Description
Actinomycin D (50-76-0) is a cyclopeptide antibiotic and intercalating transcription inhibitor with anti-neoplastic activity. Potent inhibitor of RNA polymerase.1Induces apoptosis in a variety of cancer cell lines2,3via the intrinsic pathway4. Upregulates proapoptotic PUMA and downregulates Bcl-2 mRNA in peripheral blood lymphocytes.5
Chemical Properties
red crystalline powder
Chemical Properties
Actinomycin D is a combustible, bright red crystalline solid.
Originator
Cosmegen,Merck Sharp and
Dohme,US,1965
Uses
An antineoplastic antibiotic that inhibits cell proliferation by forming a stable complex with DNA and blocking the movement of RNA polymerase which interferes with DNA-dependent RNA synthesis. Induces apoptosis. Potent antitumor agent.
Uses
Antibiotic substance belonging to the actinomycin complex, produced by several Streptomyces spp. Antineoplastic
Uses
antineoplastic, intercalating agent
Uses
Actinomycin D is the most studied member of a family of unique bicyclic depsipeptides produced by several Streptomyces species. The depsipeptides are linked by a heterocyclic benzoxazone "anchor" that gives the metabolites a highly distinctive red/orange colour. Actinomycin D exhibits potent antibiotic and antitumour activity via DNA intercalation leading to the inhibition of nucleic acid synthesis. Tumour cell death has been demonstrated to occur by apoptosis.
Definition
ChEBI: Actinomycin D is an actinomycin. It has a role as a mutagen.
Indications
Dactinomycin (actinomycin D, Cosmegen) is one of a
family of chromopeptides produced by Streptomyces. It
is known to bind noncovalently to double-strand DNA
by partial intercalation, inhibiting DNA-directed RNA
synthesis. The drug is most toxic to proliferating cells,
but it is not specific for any one phase of the cell cycle.
Resistance to dactinomycin is caused by decreased ability
of tumor cells to take up and retain the drug, and it
is associated with cross-resistance to vinca alkaloids, the
anthracyclines, and certain other agents (multidrug resistance).
Manufacturing Process
An incubated culture of Actinomyces antibioticus was prepared using a
medium consisting of 1% tryptone-peptone, 0.5% starch, 0.2% K2HPO4, 0.2%
NaCl and 0.25% agar in distilled water, grown at a temperature of
approximately 25° to 35°C, the incubation being complete after 6 to 10 days.
50 liters of this incubated culture are extracted approximately six times with
ether, using 20 liters of ether for each extraction.
The final extract is faintly pale yellow in color, whereas the previous extracts
are orange. The combined ether extracts are concentrated to dryness and
about 3 grams of a reddish-brown residue is obtained. The residue is stirred
with approximately 400 cc of petroleum ether for two to three hours, the
solvent decanted and the residue treated again with approximately 400 cc of
petroleum ether. A pale yellow oil constituting crude actinomycin B is
recovered by evaporation from the petroleum ether.
The dark petroleum ether insoluble residue is dissolved in 1 liter of benzene
with gentle heating. Usually a small amount of black amorphous material
remains undissolved and is filtered off. The benzene solution is permitted to
drop through a chromatographic tower (60 x 5 cm) packed with aluminum
oxide (according to Brockman). The pigment is readily adsorbed. The column
is washed with about 1 liter of benzene during which operation very little
migration of the color bands occurs.
The column is then washed with benzene-acetone solution (15:85) whereby a
chromatogram develops. By continued washing, light yellow colored pigments
pass out of the column. When the main band (orange-red) reaches the lower
end of the column, a solution of 30:70 acetone-benzene is passed through the
column. The latter solvent elutes the pigment and when the eluate is very
pale in color, washing is discontinued.
The eluate is concentrated to dryness under reduced pressure, taken up in 25
cc of hot acetone, filtered, and diluted with ether. The pigment which
crystallizes as red-brick colored platelets is essentially pure but may be
recrystallized if desired from hot ethyl acetate. An analysis of the product
showed C = 59.01; H = 6.81; N = 13.38.
brand name
Cosmegen (Ovation).
Therapeutic Function
Cancer chemotherapy
General Description
Bright red rhomboid prisms or red powder.
General Description
Dactinomycin is available in vials containing 0.5 mg of drugfor reconstitution in sterile water for IV administration Thisantibiotic is most effective in the treatment of rhabdomyosarcomaand Wilms tumor in children as well as in the treatmentof choriocarcinoma, Ewing sarcoma, Kaposi sarcoma, andtesticular carcinoma. The pharmacokinetics of dactinomycinhas not been well characterized, but it appears to concentratein nucleated blood cells. The agent is 5% to 15% plasmaprotein bound and is excreted mostly unchanged in urineand bile. Other metabolites have not been characterized.The terminal elimination half-life is 30 to 40 hours.Myelosuppression is dose limiting with both leucopenia andthrombocytopenia being the most likely presentation. Nauseaand vomiting occur shortly (2 hours) after treatment and maybe severe. Mucositis and diarrhea also result from irritation ofthe GI tract. Hair loss is commonly associated with the agentas is hyperpigmentation of the skin and erythema.
Air & Water Reactions
Water soluble.
Reactivity Profile
Actinomycin D can react with strong oxidizing agents, strong acids and strong bases.
