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PubMed1981

The effect of hyperthermia alone or in combination with actinomycin D on the RNA metabolism of solid tumors in children.

The incorporation of 3H-uridine into the RNA was studied under normothermia 37 degrees C/120 min, hyperthermia 42.5 degrees/120 min, and both in combination with Actinomycin D by an autoradiographic in vitro method in 19 solid tumors of children: 6 Wilms' tumors, 5 neuroblastomas, 4 osteogenic sarcomas, and 4 different tumors. Hyperthermia invariably reduces the 3H-uridine incorporation into RNA by 11.7--86.4%, with an average of 47.5%. Actinomycin D consistently inhibits the 3H-uridine incorporation between 27.7 and 99.8%, with the average inhibition of 62.0% being far greater than that recorded for hyperthermia. The highest degree of 3H-uridine incorporation inhibition is obtained using hyperthermia in combination with Actinomycin D. The inhibition varies from 45.5--99.8%, with an average of 81.4%. In spite of the general regularity, the effect of hyperthermia and Actinomycin D are characterized by individual patterns. Obviously, they are dependent on proliferative activity rather than upon the particular type of tumor. The use of supranormal temperatures for the treatment of malignant tumors in man, also in combination with radiation or cytostatic drugs, is a possible and promising method of therapy.

Child↗
PubMed1997

[Actinomycin D influence on biosynthesis of extracellular ribonucleases by sporulating bacteria].

The influence of actinomycin D on the synthesis of extracellular ribonucleases by "Bacillus intermedius" (binase), B.pumilus (RNAse Bp) and B.amyloliquefaciens (barnase) was studied comparatively. When added during the active synthesis of the enzymes actinomycin D stimulated the biosynthesis of binase and RNAse Bp and had no influence on the barnase biosynthesis. The response of the bacillary RNAse biosynthesis to the added actinomycin D correlated with the differences in the nucleotide sequences of the genes encoding the enzymes. The Escherichia coli SURE recombinant strains carrying the plasmids with the genes of binase, RNAse Bp and barnase under different regulatory sequences, as well as the E.coli MC4100 recombinant strains carrying the plasmids with the beta-galactosidase gene under the promoters of the bacillary RNAse were isolated. However, the expression of the bacillary ribonuclease genes in the E.coli recombinant strains carrying the plasmids with the genes of the enzymes, as well as the expression of the beta-galactosidase gene from the promotors of the bacillary RNAses was not stimulated by actinomycin D irrespective of the dose and addition time.

Bacillus↗
PubMed1997

[Interaction of actinomycin D with suspended mycelium of streptomyces].

Binding of exogenous actinomycin D (AMD) by washed mycelium of streptomycetes i.e. variants of Streptomyces chrysomallus producing and not producing actinomycins and Streptomyces lividans not synthesizing the antibiotics was studied. Dependence of the bound quantity of AMD on its concentration, incubation time and temperature, energy source availability, influence of respiration inhibitors and the membranotropic antibiotic gramicidin S was shown. The intracellularly localized portion of the bound AMD likely penetrated to the cells by diffusion and was strongly bound presumably to DNA in the AMD sensitive S.lividans and to the specific intracellular actinomycin-binding proteins in the AMD resistant variants of S.chrysomallus. The ratio of AMD strongly bound by the mycelium and AMD easily washed with physiological solution and probably localized on the surface was determined. The ratio depended on sensitivity of the culture to AMD and for the variants of S.chrysomallus on the age of the culture and its ability to synthesize actinomycins.

Anti-Bacterial Agents↗
PubMed1965

EXTRACELLULAR RIBONUCLEASE FORMATION IN BACILLUS SUBTILIS AND ITS STIMULATION BY ACTINOMYCIN D.

