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PubMed1981

A phase II evaluation of methyl CCNU and actinomycin D in the treatment of advanced sarcomas in adults.

Twenty-nine patients with metastatic sarcoma were treated with a combination of methyl CCNU and actinomycin D. Patients with adequate bone marrow reserve received methyl CCNU 100 mg/m2 orally on day 1 and actinomycin D 0.3 mg/m2/day intravenously for five days. Both drugs were repeated every four weeks. Patients with inadequate bone marrow reserve received methyl CCNU 75 mg/m2 and actinomycin D 0.2 mg/m2/day for five days. All patients had received prior chemotherapy and had progressive disease at the start of the study. There was one complete response in a patient with peritoneal mesothelioma which lasted 18 months and the patient is still alive at 38+ months. Ten patients had stable disease including three patients who had responses between 25% to 50%. No responses were seen in 18 patients. The median time to progression for patients with stable disease was five months and for those with progressive disease was two months (P = 0.001). The median survival for patients with stable disease was 20 months compared with three months for patients with progressive disease (P = 0.001). The combination was generally very well tolerated and myelosuppression was insignificant. However, with the dosages and schedule used in this study, the combination of methyl CCNU and actinomycin D does not appear to have significant activity in advanced soft tissue sarcomas. Further studies with this combination are indicated in patients with mesothelioma.

Adult↗
PubMed1974

Actinomycin-D-resistant in vitro mouse cell line derived from a methylcholanthrene-induced sarcoma: decrease of malignancy and antigenic characteristics.

The tumorigenic EPO clonal cell line, derived from a methylcholanthrene-induced murine sarcoma, was exposed to increasing concentrations of actinomycin D and gave rise to a subline, resistant to 0.02 mug of actinomycin D per ml of medium, which was designated EPO/ADj. Drug resistance was accompained by a striking decrease of tumorigenic capacity as determined by the tumor take incidence and tumor growth rate in syngeneic C57BL/6 mice (normal and X-irradiated), as well as by tumor take incidence in the cheek pouch of cortisone-treated weanling Syrian hamsters. One of the tumors obtained after inoculation of EPO/ADj cells into syngeneic mice was reexplanted in culture and developed as the EPO/ADj/T subline. It was found to be relatively resistant to actinomycin D as compared to the parental EPO cells. The morphology of cells changed with actinomycin-D-resistance: EPO/ADj cells were more spread and flattened and less overlapping than the original fibroblast-like EPO cells. EPO/ADj/T cells, however, had an aspect similar to that of EPO cells. No major differences were seen between the karyotypes of EPO, EPO/ADj and EPO/ADj/T cells. Tumor-specific antigen(s), characteristic of drug-sensitive, parental EPO line, was expressed in the resistant EPO/ADj and EPO/ADj/T lines, as shown by: (a) transplantation resistance to challenge with EPO cells in syngeneic mice pretreated with EPO/ADj cells; and (b) cross-reactivity in indirect immunofluorescence tests performed with sera from syngeneic animals hyperimmunized with EPO or EPO/ADj cells. Furthermore, an additional surface antigen(s), absent from EPO cells, was demonstrated in EPO/ADj and EPO/ADj/T cells by means of immunofluorescence tests performed with specific anti-EPO/ADj syngeneic sera previously absorbed on EPO or EPO/ADj cells.

Animals↗
PubMed1982

Prevention of intravascular metastases of B16 murine melanoma: adjuvant chemotherapy with actinomycin D.

Actinomycin D was tested in an experimental preparation to determine its efficacy in the prevention of intravenous metastases. B16 melanoma cells were injected intravenously in syngeneic C57/BL6 mice. Two cell lines of the tumor, designated F1 and F10, with widely different metastatic potentials, were maintained in tissue culture and utilized for evaluation of pulmonary metastases. When actinomycin D was given intraperitoneally at doses of 0.05 and 0.075 mg/kg for 5 days, the number of pulmonary metastases was significantly decreased (P less than .001) in both the F1 and F10 cell lines. Although reduction did occur with a single dose, maximum reduction of pulmonary metastases was effected with a dose schedule administered over 5 days. Evaluation of a group of mice 2 and 3 wk after injection of tumor cells revealed that the effects of actinomycin D were not secondary to delay in tumor growth but did represent highly significant differences in numbers of metastatic lesions. It is concluded that in this experimental preparation actinomycin D, given in an adjuvant setting, can significantly reduce the number of pulmonary metastases. This study may have bearing on the design of adjuvant intraoperative and perioperative chemotherapy in order to destroy circulating tumor cells.

Animals↗
PubMed1991

Effects of actinomycin D and cycloheximide on transcript levels of IGF-I, actin, and albumin in hepatocyte primary cultures treated with growth hormone and insulin.

