50-76-0 Usage
Description
Actinomycin D, also known as Dactinomycin, is a cyclopeptide antibiotic and intercalating transcription inhibitor with potent anti-neoplastic activity. It is a member of the actinomycin complex, produced by several Streptomyces species. The antibiotic exhibits a bright red crystalline solid appearance and is characterized by its distinctive red/orange color due to the heterocyclic benzoxazone "anchor" that links the depsipeptides. Actinomycin D is a potent inhibitor of RNA polymerase and induces apoptosis in various cancer cell lines.
Uses
Used in Anticancer Applications:
Actinomycin D is used as an antineoplastic antibiotic for inhibiting cell proliferation by forming a stable complex with DNA and blocking the movement of RNA polymerase, which interferes with DNA-dependent RNA synthesis. This potent antitumor agent induces apoptosis in cancer cells and has been demonstrated to be effective in the treatment of various types of cancer, including rhabdomyosarcoma, Wilms tumor, choriocarcinoma, Ewing sarcoma, Kaposi sarcoma, and testicular carcinoma.
Used in Pharmaceutical Industry:
Actinomycin D is used as an intercalating agent for its potent antibiotic and antitumor activity via DNA intercalation, leading to the inhibition of nucleic acid synthesis. This property makes it a valuable compound in the development of new drugs and therapies for cancer treatment.
Used in Research and Development:
Actinomycin D is used as a research tool for studying the mechanisms of apoptosis and the regulation of gene expression in cancer cells. Its ability to upregulate proapoptotic PUMA and downregulate Bcl-2 mRNA in peripheral blood lymphocytes makes it a useful compound for understanding the intrinsic pathway of apoptosis and its role in cancer cell death.
Brand Name:
Actinomycin D is commercially available under the brand name Cosmegen (Ovation).
Originator
Cosmegen,Merck Sharp and
Dohme,US,1965
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.
Therapeutic Function
Cancer chemotherapy
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 drugsAntipsychotics: 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.
References
1) Wagner?et al.(2013)?RNA Polymerase II acts as an RNA-dependent RNA polymerase to extend and destabilize a non-coding RNA ; EMBO J.?32?781
2) J. Kleeff?et al.?(2000)?Actinomycin D induces apoptosis and inhibits growth of pancreatic cancer cells; Int. J. Cancer,?86?399
3) Kasim?et al.?(2013)?Live fluorescence and transmission-through-dye microscopic study of actinomycin D-induced apoptosis and apoptotic volume decrease?; Apoptosis,18?521
4) Liu?et al.?(2016)?Actinomycin D enhances killing of cancer cells by immunotoxin RG7787 through activation of the extrinsic pathway of apoptosis; Proc. Natl. Acad. Sci. USA,?113?10666
5) Kalousec?et al.?(2007)?Actinomycin D upregulates proapoptotic protein Puma and downregulates Bcl-2 mRNA in normal peripheral blood lymphocytes; Anticancer Drugs,?18?763
6) Matsuzaka?et al. (2016)?Characterization and functional analysis of extracellular vesicles and muscle-abundant miRNA in C2C12 myocytes and Mdx mice; PLoS One11(12)?e0167811 [Focus Biomolecules Citation]
Check Digit Verification of cas no
The CAS Registry Mumber 50-76-0 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 0 respectively; the second part has 2 digits, 7 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 50-76:
(4*5)+(3*0)+(2*7)+(1*6)=40
40 % 10 = 0
So 50-76-0 is a valid CAS Registry Number.
InChI:InChI=1/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
50-76-0Relevant articles and documents
THERAPEUTIC FOR HEPATIC CANCER
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, (2011/02/18)
A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
Synthetic lipid-a-analogs and uses thereof
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, (2009/03/07)
New synthetic Lipid-A analogs based on monosaccharide (1) and disaccharide (2) derivatives were designed and prepared in the present invention. Both structures (1) and (2) incorporate novel lipid structures (3) and (4) that are not found in nature. Also, novel disaccharide Lipid-A structures (2) that incorporate novel contingents of uniform lipids and where R1, R4 and R5 are the same substitution group of structure (III) were synthesized. Liposome formulations containing totally synthetic components such as synthetic Lipid-A and synthetic lipopeptide derived from tumor-associated MUC1 mucin are described along with their therapeutic utility. Comparative test results of immunostimulating properties and toxicity of Lipid-A analogs (1) and (2) are included.
Modified nucleosides for the treatment of viral infections and abnormal cellular proliferation
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, (2008/06/13)
The disclosed invention is a composition for and a method of treating a Flaviviridae (including BVDV and HCV), Orthomyxoviridae (including Influenza A and B) or Paramyxoviridae (including RSV) infection, or conditions related to abnormal cellular proliferation, in a host, including animals, and especially humans, using a nucleoside of general formula (I)-(XXIII) or its pharmaceutically acceptable salt or prodrug. This invention also provides an effective process to quantify the viral load, and in particular BVDV, HCV or West Nile Virus load, in a host, using real-time polymerase chain reaction (""RT-PCR""). Additionally, the invention discloses probe molecules that can fluoresce proportionally to the amount of virus present in a sample.
