Dactinomycin

Actinomycin D
Systematic (IUPAC) name
2-Amino-N,N′- bis[(6S,9R,10S,13R,18aS)-6,13-diisopropyl-2,5,9-trimethyl-1,4,7,11,14-pentaoxohexadecahydro-1H-pyrrolo[2,1-i][1,4,7,10,13]oxatetraazacyclohexadecin-10-yl]-4,6-dimethyl-3-oxo-3H-phenoxazine-1,9-dicarboxamide
Clinical data
Trade names Cosmegen
AHFS/Drugs.com monograph
MedlinePlus a682224
  • AU: D
  • US: D (Evidence of risk)
IV
Pharmacokinetic data
Protein binding 5%
Half-life 36 hours
Identifiers
50-76-0 Yes
L01DA01
PubChem CID 2019
DrugBank DB00970 
ChemSpider 10482167 Yes
UNII 1CC1JFE158 Yes
KEGG C06770 
ChEBI CHEBI:27666 Yes
ChEMBL CHEMBL1554 Yes
NIAID ChemDB 009885
Synonyms 2-Amino- 4,6-dimethyl- 3-oxo- 3H-phenoxazine- 1,9-dicarboxylic acid bis- [(5,12-diisopropyl- 9,13,16-trimethyl- 4,7,11,14,17-pentaoxo- hexadecahydro- 10-oxa- 3a,6,13,16-tetraaza- cyclopentacyclohexadecen- 8-yl)- amide]
Chemical data
Formula C62H86N12O16
1255.42 g/mol
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Dactinomycin (INN, BAN, AAN and USAN also known generically as actinomycin D), is the most significant member of actinomycines, which are a class of polypeptide antitumor antibiotics isolated from soil bacteria of the genus Streptomyces.[1] It is one of the older anticancer drugs, and has been used for many years.

History

Actinomycin D was the first antibiotic shown to have anti-cancer activity.[1] It was first isolated by Selman Waksman and his co-worker H. B. Woodruff in 1940.[2] It was approved by the U.S. Food and Drug Administration (FDA) on December 10, 1964 and launched by Merck Sharp and Dohme under the trade name Cosmegen.

Mechanism

In cell biology, Actinomycin D is shown to have the ability to inhibit transcription. Actinomycin D does this by binding DNA at the transcription initiation complex and preventing elongation of RNA chain by RNA polymerase.[3]

Clinical use

Actinomycin is a clear, yellow liquid administered intravenously and most commonly used in treatment of a variety of cancers, including:

Sometimes it will be combined with other drugs in Chemotherapy regimens, like the VAC regimen (with Vincristine and Cyclophosphamide) for treating rhabdomyosarcoma and Ewing's Sarcoma.

It is also used as a radiosensitizer in adjunct to radiotherapies, since it can increase the radiosensitivity of tumor cells by inhibiting repair of sublethal radiation damage and delay the onset of the compensatory hyperplasia that occurs following irradiation.[9]

Side effects

Common adverse drug reaction includes bone marrow suppression, fatigue, hair loss, mouth ulcer, loss of appetite and diarrhea. Actinomycin is a vesicant, if extravasation occurs.

Research use

Because Actinomycin can bind DNA duplexes, it can also interfere with DNA replication, although other chemicals such as hydroxyurea are better suited for use in the laboratory as inhibitors of DNA synthesis.

Actinomycin D and its fluorescent derivative, 7-aminoactinomycin D (7-AAD), are used as stains in microscopy and flow cytometry applications. The affinity of these stains/compounds for GC-rich regions of DNA strands makes them excellent markers for DNA. 7-AAD binds to single stranded DNA; therefore it is a useful tool in determining apoptosis and distinguishing between dead cells and live ones.[10]

References

  1. ↑ 1.0 1.1 Hollstein, U. (1974). "Actinomycin. Chemistry and mechanism of action". Chemical Reviews 74 (6): 625–652. doi:10.1021/cr60292a002.
  2. ↑ Waksman S A, Woodruff H B (1940). "Bacteriostatic and bacteriocidal substances produced by soil actinomycetes". Proc Soc Exper Biol 45: 609–614.
  3. ↑ Sobell H (1985). "Actinomycin and DNA transcription". Proceedings of the National Academy of Sciences of the United States of America 82 (16): 5328–31. doi:10.1073/pnas.82.16.5328. PMC 390561. PMID 2410919.
  4. ↑ Turan T, Karacay O, Tulunay G, Boran N, Koc S, Bozok S, Kose M (2006). "Results with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) chemotherapy in gestational trophoblastic neoplasia". Int J Gynecol Cancer 16 (3): 1432–8. doi:10.1111/j.1525-1438.2006.00606.x. PMID 16803542.
  5. ↑ D'Angio GJ, Evans A, Breslow N, Beckwith B, Bishop H, Farewell V, Goodwin W, Leape L, Palmer N, Sinks L, Sutow W, Tefft M, Wolff J (1981). "The treatment of Wilms' tumor: results of the Second National Wilms' Tumor Study.". Cancer 47 (9): 2302–11. PMID 6164480.
  6. ↑ Khatua S, Nair C, Ghosh K (2004). "Immune-mediated thrombocytopenia following dactinomycin therapy in a child with alveolar rhabdomyosarcoma: the unresolved issues". J Pediatr Hematol Oncol 26 (11): 777–9. doi:10.1097/00043426-200411000-00020. PMID 15543019.
  7. ↑ Jaffe, N.; Paed, D.; Traggis, D.; Salian, S.; Cassady, J. R. (1976). "Improved outlook for Ewing's sarcoma with combination chemotherapy (vincristine, actinomycin D and cyclophosphamide) and radiation therapy". Cancer 38 (5): 1925–1930. doi:10.1002/1097-0142(197611)38:5<1925::AID-CNCR2820380510>3.0.CO;2-J. PMID 991106.
  8. ↑ Uberti, E. M. H.; Fajardo, M. D. C.; Ferreira, S. V. V. R.; Pereira, M. C. V.; Seger, R. C.; Moreira, M. A. L. R.; Torres, M. D.; De Nápoli, G.; Schmid, H. (2009). "Reproductive outcome after discharge of patients with high-risk hydatidiform mole with or without use of one bolus dose of actinomycin D, as prophylactic chemotherapy, during the uterine evacuation of molar pregnancy". Gynecologic Oncology 115 (3): 476–481. doi:10.1016/j.ygyno.2009.09.012. PMID 19818481.
  9. ↑ Hagemann, R. F.; Concannon, J. P. (1973). "Mechanism of intestinal radiosensitization by actinomycin D". British Journal of Radiology 46 (544): 302–308. doi:10.1259/0007-1285-46-544-302. PMID 4720744.
  10. ↑ Toba, K.; Koike, T.; Watanabe, K.; Fuse, I.; Takahashi, M.; Hashimoto, S.; Takahashi, H.; Abe, T.; Yano, T.; Shibazaki, Y.; Itoh, H.; Aizawa, Y. (2000). "Cell kinetic study of normal humanbone marrow hematopoiesis andacute leukemia using 7AAD/PY". European Journal of Haematology 64 (1): 10–21. doi:10.1034/j.1600-0609.2000.09005.x. PMID 10680701.

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