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PubMed1977

Regeneration of proximal and distal part of hydra body cut in the middle of gastral cavity and treated with dactinomycine.

Hydras were cut in the middle of the gastral part of the body. The part with the hypostome is marked as H, and the one with the foot as P. Both parts were treated with actinomycine D in 0,5 mg : 200 ml water solution. H-parts are much more sensitive to the effect of actinomycine than P-parts, and P lives considerably longer. It is supposed that such reaction are the result of specificity of H and P cell composition, and of the growth direction which is characteristic of hydra in general. H-part has a proportionally greater number of differentiated cells and this relatively smaller number of non-differentiated cells is spent in it quicker than in P-part in which they are more numerous. The growth direction has a decisive influence on further life of H- respectively P-part. Namely, H- in growth direction does not have any damaged body regions (hypostome and tentacles are intact) and it lacks the amputated P-part i.e. gastral region with foot: the region which is on the opposite side of growth direction of hydra. H-part has all the characteristic cells of this body region, so after amputation mostly it does not change. Unfavourable effect of citostatic manifests sooner and H-part desintegrates quicker. On the contrary, P-part lacks the hypostome with tentacles, and these are the body parts in the growth direction. Zimogen cells can dedifferentiate and differentiate. The hypostome and tentacles regenerate as far as is allowed by actinomycine.

Animals↗
PubMed1997

Therapeutic dose and timing of administration of RNA synthesis inhibitors for preventing cerebral vasospasm after subarachnoid hemorrhage.

A RNA synthesis inhibitor, dactinomycin, intended to suppress induction of vasoconstrictor peptide endothelin, prevented cerebral vasospasm almost completely in the dog subarachnoid hemorrhage (SAM) model [8]. Since endothelin receptor antagonists have not shown so potent effect as dactinomycin in animal SAH models, we aimed clinical use of dactinomycin for improvement of final outcomes of severe SAH patients now suffering vasospasm. Before clinical application, we examined therapeutic dose and timing of administration of dactinomycin in animal models. In the dog two-hemorrhage model, dactinomycin treatment (0.01 mg/kg i.v. for 5 days) started at 6 hours after the second blood injection on Day 2 prevented vasospasm, but that started on Day 3 did not. Low dose of dactinomycin (0.003 mg/kg i.v. for 5 days) rather aggravated vasospasm even though the treatment started on Day 0. In the rat vasospasm model, high dose of dactinomycin (0.03 mg/kg i.p. for 3 days) or relatively low dose of doxorubicin (0.6 mg/kg i.p. once) prevented vasospasm even though the treatment started on Day 4. The present study suggests that RNA synthesis inhibitors, such as dactinomycin and doxorubicin, may aufficiently prevent or ameliorate cerebral vasospasm in severe SAH patients.

Animals↗
PubMed1995

Selective sensitivity of macrophages to cytotoxicity by inhibitors of macromolecular synthesis: induction of apoptosis.

Initial studies designed to measure the effect of inhibiting RNA synthesis by dactinomycin on macrophage functions revealed that the cells were uniformly killed at concentrations that have been routinely used to inhibit RNA synthesis in other cell types. We, thus, determined the dose curve for the cytotoxicity of dactinomycin for macrophages and two other cell types, L929 cells and splenic lymphocytes. Macrophages were extremely sensitive to the cytotoxicity of dactinomycin compared to the other cell types. Submicromolar concentrations that induced 100% cytotoxicity in macrophages caused little death in L929 cells or lymphocytes. Concentrations of dactinomycin that inhibited RNA synthesis by 40% in macrophages induced almost complete cell death but inhibition of over 80% of RNA synthesis in L929 cells or lymphocytes induced no measurable cytotoxicity. Macrophages did take up more dactinomycin than other cells but the amount was not sufficient to account for the large differences in cytotoxicity. We next tested the effects of doxorubicin and cycloheximide and found that macrophages were also extremely sensitive to killing by these compounds, and there was a very close association between the amount of inhibition of protein synthesis and the amount of toxicity. The morphology of macrophages exposed to these agents was consistent with death by apoptosis. This was further supported by assays measuring membrane integrity and DNA fragmentation. These data demonstrate that inhibition of macromolecular synthesis in macrophages, by different mechanisms, causes macrophages to undergo apoptosis. They further suggest that, in contrast to other cell types that require protein synthesis for apoptosis, macrophages require the synthesis of certain proteins to avoid apoptosis.

Animals↗
PubMed1989

Acquired drug resistance in human lung carcinoma xenografts.