Fire Hazard
Flash point data for Actinomycin D are not available. Actinomycin D is probably combustible.
Biological Activity
Anti-neoplastic antibiotic. Inhibits RNA polymerase and is a potent inducer of apoptosis.
Mechanism of action
Dactinomycin is cleared rapidly from plasma, does
not enter the brain, is not appreciably metabolized or
protein bound, and is gradually excreted in both bile
and urine.Virtually no drug is detected in CSF.
Clinical Use
Dactinomycin is used in curative combined treatment
of Wilms’ tumor, Ewing’s sarcoma, rhabdomyosarcoma,
and gestational choriocarcinoma. It is active in
testicular tumors, lymphomas, melanomas, and sarcomas,
although its use in most of these malignancies has
been supplanted by other agents.
Side effects
The major side effects of dactinomycin are severe
nausea, vomiting, and myelosuppression. Mucositis, diarrhea,
alopecia, and radiation recall reactions may occur.
The drug is immunosuppressive and carcinogenic.
Potential Exposure
An antibiotic product from streptomyces, used as anticancer and veterinary drug
Veterinary Drugs and Treatments
Dactinomycin has been used as adjunctive treatment of lymphoreticular
neoplasms,
bone and soft tissue sarcomas, and carcinomas
in small animals. It appears to have low efficacy against most carcinomas
and sarcomas. It is being investigated as a part of protocols
for rescue therapy for canine lymphomas.
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: increased risk of agranulocytosis
with clozapine - avoid.
Cytotoxics: increased risk of hepatotoxicity with
vincristine.
Vaccines: risk of generalised infections with live
vaccines - avoid.
Metabolism
Intravenous doses of dactinomycin are rapidly distributed
with high concentrations in bone marrow and nucleated
cells. It undergoes only minimal metabolism and is
slowly excreted in urine and bile. 15% is eliminated by
hepatic metabolism. Approximately 30% of the dose was
recovered in the urine and faeces in 1 week.
Shipping
UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required.
Purification Methods
It crystallises as bright red rhombic crystals from absolute EtOH or from MeOH/EtOH (1:3). It will also crystallise from EtOAc/cyclohexane (m 246-247o dec), CHCl3/pet ether ( m 245-246o dec), and EtOAc/MeOH/*C6H6 (m 241-243o dec). Its solubility in MeCN is 1mg/mL. [] D varies from -296o to -327o (c 0.2, MeOH). max (MeOH) 445, 240nm (log 4.43, 4.49), max (MeOH, 10N HCl, 1:1) 477nm (log 4.21) and max (MeOH, 0.1N NaOH) 458, 344, 285 (log 3.05, 4.28, 4.13). It is HIGHLY TOXIC, light sensitive and anti-neoplastic. [Bullock & Johnson, J Chem Soc 3280 1957, Beilstein 27 III/IV 9642.]
Incompatibilities
Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides.
Background
Actinomycin D is an effective anti-tumor agent and the most widely studied member of the actinomycin group of antibiotics. The compound, isolated from soil bacteria of the Streptomyces genus, is comprised of two cyclic pentapeptides bound by a phenoxazone group. Actinomycin D inhibits mRNA transcription in mammalian cells. Actinomycin D intercalates DNA and stabilizes topoisomerase I-DNA covalent complexes, blocking RNA chain elongation by RNA polymerase and consequently inhibiting protein synthesis. This mechanism of action induces p53-mediated cell cycle arrest in numerous cancer cell lines and at high concentrations can induce apoptosis. Additional research studies show that Akt mediates actinomycin D-induced p53 expression.
References
[1] STACEY D WAGNER. RNA polymerase II acts as an RNA-dependent RNA polymerase to extend and destabilize a non-coding RNA.[J]. The EMBO Journal, 2013: 781-790. DOI:
10.1038/emboj.2013.18[2] JÖRG KLEEFF. Actinomycin D induces apoptosis and inhibits growth of pancreatic cancer cells[J]. International Journal of Cancer, 2000, 86 3: 399-407. DOI:
10.1002/(sici)1097-0215(20000501)86:3<399::aid-ijc15>3.0.co;2-g[3] NEDA R. KASIM. Live fluorescence and transmission-through-dye microscopic study of actinomycin D-induced apoptosis and apoptotic volume decrease[J]. Apoptosis, 2013, 18 4: 521-532. DOI:
10.1007/s10495-013-0804-z[4] XIU FEN LIU. Actinomycin D enhances killing of cancer cells by immunotoxin RG7787 through activation of the extrinsic pathway of apoptosis.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 38: 10666-10671. DOI:
10.1073/pnas.1611481113[5] IVAN KALOUSEK. Actinomycin D upregulates proapoptotic protein Puma and downregulates Bcl-2 mRNA in normal peripheral blood lymphocytes.[J]. Anti-Cancer Drugs, 2007, 18 7: 763-772. DOI:
10.1097/cad.0b013e3280adc905[6] Y. MATSUZAKA. Characterization and Functional Analysis of Extracellular Vesicles and Muscle-Abundant miRNAs (miR-1, miR-133a, and miR-206) in C2C12 Myocytes and mdx Mice[J]. PLoS ONE, 2016, 11 1. DOI:
10.1371/journal.pone.0167811
