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Actinomycin D

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General Features                  Clinical Study                  Chemical Intervention                 Pharmacological Aspects                 
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GENERAL FEATURES

Name: Actinomycin D
Generic Names: Actinomycin C1[1],[2]
NSC-3053[3]
Dactinomycin[2]
Trade Names: Cosmegen®,Merck[2]
IUPAC name:
Molecular Weight: 1255.45 daltons[2]
Structure:
[4],[5],[6],[1],[7],[8],[9],[10],[11]

Molecule consists of an approximately planar phenoxazone ring system connected by amide linkages to two identical cyclic pentapeptide lactones[2]
The outer face of the drug is mainly hydrophobic, with a few carbonyl oxygen atoms coming out. This characteristic is necessary for transporting the molecule through membranes before it actually reaches its target.[2]
Drug exhibited conformational flexibility controlled by localized hinge regions[2]
Functional Group/
chemical
constitution:
Lactone groupimgs, D-valyl groups[12]
two cyclic pentapeptide linkages [7], termed as alpha-ring and beta-ring, attached to the quinonoid and benzenoid rings of the phenoxazone group[4]
phenoxazone chromophore of the drug has amino-substituted quinonoid end and the benzenoid end [2]
Chemical Nature: Lipid-soluble, uncharged[13]
Actinomycin D is soluble in alcohols, but only sparingly soluble in water.[2]
Actinomycin shows a remarkable increase in solubility with temperature decrease[14]
Actions
& Indications:
Pharmcological Action-
Anti-timor activity[15], [16]
Bacteriostatic activity especially against gram-positive bacteria[17]
cytotoxic antibiotic[18], [16]
Preclinical study-
Actinomycin D alone proved effective in children with rhabdomyosarcoma, Wilm’s tumor, sarcoma of mesentry[19]
Actinomycin D at, 0.1 µg/ml inhibits production of mouse leukemia virus(MLV) by JLS V-5 cells in tissue culture.[20]
Notes: Actinomycin D activity is dependent on ability of cells to accumulate and retain the drug, as evidenced by study with mouse leukemia in vitro[13]
Treatment of amphibian embryonic cell with Actinomycin D, led to appearance of chromosomal threads in area of nucleus which are otherwise empty[21]
actinomycin D(IP injection) from same lot has been shown to exhibit unexplainable variation in its antitumor effect in mouse tumors [22]
It was shown that under anaerobic conditions the ferredoxin reductase/NADPH system could reduce actinomycin D to produce a semiquinone-imine free radical; however intercalated actinomycin D did not undergo reduction by this system. Under aerobic conditions the ferredoxin reductase/NADPH/actinomycin D system generated the superoxide anion radical[23]
To minimize cell-to-and dish-to-cell Interactions and toxicity of the drug, adequate rinsing, minimal cell inocula, and large final volumes of growth medium should be used[24]
Actinomycin D
resistance:
Resistant cells:
HeLa-R-4 cells[25]
Sensitive cells:
HeLa-S cell[25]
Cells in G2(G-mitosis) phase are found to be resistant to action of actinomycin D in an in vitro study with Chinese hamster ovary cells[26],[24]
Chinese hamster ovary cells become resistant to actinomycin D in the latter part of S phase. [25]
G1 phase was found to be sensitive to the action of actinomycin D in a study with mice crypt cells in vivo[27]
REFERENCES
1. Hamilton LD, Fuller W, Reich E, X-ray diffraction and molecular model building studies of the interaction of actinomycin with nucleic acids. Nature. 1963 ;198:538-40.
http://dx.doi.org/10.1038/198538b0
2. Ginell S, Lessinger L, Berman HM, The crystal and molecular structure of the anticancer drug actinomycin D--some explanations for its unusual properties.Biopolymers. 1988;27(5):843-64.
http://dx.doi.org/10.1002/bip.360270511
3. Galbraith WM, Mellett LB, Tissue disposition of 3H-actinomycin D (NSC-3053) in the rat, monkey, and dog. Cancer Chemother Rep. 1975;59(6):1601-9.
http://www.ncbi.nlm.nih.gov/pubmed/816458
4. Lo YS et al,The structural basis of actinomycin D–binding induces nucleotide flipping out, a sharp bend and a left-handed twist in CGG triplet repeats. Nucleic Acids Res. 2013;41(7):4284-94.
http://dx.doi.org/10.1093/nar/gkt084
5. Takusagawa HL, Takusagawa F, Crystallization and preliminary X-ray diffraction studies of d(ACGTAGCTACGT)2:[actinomycin D, (echinomycin)2] and d(ACGTAGCTACGT)2:[actinomycin D, (triostin A)2] complexes. Acta Crystallogr D Biol Crystallogr. 2000;56(Pt 3):344-7.
