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ChemMedChem Jan 2017Cell-penetrating peptides (CPPs) are still an interesting and viable alternative for drug delivery applications. CPPs contain considerably high amounts of positively...
Cell-penetrating peptides (CPPs) are still an interesting and viable alternative for drug delivery applications. CPPs contain considerably high amounts of positively charged amino acids, imparting them with cationic character. Tumor cells are characterized by an enhanced anionic nature of their membrane surface, a property that could be used by CPPs to target these cells. We recently identified a branched CPP that displays a high internalization capacity while exhibiting selectivity for certain tumor cell types. In this study we elucidated this observation in greater detail by investigating the underlying mechanism behind the cellular uptake of this peptide. An additional cytotoxicity screen against several cancer cell lines indeed demonstrates high cytotoxic activity against cancer cells over normal fibroblasts. Furthermore, we show that this feature can be used for delivering the anticancer drug actinomycin D with high efficiency in the MCF-7 cancer cell line.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cell-Penetrating Peptides; Dactinomycin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Structure-Activity Relationship
PubMed: 27860402
DOI: 10.1002/cmdc.201600498 -
Canadian Medical Association Journal Jul 1976In an unselected series of 49 children with Wilms' tumour treated in 1969-74 the 5-year relapse-free survival and survival rates were 78% and 81%, respectively, whereas...
In an unselected series of 49 children with Wilms' tumour treated in 1969-74 the 5-year relapse-free survival and survival rates were 78% and 81%, respectively, whereas in the series of children treated in 1963-68 the corresponding rates were 49% and 70%. The significant improvement in the relapse-free survival rate was a result of adjuvant treatment with actinomycin D and vincristine (AMD + VCR), which, in some patients, eradicated occult metastatic disease. In the treatment of lung metastases the combination of whole-lung irradiation and maintained chemotherapy with AMD + VCR proved excessively toxic: in 5 of 11 patients acute diffuse pneumonitis developed, and it was fatal in 3. Adjuvant AMD + VCR therapy is advocated in all patients with Wilms' tumour except children less than 12 months old with a tumour of moderate size, limited to the kidney and completely resectable.
Topics: Child; Child, Preschool; Dactinomycin; Drug Therapy, Combination; Female; Humans; Kidney Neoplasms; Male; Neoplasm Metastasis; Pneumonia; Recurrence; Remission, Spontaneous; Vincristine; Wilms Tumor
PubMed: 179690
DOI: No ID Found -
Journal of Virology Dec 1980Analysis of purified respiratory syncytial virus revealed that the virion RNA was composed of 50S, 28S, 18S, and 4S species. The 18S and 28S species were presumed to...
Analysis of purified respiratory syncytial virus revealed that the virion RNA was composed of 50S, 28S, 18S, and 4S species. The 18S and 28S species were presumed to represent host rRNA since virus grown in actinomycin D-treated cells contained only 50S and 4S RNAs. Actinomycin D treatment stimulated production of infectious respiratory syncytial virus 5- to 10-fold. The 50S virion RNA was shown to hybridize with polyadenylated mRNA's isolated from infected cells, indicating that respiratory syncytial virus RNA is of negative-strand sense. Six mRNA's were identified by polyacrylamide gel electrophoresis.
Topics: Cell Line; Dactinomycin; Electrophoresis, Polyacrylamide Gel; Molecular Weight; RNA, Messenger; RNA, Viral; Respiratory Syncytial Viruses
PubMed: 7463558
DOI: 10.1128/JVI.36.3.837-846.1980 -
Gynecologic Oncology Aug 2020Methotrexate and actinomycin-D are both effective first-line drugs for low-risk (WHO score 0-6) Gestational Trophoblastic Neoplasia (GTN) with considerable debate about... (Randomized Controlled Trial)
Randomized Controlled Trial
An international randomized phase III trial of pulse actinomycin-D versus multi-day methotrexate for the treatment of low risk gestational trophoblastic neoplasia; NRG/GOG 275.
OBJECTIVES
Methotrexate and actinomycin-D are both effective first-line drugs for low-risk (WHO score 0-6) Gestational Trophoblastic Neoplasia (GTN) with considerable debate about which is more effective, less toxic, and better tolerated. The primary trial objective was to test if treatment with multi-day methotrexate (MTX) was inferior to pulse actinomycin-D (ACT-D). Secondary objectives included evaluation of severity and frequency of adverse events, and impact on quality of life (QOL).
METHODS
This was a prospective international cooperative group randomized phase III two arm non-inferiority study (Clinical Trials Identifier: (NCT01535053). The control arm was ACT-D; the experimental arm was multi-day MTX regimen (institutional preference of 5 or 8 day). Outcome measures included complete response rate, recurrence rate, toxicity, and QOL as measured by FACT-G and FACIT supplemental items.