1. Extracellular ribonuclease is produced linearly for at least 3hr. by washed post-logarithmic-phase cells of Bacillus subtilis suspended in a medium containing maltose (1%) and casein hydrolysate (0.5%). 2. Low concentrations of actinomycin D (less than 2mug./ml.) stimulate ribonuclease formation, the maximum effect being observed with a concentration of 1mug./ml. Concentrations greater than 2mug./ml. are inhibitory. There is no parallel stimulation of alpha-amylase formed under the same conditions, and [(14)C]uracil incorporation into a perchloric acid-insoluble form is inhibited. 3. The actinomycin D-induced stimulation is not due to the presence of an activator, nor is the inhibition due to the release of an inhibitor by the cells. The effect is on the amount of ribonuclease produced in the medium. 4. Extracellular ribonuclease formation is partially inhibited by anaerobiosis, 2,4-dinitrophenol, sodium azide and by chloramphenicol and puromycin. 5. High concentrations of antibiotic do not completely inhibit ribonuclease formation, but a basal amount of enzyme representing 20min. synthesis in an uninhibited system is always produced. This ;antibiotic-insensitive' enzyme could possibly represent preformed enzyme ;in the pipe-line' en route to secretion. 6. The stimulated appearance of ribonuclease in the presence of 1mug. of actinomycin D/ml. is shown to be dependent on enzyme synthesis. The mechanism of this effect is discussed.

Anti-Bacterial Agents↗
PubMed1964

ACTINOMYCIN RESISTANCE IN BACILLUS SUBTILIS.

The incorporation of uracil-C(14), a precursor of cellular RNA, into whole cells of the sensitive parent strain Bacillus subtilis No. 6051 is completely inhibited by actinomycin D, whereas only partial inhibition of uracil-(14) incorporation occurs with actinomycin-resistant intact cells of B. subtilis strain II 15. Incorporation of uracil-C(14) into protoplasts of the resistant strain of B. subtilis is completely inhibited. The sensitivity of resistant-cell protoplasts to drug effect clearly supports the conclusion that actinomycin penetration is altered in resistant intact whole cells. Since other experiments have shown that the antibiotic is not broken down in the presence of resistant cells, resistance is considered to result from a change in cell permeability.

Bacillus subtilis↗
PubMed1964

INDUCTION OF SEVERAL ADAPTIVE ENZYMES BY ACTINOMYCIN D.

Although actinomycin D has been used to prevent protein synthesis in experiments of several hours' duration, its effects on the synthesis of adaptive enzymes which are induced over a period of several days have received less attention. Treatment of young rats with doses of actinomycin D, which permitted survival for a period of 5 days, resulted in marked increases in the activities of four hepatic enzymes known to be induced by cortisol: alanine transaminase, tyrosine transaminase, serine dehydrase, and tryptophan pyrrolase. Actinomycin D also induced responses of two of these enzymes in adrenalectomized rats.

Adrenalectomy↗
PubMed1997

Venoocclusive disease of the liver after chemotherapy with vincristine, actinomycin D, and cyclophosphamide for the treatment of rhabdomyosarcoma. A report of the Intergroup Rhabdomyosarcoma Study Group. Childrens Cancer Group, the Pediatric Oncology Group, and the Pediatric Intergroup Statistical Center.

BACKGROUND: Venoocclusive disease (VOD) of the liver is a common complication after allogenic and autologous bone marrow transplantation for malignant disease. The authors report the unusual and unexpected complication of VOD of the liver occurring in children with rhabdomyosarcoma who were receiving vincristine, actinomycin D, and cyclophosphamide (VAC) according to the chemotherapy regimens of the Intergroup Rhabdomyosarcoma Study (IRS) IV. METHODS: The authors evaluated 821 patients with newly diagnosed rhabdomyosarcoma receiving treatment according to IRS IV who were considered at risk for VOD. RESULTS: Ten patients developed VOD of the liver for an overall incidence of 1.2%. VOD was found only after the administration of VAC chemotherapy. The highest incidence of VOD was observed among patients who had previously received vincristine and melphalan (Regimen 48). None of the patients receiving the chemotherapy regimen of vincristine and actinomycin D (Regimen 44) developed VOD. CONCLUSIONS: Patients receiving VAC-containing regimens on the IRS IV were found to be at risk for VOD. The VAC combination was used extensively in previous IRS studies (I, II, and III) and VOD was not reported during these studies, strongly suggesting that the escalation of the cyclophosphamide dose to 2.2 g/m2 (with the vincristine and actinomycin D doses and schedule remaining unchanged) triggered the development of VOD. The contributing role of previous therapy or events is unknown. At last follow-up, none of the nine surviving patients had developed recurrent VOD on continuation of chemotherapy.

