DACTICIN

Indications

• Wilms' tumor
• Rhabdomyosarcoma (metastatic and non-metastatic)
• Soft-tissue sarcomas
• Retinoblastoma
• High risk Wilms' tumor
• Certain liver tumors

Dosage

Adults: Dactinomycin is typically administered as an intravenous infusion; dosage may

Mechanism of action

Dactinomycin binds strongly and reversibly to DNA, interfering with RNA synthesis by preventing RNA polymerase elongation. Its planar phenoxazone ring intercalates between adjacent guanine-cytosine base pairs in DNA, while the polypeptide chains extend along the minor groove of the helix. This results in a stable dactinomycin-DNA complex, blocking the transcription process. The drug is particularly effective against DNA-dependent RNA polymerases, causing single-strand breaks in DNA, which enhances its cytotoxic activity.

Pharmacodynamics

Dactinomycin exhibits strong cytotoxicity, particularly against rapidly dividing cancer cells. While it has some bacteriostatic activity against gram-positive organisms, its use as an antibacterial agent is limited due to its high toxicity. The drug's antineoplastic effects have been validated in various animal studies, and its mechanism of action primarily involves the inhibition of RNA synthesis through DNA binding.

Pharmacokinetics

Dactinomycin is administered intravenously and is distributed widely throughout the body. It is metabolized in the liver and exhibits a half-life that may vary depending on the patient's condition and liver function. The drug is excreted primarily through the kidneys. Due to its potential for severe toxicity and interactions, careful monitoring is required during its use, especially in patients with renal or hepatic impairment.

Contra-indications

• Pregnancy
• Known hypersensitivity to dactinomycin or any of its components

Adverse effects

• Alopecia
• Anemia
• Asthenia
• Gastrointestinal disorders
• Fatigue
• Fever
• Thrombocytopenia
• Oral disorders
• Vision disorders
• Neutropenia
• Dehydration
• Pneumonitis
• Renal failure
• Malaise
• Myalgia
• Nausea

Interactions

• Live vaccines (increased risk of generalized infection, possibly life-threatening)

Precautions

• Monitor pulmonary function prior to initiation and during treatment
• Use with caution in patients with renal and hepatic impairment
• Consider dose adjustments in cases of raised serum bilirubin or biliary obstruction

Pregnancy

Avoid due to teratogenic and carcinogenic effects observed in animal studies. Consult specialist advice if chemotherapy is required during pregnancy.

Breast-feeding

Discontinue breastfeeding during treatment.

Storage

Store in a cool, dry place away from direct light. Reconstituted solutions should be used promptly and any unused portions discarded.

Formulations

• Dactinomycin 500 microgram powder for solution for injection

Mechanism of action

Good evidence exists that this drug bind strongly, but reversibly, to DNA, interfering with synthesis of RNA (prevention of RNA polymerase elongation) and, consequently, with protein synthesis. The capacity of actinomycins to bind with double-helical DNA is responsible for their biological activity and cytotoxicity. X-ray studies of a crystalline complex between dactinomycin and deoxyguanosine permitted formulation of a model that appears to explain the binding of the drug to DNA. The planar phenoxazone ring intercalates between adjacent guanine-cytosine base pairs of DNA, while the polypeptide chains extend along the minor groove of the helix. The summation of these interactions provides great stability to the dactinomycin-DNA complex, and as a result of the binding of dactinomycin, the transcription of DNA by RNA polymerase is blocked. The DNA-dependent RNA polymerases are much more sensitive to the effects of dactinomycin than are the DNA polymerases. In addition, dactinomycin causes single-strand breaks in DNA, possibly through a free-radical intermediate or as a result of the action of topoisomerase II Dactinomycin is an antineoplastic antibiotic. The drug has bacteriostatic activity, particularly against gram-positive organisms, but its cytotoxicity precludes its use as an anti-infective agent. Although the exact mechanism(s) of action has not been fully elucidated, the drug appears to inhibit DNA-dependent RNA synthesis by forming a complex with DNA by intercalating with guanine residues and impairing the template activity of DNA. Protein and DNA synthesis are also inhibited but less extensively and at higher concentrations of dactinomycin than are needed to inhibit RNA synthesis. Dactinomycin is immunosuppressive and also possesses some hypocalcemic activity similar to plicamycin. Generally, the actinomycins exert an inhibitory effect on gram-positive and gram-negative bacteria and on some fungi. However, the toxic properties of the actinomycins (including dactinomycin) in relation to antibacterial activity are such as to preclude their use as antibiotics in the treatment of infectious diseases. Dactinomycin acts by forming stable complexes with double-helical DNA that inhibit DNA-directed RNA synthesis (interfere with RNA polymerase) more than DNA synthesis. The drug is cell-cycle active. The effect of dactinomycin on cellular respiration and accompanying ATP formation was investigated in Jurkat and HL-60 cells. Cellular mitochondrial oxygen consumption (measured by a homemade phosphorescence analyzer) and ATP content (measured by the luciferin-luciferase bioluminescence system) were determined as functions of time t during continuous exposure to the drug. The rate of respiration, k, was the negative of the slope of [O2] versus t. Oxygen consumption and ATP content were diminished by cyanide, confirming that both processes involved oxidations in the mitochondrial respiratory chain. In the presence of dactinomycin, k decreased gradually with t, the decrease being more pronounced at higher drug concentrations. Cellular ATP remained constant for 5 h in untreated cells, but in the presence of 20 microM dactinomycin it decreased gradually (to one-tenth the value at 5 h for untreated cells). The drug-induced inhibition of respiration and decrease in ATP were blocked by the pancaspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethyl ketone (zVAD-fmk). A rapid but temporary decrease in cellular ATP observed on the addition of zVAD-fmk was shown to be due to DMSO (added with zVAD-fmk). The effect of dactinomycin on respiration differed from that of doxorubicin. Plots of [O2] versus t were curved for dactinomycin so that k decreased gradually with t. The corresponding plots for doxorubicin were well fit by two straight lines; so k was constant for approximately 150 min, at which time k decreased, remaining constant at a lower level thereafter. The results for cells treated with mixtures of the two drugs indicated that th

Pharmacodynamics

Generally, the actinomycins exert an inhibitory effect on gram-positive and gram-negative bacteria and on some fungi. However, the toxic properties of the actinomycins (including dactinomycin) in relation to antibacterial activity are such as to preclude their use as antibiotics in the treatment of infectious diseases. Because the actinomycins are cytotoxic, they have an antineoplastic effect which has been demonstrated in experimental animals with various types of tumor implant. This cytotoxic action is the basis for their use in the treatment of certain types of cancer. Dactinomycin is believed to produce its cytotoxic effects by binding DNA and inhibiting RNA synthesis.