Actinomycin D Dactinomycin

Actinomycins are chromopeptides, generally containing the same chro-mophore, based on the tricyclic system of phenoxazinone (phenoxazone), and known as actinocin, Fig. (8). The chromophore is responsible for the intense yellow, orange or red colours of actinomycins. The first known actinomycin was isolated from a culture medium of an actinomyces, Streptomyces sp. [174], and caused some interest on account of its antibiotic activity. Many other actinomycins were isolated later and characterised by their antibiotic and/or antitumor activities [175]. Among these, the best known is actinomycin D (Dactinomycin), Fig. (8). 

Actinomycins have essentially a historic importance, being the first antibiotics isolated from a streptomycete, Actinomyces antibioticus (Waksman and Woodruff 1941). Due to their toxicity, clinical application was not considered for years, but they attracted much attention after their antitumor activity in animals was demonstrated. However, at the curative doses, their toxicity was in general too high for allowing human clinical use and was used primarily as investigating tools for studies of molecular biology. The only substance that found a clinical application is actinomycin D (dactinomycin), in use since 1964 for the treatment of Wilms tumor in children. 

Dactinomycin. Dactinomycin [50-76-0] (actinomycin D, actinomycin Cl, Cosmegen), is the only actinomycin in clinical use. 

Fig. 12. Stmcture of dactinomycin (actinomycin D) where MeVal = N-methylvaline and Sar = sarcosine.

Total synthesis of dactinomycin has been accompHshed, and at least thirty natural actinomycins and many synthetic and semisynthetic actinomycins have been tested (220,221,228). At one time cactinomycin [8052-16-2] (actinomycin C), a mixture of actinomycins D, C2, and C3, was sold as an antineoplastic. 

Perhaps a bit more subtle than those agents that react chemically with DNA are those that insert themselves between the stacked bases of the DNA double helix— intercalation. This alters the regular structure of the DNA molecule and may lead, for instance, to inhibition of mRNA synthesis. The structures of the intercalcating agents are generally quite complex and I will spare you the complexity. However, three names may be familiar—dactinomycin (Actinomycin D), daunorubicin (daunomycin), and doxorubicin (Adriamycin)— and intercalation is how they work. All three are natural products and were isolated from the fermentation broths of Streptomyces species. 

The first antitumor antibiotic was actinomycin A which was isolated from a Streptomyces species. The actinomycins are chromopeptides containing a planar chromophore, responsible for the bright color of the compounds, with peptide side chains. The most important representative of this group which is in clinical use is actinomycin D, or dactinomycin. 

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). 

The antibiotics that bind to DNA are nonspecific to the cell-cycle phase. Dactinomycin (actinomycin D and Cosmegen) binds to double-stranded DNA and prevents RNA synthesis by inhibiting DNA-dependent RNA polymerase. It is administered intravenously in the treatment of pediatric solid tumors such as Wilms tumor and rhabdomyosarcoma and for gestational choriocarcinoma. Dactinomycin causes skin reactions, gastrointestinal injury, and delayed bone marrow depression. 

Dactinomycin (actinomycin D) 0.04 mg/kg IV weekly Nausea and vomiting Stomatitis, gastrointestinal tract upset, alopecia, bone marrow depression... 

Anthracyclines (SEDA-25, 533) aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin. Others acivicin, amsacrine, bleomycin, dactinomycin (actinomycin D), mitoxantrone. 

---