The stability of several RNA transcripts in cultured hepatocytes is known to increase when serum is omitted from the culture medium. In order to investigate possible mechanisms for this phenomenon, we examined the effects of actinomycin D and cycloheximide on the levels of actin, albumin, and insulin-like growth factor I transcripts in primary cultures incubated in serum-free medium. The levels of IGF-I and albumin transcripts per culture increased for the first 4 hours following addition of actinomycin D and then declined. The levels of actin transcripts and total RNA per culture declined immediately following actinomycin D addition in a manner consistent with exponential decay. IGF-I and albumin transcript levels were relatively unaffected by cycloheximide, while actin transcript levels increased 7-fold over 7 hours. The half-lives of actin transcripts and total RNA were calculated to be 4.6 to 7.7 hours and 11 to 19 hours, respectively, with no statistically significant correlation with hormone treatment. The data suggest that the stability of albumin and IGF-I transcripts, but not actin transcripts, is controlled in part by an actinomycin D-sensitive process.

Actins↗
PubMed1994

Involvement of a DNA binding protein, MDR-NF1/YB-1, in human MDR1 gene expression by actinomycin D.

The human multidrug resistance 1 (MDR1) gene is an SOS gene that responds to environmental stress including various anticancer agents. The chloramphenicol acetyltransferase (CAT) gene was linked to various lengths of MDR1 promoter, and these constructs were integrated into the genome of human cancer KB cells. Using these cell lines, we previously demonstrated that various environmental stimuli lead to an increased abundance of both CAT enzymatic activity and CAT mRNA in a sequence dependent manner. We examined the molecular mechanism of this stress response using actinomycin D, a potent RNA synthesis inhibitor. We found that CAT activity was significantly increased more than 10 fold by actinomycin D itself without comparable elevation of CAT mRNA. CAT induction was, however, lost in the presence of a deletion from position -136 to -76. Gel mobility shift assays showed that the specific DNA binding activity of the transacting protein, MDR-NF1/YB-1, which binds to the inverted CCAAT box, was augmented in nuclear extracts from the cells treated with actinomycin D. We also found that actinomycin D increased the steady state levels of MDR-NF1/YB-1 mRNA, which encodes the inverted CCAAT box binding protein. These results indicate that MDR-NF1/YB-1 mediates the response of the MDR1 gene to environmental stress.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1976

The effect of actinomycin D on the formation of gametangia and mitosporangia in Allomyces.

The effect of actinomycin on gametangium and mitosporangium production in Allomyces arbuscula and A. macrogynus has been investigated. Male gametangium production was not more sensitive to actinomycin than female development. Actinomycin at 20 mug/ml added at the commencement of induction was completely inhibitory. The process became insensitive to actinomycin just before the first septum was laid down.

Chytridiomycota↗
PubMed1995

Inhibition of the intracellular transport of influenza viral RNA by actinomycin D.

In primary chicken embryo cells infected with fowl plague virus addition of actinomycin D at defined times during the infection cycle has different consequences on viral replication. If actinomycin D is added immediately after infection with a concentration, which inhibits viral RNA synthesis only partially, it interferes with the nucleo-cytoplasmic transport of all viral RNA species (mRNA and vRNA) so far tested. If actinomycin D is present during infection (adsorption, penetration and uncoating) no viral RNA is synthesized, and the nucleocapsid of the infecting virus does not reach the nucleus, as shown by fluorescent antibodies. Therefore the primary effect of actinomycin D on influenza virus replication is on the transport of the incoming vRNPs from the cytoplasm to the cell nucleus, which is the cell compartment where transcription takes place.

Animals↗
PubMed1994

Retinoic acid modulation of mucin mRNA in rat tracheal explants: response to actinomycin D, cycloheximide, signal transduction effectors and antisense oligodeoxynucleotide.

Factors affecting the retinoic acid modulated expression of mucin mRNA in rat tracheal cultures were studied. Actinomycin D had no effect on mucin mRNA in cultures grown with retinoic acid (RA+). The usual precipitous drop in mucin mRNA in cultures lacking retinoic acid (RA-) was prevented by actinomycin D. Cycloheximide also had no effect on mucin mRNA in RA+ cultures, but, like actinomycin D, it prevented the precipitous drop in mucin mRNA in RA- cultures. cAMP agonists had some marginal effects on the mucin mRNA, but none as dramatic as those noted by actinomycin D and cycloheximide in the RA- cultures. An antisense oligomer (18 bases) to rat mucin cDNA inhibited the mucin mRNA expression in RA+ cultures.

Animals↗
PubMed1982

Reversible depression of spontaneous brain electrical activity induced by actinomycin D and 7-aminoactinomycin D in rats.