The development of resistance to vincristine and dactinomycin has been investigated in a human epidermoid lung xenograft line grown in nude mice. With 1 mg/kg BW vincristine and 0.5 mg/kg BW dactinomycin per passage, resistance of the solid tumors was visible already at the second transplantation. The vincristine-resistant subline showed cross-resistance to dactinomycin and doxorubicin, and the dactinomycin-resistant subline only to vincristine. To determine whether multidrug resistance genes were overexpressed in the resistant sublines, slot blots were performed using the cDNA probe pcDR 1.5. Slightly elevated RNA levels could be detected in the vincristine-resistant subline and in the dactinomycin-resistant subline.

Animals↗
PubMed1991

Results of two radiation therapy randomizations in the third National Wilms' Tumor Study.

In the third National Wilms' Tumor Study (NWTS-3), patients with Stage II favorable histologic type (FH) or Stage III FH Wilms' tumor were randomized according to a factorial design for both radiation therapy (RT) and chemotherapy to be given after nephrectomy. Patients with Stage II FH disease were randomized between 2000 cGy and no postoperative RT; patients with Stage III FH disease were randomized between 2000 and 1000 cGy. No significant differences in survival were noticed. Although there were no significant differences in the rate of intraabdominal relapses, those patients with Stage III disease who received 1000 cGy and dactinomycin and vincristine (seven patients) experienced a relapse in the abdomen more frequently than those who received 2000 cGy and dactinomycin and vincristine (three patients), 1000 cGy and dactinomycin, vincristine, and doxorubicin (three patients), or 2000 cGy and dactinomycin, vincristine, and doxorubicin (two patients). This would suggest that doxorubicin might be a good substitute for the second 1000 cGy of RT. Boost doses of RT, although allowed, were rarely given and no assessment of the value of supplemental RT can be made. The dismal prognosis of abdominal relapse after RT is confirmed and delay of initiation of treatment beyond 10 days after surgery was a significant adverse factor as in NWTS-1 and NWTS-2.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation.

We analyzed the der(11) and der(4) genomic breakpoint junctions of a t(4;11) in the leukemia of a patient previously administered etoposide and dactinomycin by molecular and biochemical approaches to gain insights about the translocation mechanism and the relevant drug exposure. The genomic breakpoint junctions were amplified by PCR. Cleavage of DNA substrates containing the normal homologues of the MLL and AF-4 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase IIalpha and etoposide, etoposide catechol, etoposide quinone, or dactinomycin. The der(11) and der(4) genomic breakpoint junctions both involved MLL intron 6 and AF-4 intron 3. Recombination was precise at the sequence level except for the overall gain of a single templated nucleotide. The translocation breakpoints in MLL and AF-4 were DNA topoisomerase II cleavage sites. Etoposide and its metabolites, but not dactinomycin, enhanced cleavage at these sites. Assuming that DNA topoisomerase II was the mediator of the breakage, processing of the staggered nicks induced by DNA topoisomerase II, including exonucleolytic deletion and template-directed polymerization, would have been required before ligation of the ends to generate the observed genomic breakpoint junctions. These data are inconsistent with a translocation mechanism involving interchromosomal recombination by simple exchange of DNA topoisomerase II subunits and DNA-strand transfer; however, consistent with reciprocal DNA topoisomerase II cleavage events in MLL and AF-4 in which both breaks became stable, the DNA ends were processed and underwent ligation. Etoposide and/or its metabolites, but not dactinomycin, likely were the relevant exposures in this patient.

Antigens, Neoplasm↗
PubMed2003

Interleukin-1 beta rapidly inhibits aortic endothelium-dependent relaxation by a DNA transcription-dependent mechanism.

