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targets (1) transporters (5)
for drugs
Identification
Name Dactinomycin
Accession Number DB00970 (APRD00124)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • AD
  • Antibiotic From Streptomyces Parvullus
  • Dactinomicina [INN-Spanish]
  • Dactinomycine [INN-French]
  • Dactinomycinum [INN-Latin]
Brand names
  • ACT
  • ACT D
  • Actactinomycin a Iv
  • Actinomycin 11 Cosmegen
  • Actinomycin 7
  • Actinomycin Aiv
  • Actinomycin C1
  • ACTINOMYCIN D
  • Actinomycin I
  • Actinomycin I1
  • Actinomycin Iv
  • Actinomycin X 1
  • Actinomycindioic D Acid, Dilactone
  • ACTO-D
  • Chounghwamycin B
  • Cosmegen
  • Dactinomycin D
  • Dilactone Actinomycin D Acid
  • Dilactone Actinomycindioic D Acid
  • HBF 386 Meractinomycin
  • Lyovac Cosmegen
  • Meractinomycin
  • Oncostatin K
  • Oxamide
Brand name mixtures Not Available
Categories
  • Antineoplastic Agents
  • Anti-Bacterial Agents
  • Nucleic Acid Synthesis Inhibitors
  • Antibiotics
  • Antibiotics, Antineoplastic
  • Protein Synthesis Inhibitors
CAS number 50-76-0
Weight Average: 1255.417
Monoisotopic: 1254.628474764
Chemical Formula C62H86N12O16
InChI Key InChIKey=RJURFGZVJUQBHK-UHFFFAOYSA-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)
Plain Text
IUPAC Name
2-amino-4,6-dimethyl-3-oxo-1-N,9-N-bis[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]-3H-phenoxazine-1,9-dicarboxamide
SMILES
CC(C)C1NC(=O)C(NC(=O)C2=CC=C(C)C3=C2N=C2C(O3)=C(C)C(=O)C(N)=C2C(=O)NC2C(C)OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C3CCCN3C(=O)C(NC2=O)C(C)C)C(C)OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C1=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Lactams
  • Benzoyl Derivatives
  • Benzamides
Substructures
  • Carboxylic Acids and Derivatives
  • Acetates
  • Lactones
  • Amino Ketones
  • Aliphatic and Aryl Amines
  • Pyrrolidines
  • Ethers
  • Benzene and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Lactams
  • Imines
  • Benzoyl Derivatives
  • Benzamides
Pharmacology
Indication For 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
Pharmacodynamics Generally, 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 action Good 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.
Absorption poorly absorbed from gastrointestinal tract
Volume of distribution Not Available
Protein binding 5%
Metabolism

hepatic
Route of elimination Not Available
Half life 36 hours
Clearance Not Available
Toxicity hepatoxicity
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Lundbeck inc
  • Bedford laboratories div ben venue laboratories inc
Packagers
Dosage forms
Form Route Strength
Powder, for solution Intravenous
Prices
Unit description Cost Unit
Cosmegen 0.5 mg vial 684.36 USD vial
Patents Not Available
Properties
State solid
Melting point 241.5 - 243 oC
Experimental Properties
Property Value Source
water solubility Soluble at 10°C PhysProp
logP 1.6 PhysProp
Predicted Properties
Property Value Source
water solubility 2.00e-02 g/l ALOGPS
logP 2.76 ALOGPS
logP -0.10 ChemAxon Molconvert
logS -4.80 ALOGPS
pKa 11.10 ChemAxon Molconvert
hydrogen acceptor count 16 ChemAxon Molconvert
hydrogen donor count 5 ChemAxon Molconvert
polar surface area 355.54 ChemAxon Molconvert
rotatable bond count 8 ChemAxon Molconvert
refractivity 326.17 ChemAxon Molconvert
polarizability 131.82 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Sobell HM: Actinomycin and DNA transcription. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5328-31. Pubmed
  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
  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
  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
External Links
Resource Link
KEGG Drug D00214 Link_out
KEGG Compound C06770 Link_out
PubChem Compound 2019 Link_out
PubChem Substance 46509192 Link_out
ChemSpider 1942 Link_out
BindingDB 50023797 Link_out
ChEBI 27666 Link_out
ChEMBL 27666 Link_out
Therapeutic Targets Database DNC000380 Link_out
PharmGKB PA449199 Link_out
Drug Product Database 213071 Link_out
RxList http://www.rxlist.com/cgi/generic2/dactinomycin.htm Link_out
Drugs.com http://www.drugs.com/cdi/dactinomycin.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Dactinomycin Link_out
ATC Codes
  • L01DA01
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. DNA

Pharmacological action: yes
Actions: adduct

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

Gene Sequence: FASTA

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
  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
  3. Yang XL, Wang AH: Structural studies of atom-specific anticancer drugs acting on DNA. Pharmacol Ther. 1999 Sep;83(3):181-215. Pubmed
  4. Sobell HM: Actinomycin and DNA transcription. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5328-31. Pubmed
  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. Pubmed
Transporters

1. Organic cation/carnitine transporter 2

Actions: inhibitor

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

UniProt ID: O76082 Link_out
Gene: SLC22A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

2. Multidrug resistance protein 1

Actions: substrate, inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  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

3. Multidrug resistance-associated protein 6

Actions: substrate

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)

UniProt ID: O95255 Link_out
Gene: ABCC6 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

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

4. Multidrug resistance-associated protein 1

Actions: substrate

May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Confers resistance to anticancer drugs. Transports LTC4. May protect milk against xenobiotics

UniProt ID: P33527 Link_out
Gene: ABCC1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

5. ATP-binding cassette sub-family G member 2

Actions: substrate

Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. May be involved in brain-to-blood efflux. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. When overexpressed, the transfected cells become resistant to mitoxantrone, daunorubicin and doxorubicin, display diminished intracellular accumulation of daunorubicin, and manifest an ATP- dependent increase in the efflux of rhodamine 123

UniProt ID: Q9UNQ0 Link_out
Gene: ABCG2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on August 18, 2011 10:25

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.