Dactinomycin

Bleomycin and cyclosporine are the two economically most important streptomycete peptide antibiotics used as antitumor agents and immunomodulators, although dactinomycin is important medically for several tumors (see Chemotherapeutics, anticancer Immunotherapeutic agents). 

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

Dactinomycin, an antineoplastic dmg, was discovered in 1943 and is made in rather pure form by StreptomjcesparvuUus. Dactinomycin has some bacteriostatic antibacterial and antifungal activity, but high toxicity limits its use to antineoplastic therapy. It may be used alone or with other antineoplastics, with or without surgery and synergistic x-ray therapy. Dose limiting bone marrow toxicity may result in low white cell and platelet count. Intestinal mucosal damage also occurs. Reviews of more detailed chemotherapeutic information are available (217—222). 

Almost all actinomycins have the same chromophore, a planar phenoxa2inone dicarboxyUc acid called actinocin. In dactinomycin, the stmcture of which is shown in Figure 12, the two pendent pentapeptide lactones are identical, but in other actinomycins these lactones may be different. In other actinomycins the first amino acid, amide linked with actinocin, is usually L-threonine, as in dactinomycin the second position is sometimes D-aHo-isoleucine instead of D-valine the third position may be sarcosine or oxoproline the fourth position is sarcosine and the fifth position is sometimes /V-methyl isoleucine instead of /V-methylvaline. The lactone ring is always present. 

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. 

Dactinomycin is useful against several tumors especially Wilms tumor of the kidney and rhabdomyosarcoma. Wilms tumor normally requires a combination of surgery, x-ray irradiation, and dactinomycin plus vincristine [57-22-7] or other antitumor agents. Resistance of the multidmg... 

Microorganisms, by farmantation Actinomyces antibioticus Dactinomycin Actinomyces vinaceus Viomycin... 

Plasma digoxin levels may decrease when the drug is administered with bleomycin. When bleomycin is used witii cisplatin, there is an increased risk of bleomycin toxicity Pulmonary toxicity may occur when bleomycin is administered with other antineoplastic drugs. Plicamycin, mitomycin, mitoxantrone, and dactino-mycin have an additive bone marrow depressant effect when administered with other antineoplastic drugs. In addition, mitomycin, mitoxantrone, and dactinomycin decrease antibody response to live virus vaccines. Dactinomycin potentiates or reactivates skin or gastrointestinal reactions of radiation therapy There is an increased risk of bleeding when plicamycin is administered witii aspirin, warfarin, heparin, and the NSAIDs. 

Cytarabine (greater than or equal to 1g/m2) Dactinomycin (greater than 1.5 mg/m2)... 

Poly(isobutylcyanoacrylate) 0.22 Biodegradable TDS with extracorporeal guidance [3H]Dactinomycin... 

Dactinomycin—vesicant-watch for extravasation Methotrexate Methotrexate 40 mg/M2 IM weekly... 

Dactinomycin -antitumor antibiotic inhibits transcription by complexing with DNA -bone marrow suppression -nausea and vomiting -erythema -hyperpigmentation -mucocutaneous effects (mucositis, stomatitis, diarrhea) -vesicant if extravasated -immunosuppression... 

Doxyrubicin, dactinomycin, and mitomycin—cell cycle nonsensitive... 

I 12. The answer is b. (Hardman, pp 1264-1265J Dactinomycin s major toxicities include stomatitis, alopecia, and bone marrow depression. Bleomycin s toxicities include edema of the hands, alopecia, and stomatitis. Mitomycin causes marked bone marrow depression, renal toxicity, and interstitial pneumonitis. Plicamycin causes thrombocytopenia, leukopenia, liver toxicity, and hypocalcemia. The latter may be of use in the treatment of hypercalcemia. Doxorubicin causes cardiotoxicity, as well as alopecia and bone marrow depression. The cardiotoxicity has been linked to a lipid peroxidation within cardiac cells. 

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. 

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