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The Journal of Antibiotics Jul 1976
Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Bacteria; Chemical Phenomena; Chemistry; Lethal Dose 50; Mice; Naphthoquinones; Sarcoma, Yoshida; Solubility; Streptomyces
PubMed: 956059
DOI: 10.7164/antibiotics.29.765 -
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 -
The Journal of Antibiotics Jul 1989A new antibiotic, phenazinomycin (C27H32N2O, MW 400), was isolated from the cultural mycelium of Streptomyces sp. WK-2057. This antibiotic possesses antibacterial...
A new antibiotic, phenazinomycin (C27H32N2O, MW 400), was isolated from the cultural mycelium of Streptomyces sp. WK-2057. This antibiotic possesses antibacterial activities against Gram-positive bacteria in vitro, direct cytotoxic activities against HeLa S3, P388 and P388 doxorubicin-resistant cells in vitro and antitumor activities against experimental murine tumors in vivo.
Topics: Animals; Antibiotics, Antineoplastic; Bacteria; Fermentation; HeLa Cells; Leukemia P388; Leukemia, Experimental; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Mice; Mice, Inbred ICR; Microscopy, Electron; Molecular Structure; Phenazines; Sarcoma 180; Soil Microbiology; Spectrophotometry, Infrared; Streptomyces; Tumor Cells, Cultured
PubMed: 2753810
DOI: 10.7164/antibiotics.42.1037 -
British Journal of Cancer Aug 1996Elactocin is a novel anti-tumour antibiotic which has potent activity in vitro against a range of tumours. This phase I trial of elactocin identified the dose-limiting... (Clinical Trial)
Clinical Trial
Elactocin is a novel anti-tumour antibiotic which has potent activity in vitro against a range of tumours. This phase I trial of elactocin identified the dose-limiting toxicity as profound anorexia and malaise. The schedules used included 1 h infusion 3 weekly, 24 h infusion 3 weekly, 1 h infusion daily x 5 (3 weekly), 1 h infusion weekly and finally continuous 5 day intravenous infusion. On all these schedules dose-limiting toxicity was the same and as no partial or complete responses were identified, we do not recommend that further trials of elactocin are performed.
Topics: Anorexia; Antibiotics, Antineoplastic; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatty Acids, Unsaturated; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms
PubMed: 8761384
DOI: 10.1038/bjc.1996.415 -
Nucleic Acids Research Aug 2018Small-molecule compounds that target mismatched base pairs in DNA offer a novel prospective for cancer diagnosis and therapy. The potent anticancer antibiotic...
Small-molecule compounds that target mismatched base pairs in DNA offer a novel prospective for cancer diagnosis and therapy. The potent anticancer antibiotic echinomycin functions by intercalating into DNA at CpG sites. Surprisingly, we found that the drug strongly prefers to bind to consecutive CpG steps separated by a single T:T mismatch. The preference appears to result from enhanced cooperativity associated with the binding of the second echinomycin molecule. Crystallographic studies reveal that this preference originates from the staggered quinoxaline rings of the two neighboring antibiotic molecules that surround the T:T mismatch forming continuous stacking interactions within the duplex. These and other associated changes in DNA conformation allow the formation of a minor groove pocket for tight binding of the second echinomycin molecule. We also show that echinomycin displays enhanced cytotoxicity against mismatch repair-deficient cell lines, raising the possibility of repurposing the drug for detection and treatment of mismatch repair-deficient cancers.
Topics: Antibiotics, Antineoplastic; Base Pair Mismatch; Cell Survival; Crystallography, X-Ray; DNA; Echinomycin; HCT116 Cells; Humans; Intercalating Agents; Molecular Structure; Neoplasms; Nucleic Acid Conformation
PubMed: 29741655
DOI: 10.1093/nar/gky345 -
Journal of Applied Physiology... Feb 2006Doxorubicin (Dox) is a highly effective antineoplastic antibiotic associated with a dose-limiting cardiotoxicity that may result in irreversible cardiomyopathy and heart...