OBJECTIVES: This study examined the effects of interleukin-1 beta on isometric tension development and relaxation in isolated rat aortic rings in response to the alpha-1 adrenergic agonist phenylephrine, the endothelium-dependent vasodilator acetylcholine, and the endothelium-independent vasodilator sodium nitroprusside. DESIGN: Randomized, controlled, paired design. SETTING: Animal laboratory within a university department of physiology. SUBJECTS Paired aortic thoracic aortic rings from specific pathogen-free Sprague-Dawley rats. INTERVENTIONS: Series I examined the potential for interleukin-1 beta to cause early arterial endothelial dysfunction. Paired aortic rings were incubated for 2 hrs with interleukin-1 beta or vehicle. Series II examined the potential for inhibition of DNA transcription to attenuate interleukin-1 beta-mediated endothelial dysfunction. Paired rings received either dactinomycin or vehicle before interleukin-1 beta incubation. Series III quantified the degree to which inhibition of DNA transcription inhibited early interleukin-1 beta-mediated endothelial dysfunction. Paired rings received either dactinomycin pretreatment followed by interleukin-1 beta incubation, or pretreatment and incubation with inert vehicles. Series IV assessed the effects of interleukin-1 beta on responsiveness to an exogenous nitric oxide donor, sodium nitroprusside, in the presence of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester. MEASUREMENTS AND MAIN RESULTS: Incubation with interleukin-1 beta for 2 hrs had no effect on contractile response but attenuated endothelium-dependent relaxation significantly relative to control. Dactinomycin pretreatment inhibited early interleukin-1 beta-mediated endothelial dysfunction. The combination of interleukin-1 beta and dactinomycin produced effects on endothelium-dependent relaxation that were not different from that seen in rings not exposed to interleukin-1 beta. Interleukin-1 beta attenuated responsiveness to sodium nitroprusside relative to control. CONCLUSIONS: Interleukin-1 beta causes an early impairment of endothelium-dependent vasorelaxation with an onset that precedes its effects on systemic contractility. This impairment occurs via a mechanism that is wholly or predominantly dependent on DNA transcription. The altered vasorelaxation induced by interleukin-1 beta is at least partly mediated by a reduction in nitric oxide responsiveness.

Acetylcholine↗
PubMed2002

Low-risk persistent gestational trophoblastic disease: outcome after initial treatment with low-dose methotrexate and folinic acid from 1992 to 2000.

PURPOSE: We have simplified the treatment of gestational trophoblastic disease (GTD) in order to reduce the number of patients exposed to potentially carcinogenic chemotherapy. Patients who score 0 to 8 on the Charing Cross scoring system are classified as low-risk and receive methotrexate (MTX) and folinic acid (FA), whereas those who score higher than 8 are classified as high-risk and receive the etoposide, methotrexate, and dactinomycin (EMA)/cyclophosphamide and vincristine (CO) regimen. PATIENTS AND METHODS: Between 1992 and 2000, 485 women with GTD were commenced on MTX/FA at Charing Cross Hospital, London, United Kingdom. If patients developed MTX resistance or toxicity, treatment was altered according to the level of beta human chorionic gonadotropin (hCG). If serum hCG was < or = 100 IU/L, patients received dactinomycin; if hCG was greater than 100 IU/L, patients received EMA/CO. RESULTS: The median duration of follow-up was 4.7 years. Overall survival was 100% and the relapse rate was 3.3% (16 of 485 patients). hCG values normalized in 324 (66.8%) of 485 patients with MTX alone, whereas 161 (33.2%) of 485 patients required a change in treatment, 11 because of MTX toxicity and 150 because of MTX resistance. Sixty-seven patients changed to dactinomycin, of whom 58 achieved normal hCG values, and nine required third-line chemotherapy with EMA/CO. hCG values normalized in 93 (98.9%) of 94 patients who changed directly to EMA/CO from MTX. CONCLUSION: Single-agent dactinomycin has activity in patients with low-risk GTD who develop MTX resistance and whose hCG is low. Simplifying the stratification of GTD into two classes (low- and high-risk) does not compromise overall outcome and may reduce the risk of second tumors.

Adult↗
PubMed1975

The influence of selected cytostatics on human trophoblast in vitro.

The effect of cytostatics (Methotrexate, Oncovin and Dactinomycin) on early human trophoblast in vitro was studied by the tissue (organ) culture technique according to Trowell and by brief incubation with thymidine 3H. The cytostatics were tested by the method of Tanneberger in clinical and tenfold higher doses. The criteria for cytostatic efficacy were based an activity of DNA, histologic and histochemical changes, and secretion of hormonal chorionic gonadotropin. In vitro cultures of trophoblast were found to be a good model for evaluation of cytostatics, and the tested chemotherapeutics were effective chemotherapeutically. Upon addition to in vitro cultures they changed the structure and function of trophoblastic cells, resulting in depression of DNA resynthesis, histologic changes, changes in enzyme activities assessed histochemically, and impaired HCG secretion. The most pronounced effects were obtained with Dactinomycin or with a combination of Dactinomycin and methotrexate. Methotrexate alone had the weakest effect on DNA resynthesis and structure of the trophoblastic cells. The effect achieved with methotrexate after 120 hours was equal to the effect of Dactinomycin after 48 hours. Comparison of the histologic and hormonal results with DNA activity showed concordance between the intensity of morphologic and hormonal changes and impairment of nucleic acid functions.

Acid Phosphatase↗