Adolescent↗
PubMed1978

Randomized phase II clinical trial of adriamycin, methotrexate, and actinomycin-D in advanced measurable pancreatic carcinoma: a Gastrointestinal Tumor Study Group Report.

Sixty-six patients with advanced pancreatic carcinoma were randomized to receive single agent chemotherapy with either adriamycin, methotrexate, or actinomycin-D using conventional dose, route and schedule of administration. All patients had measurable lesions which were used to objective assessment of response. For adriamycin, 2 of 25 patients (8%) evidenced a partial response (2 of 15 (13%) previously untreated patients). One of 25 patients treated with methotrexate and one of 28 received actinomycin-D responded. The duration of responses ranged from 43-64 days for those patients with no chemotherapy prior to study entry. The median survival of patients who received adriamycin as initial treatment was 12 weeks compared to 8 weeks for methotrexate and 6 weeks for actinomycin-D therapy.

Adult↗
PubMed1982

Actinomycin-D plus 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamine (DTIC) with or without intravenous Corynebacterium parvum in metastatic malignant melanoma.

Chemotherapy and chemoimmunotherapy of Stage IV B malignant melanoma were compared in 88 patients. Chemotherapy consisted of DTIC 250 mg/M2 of the body surface area daily x five days and actinomycin-D 2 mg/M2 on day 1 repeated every 3--4 weeks. Chemoimmunotherapy consisted of the same regimen plus C. parvum 2 mg/M2 I.V. daily for 14 days before every third cycle of chemotherapy, plus 2 mg/M2 I.V. daily on days 7 and 14 of each 21--28 day chemotherapy cycle. There was 32 evaluable chemotherapy and 33 evaluable chemoimmunotherapy patients and the groups were well balanced for clinical and pathologic as well as prognostic variables. The complete and partial remission rates, remission and survival durations, and hematologic and gastrointestinal toxicities were different in the two randomized groups being 6 and 3%, 9 and 9%, 7.6 and 12 months, 8.8 and 6.0 months, 20 and 16%, and 62 and 70%, respectively for these parameters. This difference was not statistically significant. Therefore, it can be concluded that the results of chemotherapy with actinomycin-D plus DTIC were not substantially different from those reported using DTIC alone, and that we cannot recommend the addition of actinomycin-D to DTIC for palliative management in these patients. Furthermore, C. parvum immunotherapy did not add to chemotherapy in terms of remission rate, remission duration, or survival for patients with Stage IV B malignant melanoma.

Adolescent↗
PubMed1982

A comparison of adriamycin versus vincristine and adriamycin, and cyclophosphamide versus vincristine, actinomycin-D, and cyclophosphamide for advanced sarcoma.

This randomized study, conducted by the Eastern cooperative Oncology Group, compared Adriamycin (doxorubicin) (70 mg/m2) versus vincristine (1.4 mg/m2) and Adriamycin (50 mg/m2); and cyclophosphamide (750 mg/m2) versus vincristine (1.4 mg/m2), actinomycin-D (0.4 mg/m2), and cyclophosphamide (750 mg/m2) for treatment of metastatic mesenchymal malignancies. The respective response rate seen in 200 evaluable patients to the treatments were, 27, 19, and 11%. The response rate to Adriamycin was significant better than the response to vincristine, actinomycin-D, and cyclophosphamide (P = 0.03, two-sided). The respective median survivals on the three treatments were 37, 34, and 41 weeks and were not significantly different. Moderate or severe vomiting occurred in 60% of patients receiving vincristine-cyclophosphamide-adriamycin, a greater frequency than in Adriamycin alone (P = .09 two-sided) Severe or life-threatening hematologic toxicity (leukocytes less than 2000, platelets less than 50,000) occurred in 30% of patients receiving the Adriamycin combination, a markedly increased frequency when compared to the other two regimens (P equals 0.07, P = 0.02, two-sided). This trial establishes that Adriamycin has a better response rate than the combination of vincristine-actinomycin-D-cyclophosphamide in advanced sarcomas. The combination of vincristine, Adriamycin, and cyclophosphamide increased toxicity and did not add to the therapeutic effect achieved with Adriamycin alone.

