteroaromatic compound
  • Vinylogous amide
  • Tertiary carboxylic acid amide
  • Pyrrolidine
  • Cyclic ketone
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Lactone
  • Lactam
  • Carboxylic acid ester
  • Carboxamide group
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of Wilms' tumor, childhood rhabdomyosarcoma, Ewing's sarcoma and metastatic, nonseminomatous testicular cancer as part of a combination chemotherapy and/or multi-modality treatment regimen
PharmacodynamicsGenerally, the actinomycins exert an inhibitory effect on gram-positive and gram-negative bacteria and on some fungi. However, the toxic properties of the actinomycins (including dactinomycin) in relation to antibacterial activity are such as to preclude their use as antibiotics in the treatment of infectious diseases. Because the actinomycins are cytotoxic, they have an antineoplastic effect which has been demonstrated in experimental animals with various types of tumor implant. This cytotoxic action is the basis for their use in the treatment of certain types of cancer. Dactinomycin is believed to produce its cytotoxic effects by binding DNA and inhibiting RNA synthesis.
Mechanism of actionGood evidence exists that this drug bind strongly, but reversibly, to DNA, interfering with synthesis of RNA (prevention of RNA polymerase elongation) and, consequently, with protein synthesis.
Related Articles
Absorptionpoorly absorbed from gastrointestinal tract
Volume of distributionNot Available
Protein binding5%
Metabolism

hepatic

Route of eliminationNot Available
Half life36 hours
ClearanceNot Available
Toxicityhepatoxicity
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.7619
Blood Brain Barrier-0.9659
Caco-2 permeable-0.6568
P-glycoprotein substrateSubstrate0.8368
P-glycoprotein inhibitor INon-inhibitor0.6482
P-glycoprotein inhibitor IINon-inhibitor0.8638
Renal organic cation transporterNon-inhibitor0.8178
CYP450 2C9 substrateNon-substrate0.8589
CYP450 2D6 substrateNon-substrate0.8535
CYP450 3A4 substrateSubstrate0.759
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.923
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8614
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8681
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.9019
BiodegradationNot ready biodegradable0.983
Rat acute toxicity4.3767 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9208
hERG inhibition (predictor II)Non-inhibitor0.5171
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Lundbeck inc
  • Bedford laboratories div ben venue laboratories inc
Packagers
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionintravenous.5 mg/mL
Powder for solutionintravenous0.5 mg
Prices
Unit descriptionCostUnit
Cosmegen 0.5 mg vial684.36USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point241.5-243 °CNot Available
water solubilitySoluble at 10 °CNot Available
logP1.6Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.02 mg/mLALOGPS
logP2.76ALOGPS
logP-0.097ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)10.52ChemAxon
pKa (Strongest Basic)-0.13ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count16ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area355.54 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity326.17 m3·mol-1ChemAxon
Polarizability129.2 Å3ChemAxon
Number of Rings7ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Waksman, S.A. and Woodruff, H.B.; US. Patent 2,378,876; June 19,1945; assigned to
Merck & Co., Inc.

General References
  1. Sobell HM: Actinomycin and DNA transcription. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5328-31. [PubMed:2410919 ]
  2. Turan T, Karacay O, Tulunay G, Boran N, Koc S, Bozok S, Kose MF: Results with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) chemotherapy in gestational trophoblastic neoplasia. Int J Gynecol Cancer. 2006 May-Jun;16(3):1432-8. [PubMed:16803542 ]
  3. Abd El-Aal HH, Habib EE, Mishrif MM: Wilms' tumor: the experience of the pediatric unit of Kasr El-Aini center of radiation oncology and nuclear medicine (NEMROCK). J Egypt Natl Canc Inst. 2005 Dec;17(4):308-14. [PubMed:17102824 ]
  4. Khatua S, Nair CN, Ghosh K: Immune-mediated thrombocytopenia following dactinomycin therapy in a child with alveolar rhabdomyosarcoma: the unresolved issues. J Pediatr Hematol Oncol. 2004 Nov;26(11):777-9. [PubMed:15543019 ]
External Links
ATC CodesL01DA01
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
ClozapineThe risk or severity of adverse effects can be increased when Dactinomycin is combined with Clozapine.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Dactinomycin.
LeflunomideThe risk or severity of adverse effects can be increased when Dactinomycin is combined with Leflunomide.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Dactinomycin.
NatalizumabThe risk or severity of adverse effects can be increased when Dactinomycin is combined with Natalizumab.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Dactinomycin.
RoflumilastRoflumilast may increase the immunosuppressive activities of Dactinomycin.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Dactinomycin.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Dactinomycin.
TofacitinibDactinomycin may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Dactinomycin.
Food InteractionsNot Available