Various types of actinomycin (C,D,S2, I and V) and 7-amino-analogue of actinomycin D were injected into the right lateral ventricle of the brain through a chronically implanted cannula. In rats but not in mice actinomycin D, actinomycin S2 and 7-aminoactinomycin D caused depression of EEG, while cardiac and respiratory activity were maintained. This effect of the EEG was reversible and a normal EEG pattern reappeared at least 3 h after administration.

Animals↗
PubMed1990

Triple combination of retinoic acid plus actinomycin D plus dimethylformamide induces differentiation of human acute myeloid leukaemic blasts in primary culture.

Differentiation induction therapy provides an alternative for treatment of acute myeloid leukaemia (AML) patients who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy. The effect of a triple combination of retinoic acid (RA) + actinomycin D (Act-D) + dimethylformamide (DMF) on differentiation of blasts from 24 AML patients was studied. Non-adherent mononuclear cells were seeded at a concentration of 5 x 10(5) cells/ml in 24-well tissue-culture plates containing RPMI 1640 culture medium with 20% fetal calf serum, 10% autologous serum and 10% 5637-conditioned medium and incubated with 10(-6) M retinoic acid, 5 nM actinomycin D and/or 100 mM dimethylformamide alone and in combination with each other for 6 days at 37 degrees C in a humidified incubator and an atmosphere containing 5% CO2. The triple combination of 10(-6) M retinoic acid + 5 nM actinomycin D + 100 mM dimethylformamide induced 90% of the blasts from 22 of the 24 AML patients to differentiate. The combination of N-methylformamide (a compound similar to dimethylformamide) with cyclophosphamide significantly increased the in vivo activity with no concomitant increase in its reversible hepatotoxicity. Since several polar compounds related to dimethyl-formamide, e.g. hexamethylene bisacetamide and N-methylformamide, are currently undergoing phase II clinical trials, it may be feasible to combine one of these with retinoic acid and/or actinomycin D in the treatment of AML patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Characterization of Streptomyces MITKK-103, a newly isolated actinomycin X2-producer.

A new actinomycete strain designated MITKK-103 was isolated from the soil of a flowerpot using a humic acid agar medium. The newly isolated strain was able to produce a large amount of actinomycin X2 even under nonoptimized growing conditions and serves as a promising source of this antibiotic. Actinomycin X2 has higher cytotoxicity toward cultured human leukemia (HL-60) cells than does actinomycin D, and it induces cell death via apoptosis. A nearly complete 16S ribosomal DNA (rDNA) sequence from the isolate was determined and found to have high identity (98.5-100%) with Streptomyces galbus, Streptomyces griseofuscus, and Streptomyces padanus, indicating that MITKK-103 belongs to the genus Streptomyces. The isolate clustered with species belonging to the S. padanus clade in a 16S-rDNA-based phylogenetic tree and showed 75% overall homology to S. padanus ATCC 25646 in DNA-DNA relatedness analysis. Although the growth of the isolate was somewhat different from the three species mentioned, the strain MITKK-103 most closely resembles S. padanus on the basis of the morphological and phenotypic characteristics, phylogenetic analysis, and genotypic data. As such, this is the first report of a strain of S. padanus capable of producing actinomycins.

Bacterial Typing Techniques↗
PubMed1977

Fluorescence of actinomycin D and its DNA complex.

In order to show that naturally occurring actinomycin D can be used as a fluorescent cytochemical probe, the fluorescence spectra of 50 micronM solution of actinomycin D in several solvents and in its DNA complex are reported. The excitation spectra of both bands observed are compared to the absorption spectrum, and the fluorescence quantum yields is estimated to be 0.65-10(-4), taking rhodamine B as a reference. Strong solvent-induced spectrum modifications are evidenced, interpreted as a solvent shell reorientation about the molecule chromophore in the excited state. The changes in the fluorescence spectrum of actinomycin due to an interaction with DNA (marked blue shift and decreased quantum yield) cannot be interpreted as a solvent effect; they express the properties of the DNA-chromophore eta-complex involving an orbital overlapping of actinomycin and guanine in DNA.

Binding Sites↗
PubMed1984

Actinomycin D inhibition of monoclonal antibody binding to nucleolar phosphoprotein 37/5.2 (B23).

Actinomycin D was found to block binding of a monoclonal antibody to nucleolar phosphoprotein 37/5.2 (B23) when incubated either simultaneously with or prior to addition of the antibody. Daunorubicin had no significant blocking activity of this antigen-antibody reaction. In comparative studies with a monoclonal antibody to nucleolar phosphoprotein 110/5.2 (C23), actinomycin D exhibited little blocking activity. When a 42-mer peptide containing the epitope of protein 37/5.2 (B23) was tested as the antigen, similar inhibition by actinomycin D of binding of the monoclonal antibody was found. These results provide evidence for binding of actinomycin D to a specific epitope of protein 37/5.2 (B23).