RESULTS
The complete response rates for multi-day methotrexate and pulse actinomycin-D were 88% (23/26 patients) and 79% (22/28 patients) (p = NS) respectively, there were two recurrences in each arm, and 100% of patients survived. Significant toxicity was minimal, but mouth sores (mucositis), and eye pain were significantly more common in the MTX arm (p = 0.001 and 0.01 respectively). Quality of life showed no significant difference in overall quality of life, body image, sexual function, or treatment related side effects. The study was closed for low accrual rate (target 384, actual accrual 57), precluding statistical analysis of the primary objective.
CONCLUSIONS
The complete response rate for multi-day methotrexate was higher than actinomycin-D, but did not reach statistical significance. The multi-day MTX regimens were associated with significantly more mucositis and were significantly less convenient.
Topics: Dactinomycin; Drug Administration Schedule; Female; Gestational Trophoblastic Disease; Humans; Methotrexate; Patient Reported Outcome Measures; Pregnancy; Quality of Life
PubMed: 32460997
DOI: 10.1016/j.ygyno.2020.05.013 -
British Journal of Clinical Pharmacology May 2016Use of the anti-tumour antibiotic actinomycin D is associated with development of hepatotoxicity, particularly in young children. A paucity of actinomycin D...
AIMS
Use of the anti-tumour antibiotic actinomycin D is associated with development of hepatotoxicity, particularly in young children. A paucity of actinomycin D pharmacokinetic data make it challenging to develop a sound rationale for defining dosing regimens in younger patients. The study aim was to develop a physiologically based pharmacokinetic (PBPK) model using a combination of data from the literature and generated from experimental analyses.
METHODS
Assays to determine actinomycin D Log P, blood:plasma partition ratio and ABCB1 kinetics were conducted. These data were combined with physiochemical properties sourced from the literature to generate a compound file for use within the modelling-simulation software Simcyp (version 14 release 1). For simulation, information was taken from two datasets, one from 117 patients under the age of 21 and one from 20 patients aged 16-48.
RESULTS
The final model incorporated clinical renal and biliary clearance data and an additional systemic clearance value. The mean AUC0-26h of simulated subjects was within 1.25-fold of the observed AUC0-26h (84 ng h ml(-1) simulated vs. 93 ng h ml(-1) observed). For the younger age ranges, AUC predictions were within two-fold of observed values, with simulated data from six of the eight age/dose ranges falling within 15% of observed data. Simulated values for actinomycin D AUC0-26h and clearance in infants aged 0-12 months ranged from 104 to 115 ng h ml(-1) and 3.5-3.8 l h(-1) , respectively.
CONCLUSIONS
The model has potential utility for prediction of actinomycin D exposure in younger patients and may help guide future dosing. However, additional independent data from neonates and infants is needed for further validation. Physiological differences between paediatric cancer patients and healthy children also need to be further characterized and incorporated into PBPK models.
Topics: ATP Binding Cassette Transporter, Subfamily B; Adolescent; Adult; Animals; Antibiotics, Antineoplastic; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cohort Studies; Computer Simulation; Dactinomycin; Dogs; Female; Humans; Infant; Madin Darby Canine Kidney Cells; Male; Models, Biological; Neoplasms; Young Adult
PubMed: 26727248
DOI: 10.1111/bcp.12878 -
Proceedings of the Royal Society of... Mar 1966
Topics: Child; Child, Preschool; Cyclophosphamide; Dactinomycin; Humans; Hydrazines; Mechlorethamine; Methotrexate; Neoplasms; Vinblastine; Vincristine
PubMed: 5909761
DOI: No ID Found -
BMC Biology Dec 2014Almost all cells display circadian rhythms, approximately 24-hour period changes in their biochemistry, physiology or behavior. These rhythms are orchestrated by an...
BACKGROUND
Almost all cells display circadian rhythms, approximately 24-hour period changes in their biochemistry, physiology or behavior. These rhythms are orchestrated by an endogenous circadian clock whose mechanism is based on transcription-translation feedback loops (TTFL) where the translated products of clock genes act to inhibit their own transcription.
RESULTS
We have used RNA-Seq to measure the abundance of all transcripts in an RNA-Seq-derived de novo gene catalog in two different experiments. One compared midday and midnight in a light-dark cycle (ZT6 and ZT18) and under constant light (CT6 and CT18). The second compared four different times (ZT2, ZT6, ZT14 and ZT18) under a light dark cycle. We show here that despite an elaborate repertoire of biological rhythms, the unicellular dinoflagellate Lingulodinium had no detectable daily variation in the abundance of any transcript in an RNA-Seq-derived de novo gene catalog. We also examined the timing of the bioluminescence and photosynthesis rhythms in the presence of the transcription inhibitors actinomycin D and cordycepin. We found that the timing of the two rhythms was unchanged even when transcription rates had decreased to roughly 5% the levels of untreated cells.