Adult↗
PubMed1989

Solution conformation of the actinomycin D related pentapeptide lactone using NMR and molecular modeling.

A detailed description of the two observed solution conformations of the pentapeptide lactone fragment of actinomycin D is presented using the distance constraints obtained from two-dimensional nuclear Overhauser enhancement spectra in combination with minimum energy calculations. Low energy conformational states that are compatible with the experimental distances are found for each of the two conformers. For one conformer, an all trans peptide bond conformer, is found with no intramolecular hydrogen bonds. For the other conformer, the D-Val-Pro and Pro-Sar peptide bonds were cis; this solution conformation is the same as that found in both the crystal structure of the pentapeptide lactone as well as of the native actinomycin D itself. These results are discussed in terms of the combined influence of conformation and the effects of mutual intramolecular association of the pentapeptide lactone moieties in native actinomycin D on its cytotoxic activity.

Computer Simulation↗
PubMed1988

Collisional activation decomposition of actinomycins using tandem mass spectrometry.

The collisional activation (xenon) decomposition of actinomycin V, dactinomycin, 7-nitrodactinomycin, 7-aminodactinomycin, and a mixture of dactinomycin, actinomycin C1 and actinomycin C2 was studied using a triple-quadrupole mass spectrometer with fast atom bombardment (xenon) ionization. Fragmentation pathways of the structurally significant ions were rationalized by assuming an initial McLafferty rearrangement at the ester linkage between the methylvaline and the threonine of both rings to form linear pentapeptides, followed by fragmentation in either pentapeptide yielding typical sequence ions and sequence cleavages from both rings.

Dactinomycin↗
PubMed2002

Salvage combination chemotherapy with 5-fluorouracil and actinomycin D for patients with refractory, high-risk gestational trophoblastic tumors.

BACKGROUND: The objective of this study was to evaluate the efficacy and toxicity of a high-dose 5-fluorouracil and actinomycin D regimen (the FA regimen) as salvage chemotherapy for patients with high-risk gestational trophoblastic tumors (GTTs). METHODS: From 1985 to 1997, 10 patients with refractory, high-risk GTTs were treated with the FA regimen at Chiba University Hospital. Of those 10 patients, 7 patients developed drug resistance to methotrexate, etoposide, and actinomycin D combination chemotherapy (the MEA regimen); 1 patient developed recurrent disease after receiving the MEA regimen; and 2 patients developed recurrent disease after receiving combination chemotherapy with etoposide, methotrexate, and actinomycin D alternating with cyclophosphamide and vincristine (the EMA/CO regimen). The hematologic toxicity of the FA regimen was graded at every chemotherapy course. RESULTS: With the FA regimen, the survival rate was 80.0% (8 of 10 patients) for a mean follow-up of 10 years. Two patients died due to multidrug resistance, and two patients subsequently developed recurrent disease. The two patients with recurrent disease were successfully salvaged again with the MEA regimen. The toxicity of the FA regimen was evaluated in 78 cycles. Myelosuppression seemed to be the dose-limiting toxicity, and the incidences of World Health Organization Grade 4 leukocytopenia and thrombocytopenia were 6.4% and 3.8%, respectively, of 78 cycles. CONCLUSIONS: Although etoposide-containing chemotherapy is currently the most effective and well-tolerated regimen for patients with high-risk GTTs, 20-30% of patients develop resistance to etoposide-containing regimens. Salvage combination chemotherapy with FA is effective for these patients with refractory disease, and the toxicity is predictable and manageable.