http://dx.doi.org/10.1107/S0907444999016790
6. Cerami A et al, The interaction of actinomycin with DNA: requirement for the 2-amino group of purines. Proc Natl Acad Sci U S A. 1967; 57(4): 1036–1042.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC224651/
7. Krugh TR, Association of actinomycin D and deoxyribodinucleotides as a model for binding of the drug to DNA. Proc Natl Acad Sci U S A. 1972;69(7):1911-4.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC426830/
8. Kamitori S, Takusagawa F, Multiple binding modes of anticancer drug Actinomycin D: X-ray, molecular modeling, and spectroscopic studies of d(GAAGCTTC)2-Actinomycin D complexes and its host DNA. J. Am. Chem. Soc., 1994; 116 (10):4154–4165.
http://dx.doi.org/10.1021/ja00089a002
9. Reich E, Actinomycin: Correlation of Structure and Function of Its Complexes with Purines and DNA. Science. 1964;143(3607):684-9.
http://dx.doi.org/10.1126/science.143.3607.684
10. Snyder JG et al, Binding of actinomycin D to DNA: evidence for a nonclassical high-affinity binding mode that does not require GpC sites. Proc Natl Acad Sci U S A. 1989 ;86(11):3968-72.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC287369/
11. Bases RE, Modification of the radiation response determined by single-cell technics: actinomycin D. Cancer Res. 1959;19:1223-9.
http://www.ncbi.nlm.nih.gov/pubmed/13797365
12. Bullock E, Johnson AW, Actinomycin. Part V. The structure of actinomycin D. J. Chem. Soc. 1957;3280-3285.
http://dx.doi.org/10.1039/JR9570003280
13. Kessel D, Wodinsky I, Uptake in vivo and in vitro of actinomycin D by mouse leukemias as factors in survival. Biochem. Pharmacol. 1968;17(1):161-164.
http://dx.doi.org/10.1016/0006-2952(68)90170-6
14. Hollstein U, Actinomycin. Chemistry and mechanism of action. Chem. Rev., 1974; 74 (6):625–652.
http://dx.doi.org/10.1021/cr60292a002
15. D’Angio G. J, The use of combined Actinomycin D and radiotherapy in children with Wilms’ tumor. Front Radiat Ther Oncol.1969;4:174-180.
http://dx.doi.org/10.1159/000387008
16. Pugh LH, Katz E, Waksman SA, Antibiotic and cytostatic proprties of the actinomycins. J Bacteriol. 1956; 72(5): 660–665.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC357973/
17. Kirk JM, The mode of action of actinomycin D. Biochimica et Biophysica Acta 1960;42:167-169.
http:///dx.doi.org/10.1016/0006-3002(60)90769-1
18. Barclay KL, Yeong ML, Actinomycin D associated hepatic veno-occlusive disease — A report of 2 cases. Pathology 1994;26:257-260.
http://dx.doi.org/10.1080/00313029400169601
19. Pinkel D, Actinomycin D in childhood cancer; a preliminary report. Pediatrics. 1959;23(2):342-7.
http://www.ncbi.nlm.nih.gov/pubmed/13633349
20. Duesberg PH, Robinson WS, Inhibition of mouse leukemia virus (MLV) replication by actinomycin D. Virology. 1967;31(4):742-6.
http://dx.doi.org/10.1016/0042-6822(67)90211-5
21. Jones KW, Elsdale TR, The effects of actinomycin D Oon the ultrastructure of the nucleus of the amphibian embryonic cells. J Cell Biol. 1964; 21(2): 245–252
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2106436/
22. Dipaolo JA, Moore GE, Niedbala TF, Experimental studies with actinomycin D. Cancer Res. 1957;17(11):1127-34.
http://www.ncbi.nlm.nih.gov/pubmed/13489720
23. Flitter WD, Mason RP, The enzymatic reduction of actinomycin D to a free radical species. Arch Biochem Biophys. 1988;267(2):632-9.
http://dx.doi.org10.1016/0003-9861(88)90071-9
24. Elkind MM, Kano E, Sutton-Gilbert H, Cell killing by actinomycin D in relation to the growth cycle of Chinese hamster cells. J Cell Biol. 1969; 42(2): 366–376.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2107666/
25. Goldstein MN, Hamm K, Amrod E, Incorporation of triated actinomycin D into drug-sensitive and drug-resistant HeLa cells. Science. 1966 ;151(3717):1555-6.
http://dx.doi.org/10.1126/science.151.3717.1555
26. Elkind MM, Sakamoto K, Kamper C, Age-dependent toxic properties of actinomycin D and X-rays in cultured Chinese hamster cells. Cell Proliferation 1968;1(3):209–224.
http://dx.doi.org/10.1111/j.1365-2184.1968.tb00319.x
27. Hagemann RF, Concannon JP, Mechanism of intestinal radiosensitization by actinomycin D. Br J Radiol. 1973;46(544):302-8.
http://dx.doi.org/10.1259/0007-1285-46-544-302