CONCLUSIONS
The lack of detectable daily variation in transcript levels indicates that the endogenous circadian timer of Lingulodinium does not require rhythmic RNA. If the circadian timer is considered as a limit cycle oscillator, then cellular time in this organism must be defined by variations in state variables that do not include the amount of a clock gene transcript.
Topics: Circadian Clocks; Circadian Rhythm; Dactinomycin; Deoxyadenosines; Dinoflagellida; Light; Photoperiod; Protein Synthesis Inhibitors; RNA; Sequence Analysis, RNA
PubMed: 25526979
DOI: 10.1186/s12915-014-0107-z -
Journal of Virology Oct 1968Purified Semliki Forest virus (SFV) contains three structural proteins while its core (nucleocapsid) contains two of these proteins. To identify all of the proteins...
Purified Semliki Forest virus (SFV) contains three structural proteins while its core (nucleocapsid) contains two of these proteins. To identify all of the proteins synthesized under virus direction, cells were infected with SFV in the presence of actinomycin D and guanidine. Cell protein synthesis was markedly and irreversibly inhibited under these conditions; virus growth was reversibly inhibited by guanidine and began when the cells were washed to remove the guanidine. When cells were treated with guanidine for 4 hr after virus infection and then were washed, five major proteins were produced early in infection. Three of these proteins corresponded to virus structural proteins. None of these five proteins was a major protein of uninfected cells or of virus-infected cells which had been incubated with partially purified interferon before infection. Late in infection, three major proteins, the virus structural proteins, were produced.
Topics: Animals; Carbon Isotopes; Culture Techniques; Dactinomycin; Electrophoresis; Guanidines; Interferons; Protein Biosynthesis; Semliki forest virus; Viral Proteins; Virus Replication
PubMed: 5723710
DOI: 10.1128/JVI.2.10.1076-1080.1968 -
Biochemical and Biophysical Research... Aug 1986We have shown previously that aspirin (ASA) ingestion by normal human volunteers inhibits peripheral blood monocyte phospholipase C (PLC) activities ex vivo. In order to...
We have shown previously that aspirin (ASA) ingestion by normal human volunteers inhibits peripheral blood monocyte phospholipase C (PLC) activities ex vivo. In order to explore further the mechanism of action of ASA, normal human monocytes and differentiated human U937 cells were treated with ASA and other salicylates. Cells preincubated with ASA were found to have decreased PLC activities. Phospholipase A2 activities were not affected by salicylates. Sodium salicylate and salicylic acid, nonacetylated relatives of ASA also inhibited PLC activity. This effect was dose and time dependent and addition of cycloheximide or actinomycin D to the preincubation mixture abrogated the inhibitory effect of salicylates on PLC. This PLC inhibitory protein induced by ASA appears distinct from lipocortin, a phospholipase A2 inhibitory protein inducible by corticosteroids.
Topics: Annexins; Aspirin; Cycloheximide; Dactinomycin; Glycoproteins; Humans; Indomethacin; Salicylates; Type C Phospholipases
PubMed: 2945550
DOI: 10.1016/s0006-291x(86)80087-0 -
Nucleic Acids Research Sep 2019DNA mismatches are highly polymorphic and dynamic in nature, albeit poorly characterized structurally. We utilized the antitumour antibiotic CoII(Chro)2 (Chro =...
DNA mismatches are highly polymorphic and dynamic in nature, albeit poorly characterized structurally. We utilized the antitumour antibiotic CoII(Chro)2 (Chro = chromomycin A3) to stabilize the palindromic duplex d(TTGGCGAA) DNA with two G:G mismatches, allowing X-ray crystallography-based monitoring of mismatch polymorphism. For the first time, the unusual geometry of several G:G mismatches including syn-syn, water mediated anti-syn and syn-syn-like conformations can be simultaneously observed in the crystal structure. The G:G mismatch sites of the d(TTGGCGAA) duplex can also act as a hotspot for the formation of alternative DNA structures with a GC/GA-5' intercalation site for binding by the GC-selective intercalator actinomycin D (ActiD). Direct intercalation of two ActiD molecules to G:G mismatch sites causes DNA rearrangements, resulting in backbone distortion to form right-handed Z-DNA structures with a single-step sharp kink. Our study provides insights on intercalators-mismatch DNA interactions and a rationale for mismatch interrogation and detection via DNA intercalation.
Topics: Antibiotics, Antineoplastic; Base Pair Mismatch; Base Pairing; Base Sequence; Binding Sites; Chromomycin A3; Crystallization; Crystallography, X-Ray; DNA, Z-Form; Dactinomycin; Humans; Intercalating Agents; Models, Molecular; Oligodeoxyribonucleotides; Solutions
PubMed: 31361900
DOI: 10.1093/nar/gkz653