Adult↗
PubMed1989

Reversal of drug resistance by erythromycin: erythromycin increases the accumulation of actinomycin D and doxorubicin in multidrug-resistant cells.

Development of resistance to one type of lipophilic chemotherapeutic drug often leads to resistance to other, structurally unrelated, lipophilic drugs. This suggests that non-toxic lipophilic agents may interfere with and reverse drug resistance by saturating the pathway through which multidrug-resistant (MDR) cells protect themselves against cytotoxic drugs. The lipophilic antibiotic, erythromycin, can significantly reverse the resistance of MDR WEHI 164 murine fibrosarcoma cells to the chemotherapeutic drugs, doxorubicin and actinomycin-D. The MDR cells showed an approximately 10-fold higher expression of the P-glycoprotein than the drug-sensitive parental cells from which the resistant cells were derived. The accumulation of actinomycin-D and doxorubicin was much lower in the drug-resistant cells than in the sensitive parental cells. The concentrations of erythromycin which reversed the drug resistance of the MDR cells increased the accumulation of actinomycin-D and doxorubicin in these cells to a level comparable to that observed in the sensitive parental cells. Our data suggest that erythromycin reverses drug resistance by saturating the drug-binding sites on the P-glycoprotein, thereby reducing the capacity of this protein to pump drugs out of resistant cells. Some of our MDR cells have also become more resistant to tumour necrosis factor (TNF). However, erythromycin did not reverse TNF resistance, suggesting that the mechanisms of multi-drug and TNF resistance are different. TNF did not influence drug accumulation in MDR cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1975

A comparative study of the effects of lucanthone (miracil D) and actinomycin D on the Chinese hamster cells grown in cultures.

Chinese hamster cells of an established clone line grown in monolayers were incubated for up to two hours with either lucanthone (0.3-30 mug/ml) or actinomycin D (0.06-0.10 MUG/ML) AND SUbjected to radioautographic investigations with 3H-uridine during the period of treatment. At concentration of 9 mug/ml lucanthone selectively inhibited the synthesis of nucleolar (ribosomal) RNA while the extranucleolar RNA synthesis proceeded at a high level. Similar results were obtained with 0.08 mug/ml actinomycin D. Protein synthesis and mitotic activity were also affected by lucanthone but the drug did not markedly interfere with DNA synthesis. Lucanthone appeared to be much less effective in cell killing than actinomycin D and its inhibitory effects on the nucleolar RNA synthesis and other cellular processes proved readily reversible. The results allow to conclude that lucanthone may be useful as a tool for studying RNA synthesis in animal cells.

Cell Line↗
PubMed1982

Hamster nasal glands: their structure, sialic acid content, and vulnerability to actinomycin D.

This study examines the structure of mucosal glands in the walls of the hamster maxillary recess, compares the histochemical appearance of nasal glands to their sialic acid content, and determines the vulnerability of nasal glands to actinomycin toxicity. Observations were made on plastic-embedded tissue with light and transmission electron microscopes. Determinations of total sialic acid in mucosal samples were conducted with thiobarbituric acid. Experimental hamsters were administered 0.2 micrograms of actinomycin D (IP)/gm body weight/day for five days. Types of granules present in the later nasal gland (LNG) and glands of the maxillary recess (MRGs) include: 2.0 micrometers lightly basophilic, lightly electron-dense granules and 1.5 micrometers strongly basophilic, electron-dense granules in the same acinar cell type in both the LNG and MRGs; 1.5 micrometers metachromatic granules in some acinar cells of the LNG; 1.0 micrometer moderately electron-dense granules in cells of MRG ducts; and 0.7 micrometers electron-dense granules in cells of LNG intercalated ducts. Acid glycoproteins, demonstrable by histochemistry, are present in the LNG but not in the MRGs. However, the total sialic acid content of tissues from MRG tissue is greater than that of other tissues measured. A minor number of LNG acini, those with metachromatic granules, have branching basal cytoplasmic projections. Many dark cells are present in striated ducts of the LNG. Histological alteration due to actinomycin-D toxicity, conspicuous in parotid salivary parenchyma, is greater in MRG than in LNG tissue.