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
yes
Actions
adduct
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
  3. Yang XL, Wang AH: Structural studies of atom-specific anticancer drugs acting on DNA. Pharmacol Ther. 1999 Sep;83(3):181-215. [PubMed:10576292 ]
  4. Sobell HM: Actinomycin and DNA transcription. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5328-31. [PubMed:2410919 ]
  5. Hudson JS, Brooks SC, Graves DE: Interactions of actinomycin D with human telomeric G-quadruplex DNA. Biochemistry. 2009 Jun 2;48(21):4440-7. doi: 10.1021/bi900203z. [PubMed:19348506 ]
Kind
Protein group
Organism
Homo sapiens
Pharmacological action
unknown
General Function:
Ubiquitin binding
Specific Function:
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes. May play a role in regulating the period length of ARNTL/BMAL1 transcriptional oscillation (By similarity).
Components:
NameUniProt IDDetails
DNA topoisomerase 2-alphaP11388 Details
DNA topoisomerase 2-betaQ02880 Details
References
  1. Felix CA, Hosler MR, Winick NJ, Masterson M, Wilson AE, Lange BJ: ALL-1 gene rearrangements in DNA topoisomerase II inhibitor-related leukemia in children. Blood. 1995 Jun 1;85(11):3250-6. [PubMed:7756657 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Symporter activity
Specific Function:
Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine. Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Also relative uptake activity ratio of carnitine to TEA is 11.3.
Gene Name:
SLC22A5
Uniprot ID:
O76082
Molecular Weight:
62751.08 Da
References
  1. Ohashi R, Tamai I, Yabuuchi H, Nezu JI, Oku A, Sai Y, Shimane M, Tsuji A: Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999 Nov;291(2):778-84. [PubMed:10525100 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
References
  1. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS: Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001 Nov;299(2):620-8. [PubMed:11602674 ]
  2. Nagy H, Goda K, Fenyvesi F, Bacso Z, Szilasi M, Kappelmayer J, Lustyik G, Cianfriglia M, Szabo G Jr: Distinct groups of multidrug resistance modulating agents are distinguished by competition of P-glycoprotein-specific antibodies. Biochem Biophys Res Commun. 2004 Mar 19;315(4):942-9. [PubMed:14985103 ]
  3. Ambudkar SV, Lelong IH, Zhang J, Cardarelli CO, Gottesman MM, Pastan I: Partial purification and reconstitution of the human multidrug-resistance pump: characterization of the drug-stimulatable ATP hydrolysis. Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8472-6. [PubMed:1356264 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Transporter activity
Specific Function:
Isoform 1: May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Transports glutathione conjugates as leukotriene-c4 (LTC4) and N-ethylmaleimide S-glutathione (NEM-GS).Isoform 2: Inhibits TNF-alpha-mediated apoptosis through blocking one or more caspases.
Gene Name:
ABCC6
Uniprot ID:
O95255
Molecular Weight:
164904.81 Da
References
  1. Belinsky MG, Chen ZS, Shchaveleva I, Zeng H, Kruh GD: Characterization of the drug resistance and transport properties of multidrug resistance protein 6 (MRP6, ABCC6). Cancer Res. 2002 Nov 1;62(21):6172-7. [PubMed:12414644 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Transporter activity
Specific Function:
Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics. Confers resistance to anticancer drugs. Hydrolyzes ATP with low efficiency.
Gene Name:
ABCC1
Uniprot ID:
P33527
Molecular Weight:
171589.5 Da
References
  1. Breuninger LM, Paul S, Gaughan K, Miki T, Chan A, Aaronson SA, Kruh GD: Expression of multidrug resistance-associated protein in NIH/3T3 cells confers multidrug resistance associated with increased drug efflux and altered intracellular drug distribution. Cancer Res. 1995 Nov 15;55(22):5342-7. [PubMed:7585598 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from t...
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
Molecular Weight:
72313.47 Da
References
  1. Wang X, Furukawa T, Nitanda T, Okamoto M, Sugimoto Y, Akiyama S, Baba M: Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. Mol Pharmacol. 2003 Jan;63(1):65-72. [PubMed:12488537 ]
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Drug created on June 13, 2005 07:24 / Updated on April 10, 2014 11:30