Amino Acid Sequence↗
PubMed1983

Pulse actinomycin D scheduling in nonmetastatic gestational trophoblastic neoplasia: cost-effective chemotherapy.

The currently accepted method of treatment of patients with nonmetastatic gestational trophoblastic neoplasia (NMGTN) is single-agent chemotherapy. While methotrexate and actinomycin D have shown superiority over other cytotoxic agents, doses of drug and length of treatment are subject to controversy. Recently, the demonstration of the long half-life of actinomycin D in both animal models and humans has necessitated a reevaluation of the method of administration of this drug for NMGTN. Following the demonstration of minimal severe toxicity of pulse actinomyin-D scheduling by E. S. Petrilli and C. P. Morrow (Actinomycin D toxicity in the treatment of trophoblastic disease, Gynecol. Oncol. 9, 18-22 (1980), 12 consecutive patients with nonmetastatic gestational trophoblastic neoplasia were treated. The remission rates, toxicity, and cost effectiveness of pulse actinomycin-D scheduling in these 12 patients are reported.

Adolescent↗
PubMed1991

Actinomycin D is a competitive and selective antagonist at NK2 tachykinin receptors.

The ability of actinomycin D, a known antineoplastic agent, to affect NK1 NK2 and NK3 tachykinin (TK) receptor types was assessed on several in vitro bioassays. Actinomycin D was completely ineffective as a TK antagonist in the guinea-pig ileum longitudinal muscle (GPI) and on the rat portal vein (RPV) (two issues containing NK1, and NK3 TK receptors, respectively) while it was a weak competitive antagonist in the endothelium-denuded rabbit pulmonary artery (RPA) and in the hamster trachea (HT) (tissues containing the NK2A and NK2B receptor subtypes, respectively). Furthermore actinomycin D was able to displace [125I]-His-NKA from NK2 receptor sites of the rat small intestine smooth muscle membranes. Although actinomycin D is about 3 orders of magnitude weaker as an NK2 antagonist as compared to the most effective ligands available, it could represent a starting point in the development of non-peptidic NK2 receptor antagonists.

Animals↗
PubMed1984

The binding of actinomycin D and Adriamycin to supercoiled DNA, single-stranded DNA and polynucleotides.

The effect of actinomycin D and adriamycin on synthetic polynucleotides, single-stranded viral DNA and supercoiled DNA has been studied employing the fluorescent probe, terbium. Marked displacement of the probe was observed when any deoxyribose-containing polynucleotide was pretreated with either drug. With supercoiled DNA, an unwinding of the supercoil was observed at very low drug concentrations (at approx. 1:500 molar ratio of drug:DNA) prior to the displacement of the terbium. This unwinding was visualized by agarose gel electrophoresis at molar ratios of approx. 1:200. The effect was more apparent and occurred at lower drug: DNA ratios with actinomycin D than with adriamycin. Unlike cis-dichlorodiammine platinum(II), actinomycin D did not protect pBR322 DNA from cleavage at its BamHI site. The hydrolysis of phi chi 174 DNA by a series of G-C-specific restriction nucleases (including HhaI, HpaII and HaeIII) was also not affected by prior treatment of the DNA with actinomycin D.

Animals↗
PubMed1987

Effect of actinomycin D on prostaglandin synthesis by and output from the guinea-pig uterus.

The intra-uterine administration of actinomycin D on Day 10 reduced the output of prostaglandin (PG) F2 alpha (the major PG released) from the Day 15 guinea-pig uterus in vitro by 80 to 85%. PGE2 output was reduced by 50%, while 6-keto-PGF1 alpha output was unaffected. Plasma progesterone levels were high (3 to 15 ng/ml) on Day 15 due to the reduction in uterine PGF2 alpha output. Endometrial PGF2 alpha synthesizing capacity was reduced by 50% by actinomycin D treatment, while endometrial PGE2 and 6-keto-PGF1 alpha synthesizing capacities were unaffected. Oestradiol treatment in vivo did not reverse the inhibitory effects of actinomycin D on uterine PG production. A23187 increased uterine PGF2 alpha, 6-keto-PGF1 alpha and PGE2 outputs irrespective of treatment, indicating that substrate supply was always rate limiting. Actinomycin D inhibited the uterotrophic action of oestradiol indicating that fresh protein synthesis had been inhibited. Overall, this study suggests that increased protein synthesis is involved in stimulating endometrial PGF2 alpha synthesis and release. Previous studies have shown that increases in enzyme activities induced by oestradiol are only secondary events in the stimulation of endometrial PGF2 alpha production. We propose that oestradiol induces the synthesis of a protein ('lipostimulin') which, acting on a progesterone-primed uterus, "switches on" endometrial PGF2 alpha synthesis and release by causing the activation of endometrial phospholipase A2.

6-Ketoprostaglandin F1 alpha↗