Animals↗
PubMed1995

Measurement of DNA integrity and structure in Xenopus embryos in the presence of hydroxyurea, actinomycin-D, and triethylenemelamine using the fluorescent probe Hoechst 33258.

Cell health assay of water quality (CHAWQ) is an assay using intracellular biomarkers measured by optical techniques. CHAWQ uses embryos of the South African clawed frog, Xenopus laevis, and optical transducers of intracellular biomarkers to obtain rapid assessment of toxicity to frog embryos. Since the biomarkers are common to all cells, CHAWQ can indicate toxicity of different classes of chemicals. Among the biomarkers used are 1) the change in synthesis rate, 2) the structure, or 3) the environment of DNA. Measurement of DNA to detect genotoxicants has previously used extracted DNA or flow cytometry to detect alterations in DNA content or configuration. We report the use of viable frog embryos and the fluorescent probe Hoechst 33258 to detect the effect of three DNA-active chemicals--actinomycin-D, hydroxyurea, and triethylenemelamine (TEM)--on DNA in intact embryos. We found that we can detect changes in the DNA in the presence of toxicants at concentrations comparable to longer-term assays but following a much shorter time of drug exposure. Actinomycin-D caused a fluorescence decrease, TEM caused a fluorescence increase, whereas hydroxyurea gave a biphasic response. Hydroxyurea caused a decrease at low concentrations and an increase at higher concentrations. Concentration-response data for TEM, hydroxyurea, and actinomycin-D generated EC50 values of 0.1 mg/ml, 1.4 mg/ml, and 6.34 micrograms/ml, respectively.

Animals↗
PubMed2000

The role of the loop in binding of an actinomycin D analog to hairpins formed by single-stranded DNA.

Our recent work has indicated that the potent antibiotic and antitumor agent actinomycin D has the ability to selectively bind and stabilize single-stranded DNA that is capable of adopting a hairpin conformation. This mechanism of DNA binding has been implicated in the drug's ability to inhibit transcription by HIV reverse transcriptase from single-stranded DNA templates. In this report, we studied the importance of the hairpin loop on the ability of the 7-amino analog of actinomycin D to selectively bind DNA hairpins. Binding dissociation constant (Kd) values were determined to be 0.22 +/- 0.11 microM for the hairpin formed from the single-stranded DNA 5'-AAAAAAATAGTTTTAAATATTTTTTT-3' (dubbed HP1). The hairpin stem without the loop resulted in binding with Kd = 2.6 +/- 0.9 microM. The drug showed low affinity for the HP1 strand fully duplexed to its complementary sequence (estimated to be at least Kd > 21 microM). Evaluation of 7-aminoactinomycin D binding to a library of thermodynamically characterized DNA hairpins revealed an affinity for the hairpin-forming sequence 5'-GGATACCCCCGTATCC-3' (dubbed ACC4) of Kd = 6.8 +/- 2.2 microM. Replacement of the terminal guanines of this sequence to generate 5'-ATATACCCCCGTATAT-3' resulted in a 10-fold increase in affinity for this hairpin compared to ACC4, to Kd = 0.74 +/- 0.06 microM. A molecular model of the ACC4actinomycin D complex reveals that significant interactions between the hairpin loop and the pentapeptide rings of the drug must occur during drug binding. Taken together, our data indicate that the composition of the stem-loop interface is critical for the selectivity of actinomycin D and its 7-amino analog for DNA hairpins and suggests that novel drugs may be designed based on selection for the desired hairpin composition.

Anti-Bacterial Agents↗