dactinomycin brands

Molecular formula: C62H86N12O16

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

Source: PubChem (NCBI) · compound 457193