Dactinomycin toxicity

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). 

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. 

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. 

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). 

Peptide antibiotics are not often the drags of first choice for systemic therapy of important human disease. However, the World Health Organization, which chooses drags especially for Third World use based on efficacy, safety, quality, price, and availability, includes as essential such peptide antibiotics as bleomycin, dactinomycin, and bacitracin (as an ointment containing neomycin), plus several /8-lactams. See also Antibiotics, Antibiotics -Lactams. Systemic use of peptide antibiotics is many times limited by nephroloxicity and other toxicities. Semisynthesis or complete chemical synthesis of analogues of peptide antibiotics has most often not resulted in improved drags. 

Adverse effects The major dose-limiting toxicity is bone marrow depression, and the drug is immunosuppressive. Other adverse reactions include nausea, vomiting, diarrhea, stomatitis, and alopecia. Extravasation during injection produces serious problems. Dactinomycin sensitizes to radiation inflammation at sites of prior radiation therapy may occur. 

Dactinomycin increases the pnlmonary toxic effects of radiation by an estimated 30%, and rednces the radiation tolerance of the Inng by at least 20% (1). 

Green DM, Finklestein JZ, Norkool P, D Angio GJ. Severe hepatic toxicity after treatment with single-dose dactinomycin and vincristine. A report of the National Wilms Tumor Study. Cancer 1988 62(2) 270-3. 

Dactinomycin is used against ihabdomyasarcoma and Wilms tumor in children. It can be liicsaving for women with choriocarcinoma resistant to methotrexate. In combination with vincristine and cyclophosphamide, it has received some use in. solid tumors in children. Toxic reaction.s include anorexia, nausea, and vomiting. Bone marrow depression, resulting in pancytopenia, may occur within a week after therapy. Alopecia, erythema, and tissue injury may ixtcur at the injection site. 

Pacific Northwest.) Encyclopedic references comment that the antibiotics doxorubicin, daunorubicin, bleomycin, mitomycin, and dactinomycin are all antineoplastic or anticancer agents, but are mostly too toxie for antibiotic use (and perhaps are too toxic to be used as anticancer agents, a ease again of adverse side effects). 

Dactinomycin is an antineoplastic agent that is the principal component of the mixture of actinomycins produced by Streptomyces parvullus. It inhibits messenger RNA synthesis. Dactinomycin (0.5 mg/day IV for 5 days), in combination with vincristine, radiotherapy, and surgery, is used in Wilms tumor in conjunction with vincristine, cyclophosphamide, and doxorubicin, it is used in choriocarcinoma in combination with methotrexate, it is used in testicular carcinoma and in combination with cyclophosphamide and radiotherapy, it is used in Ewing s sarcoma. Dactinomycin inhibits messenger RNA synthesis by anchoring to a purine-pyrimidine (DNA) base pair by intercalation (see Figure 15). The toxicity of dactinomycin increases when combined with radiation therapy. 

The usual daily dose of dactinomycin (Actinomycin D, Cosmegen) is 10 to 15 ag/kg this is given intravenously for 5 days if no manifestations of toxicity are encountered, additional courses may be given at intervals of 2 to 4 weeks. In other regimens, 3 to 6 ag/kg per day for a total of 125 ag/kg and weekly maintenance doses of 7.5 ag/kg have been used. If infiltrated during administration, the drug is extremely corrosive to soft tissues. 

Items 80-81. A patient with metastatic choriocarcinoma was ti eated first with methotrexate plus dactinomycin and subsequently with a combination of cisplatin and vincristine. In both regimens, drug dosage was maximized to a toxicity limit of a 2-log decrease in blood platelets. The effects of chemotherapy were monitored by urinary chorionic gonadotropin (UCG, U/24 h), as shown in the data below. 

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. 

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