Doxorubicin (Dox) is a highly effective antineoplastic antibiotic associated with a dose-limiting cardiotoxicity that may result in irreversible cardiomyopathy and heart failure. The purpose of this study was to examine the effects of low-intensity exercise training (LIET) during the course of Dox treatment on cardiac function, myosin heavy chain expression, oxidative stress, and apoptosis activation following treatment. Male Sprague-Dawley rats either remained sedentary or were exercise trained on a motorized treadmill at 15 m/min, 20 min/day, 5 days/wk (Monday through Friday) for 2 wk. During the same 2-wk period, Dox (2.5 mg/kg) or saline was administered intraperitoneally to sedentary and exercised rats 3 days/wk (Monday, Wednesday, Friday) 1-2 h following the exercise training sessions (cumulative Dox dose: 15 mg/kg). Five days following the final injections, hearts were isolated for determination of left ventricular (LV) function, lipid peroxidation, antioxidant enzyme protein expression, 72-kDa heat shock protein expression, caspase-3 activity, and myosin heavy chain isoform expression. Dox treatment significantly impaired LV function and increased caspase-3 activity in sedentary animals (P < 0.05). LIET attenuated the LV dysfunction and apoptotic signal activation induced by Dox treatment and increased glutathione peroxidase expression, but it had no significant effect on lipid peroxidation, protein expression of myosin heavy chain isoforms, 72-kDa heat shock protein, or superoxide dismutase isoforms. In conclusion, our data suggest that LIET applied during chronic Dox treatment protects against cardiac dysfunction following treatment, possibly by enhancing antioxidant defenses and inhibiting apoptosis.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Caspase 3; Doxorubicin; Glutathione Peroxidase; Heart; Heart Ventricles; Male; Myocardium; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Ventricular Dysfunction, Left
PubMed: 16210442
DOI: 10.1152/japplphysiol.00148.2005 -
The Biochemical Journal Apr 19891H- and 31P-n.m.r. spectroscopy were used to characterize the solution structure of the 1:1 complex formed between the antitumour antibiotic luzopeptin and the...
1H- and 31P-n.m.r. spectroscopy were used to characterize the solution structure of the 1:1 complex formed between the antitumour antibiotic luzopeptin and the self-complementary hexanucleotide d(5'-GCATGC)2. Eighteen nuclear Overhauser effects between antibiotic and nucleotide protons, together with ring-current-induced perturbations to base-pair and quinoline 1H resonances, define the position and orientation of the bound drug molecule. Luzopeptin binds in the minor groove of the DNA with full retention of dyad symmetry, its quinoline chromophores intercalating at the 5'-CpA and 5'-TpG steps and its depsipeptide ring spanning the central two A.T base-pairs. The chromophores stack principally on the adenine base with their carbocyclic rings pointing towards the deoxyribose of the cytosine. There is no evidence for Hoogsteen base-pairing in the complex, all glycosidic bond angles and sugar puckers being typical of B-DNA as found for the free hexanucleotide. The 'breathing' motions of the A.T and internal G.C base-pairs are substantially slowed in the complex compared with the free DNA, and the observation that two phosphate resonances are shifted downfield by at least 0.5 p.p.m. in the 31P-n.m.r. spectrum of the complex suggests pronounced local helix unwinding at the intercalation sites. The data are consistent with a model of the complex in which luzopeptin bisintercalates with its depsipeptide essentially in the conformation found in the crystal of the free antibiotic [Arnold & Clardy (1981) J. Am. Chem. Soc. 103, 1243-1244]. We postulate only one conformational change within the peptide ring, which involves rotation of the pyridazine-glycine amide group linkage by 90 degrees towards the DNA surface. This manoeuvre breaks the glycine-to-glycine transannular hydrogen bonds and enables the glycine NH groups to bond to the thymine O-2 atoms of the sandwiched A.T base-pairs. It also shortens the major axis of the depsipeptide so that the interchromophore distance is more suitable for spanning two base-pairs. The model further implies that the carboxy and hydroxy groups of the L-beta-hydroxyvaline residue are appropriately positioned for hydrogen-bonding to the 2-amino group of guanine and the O-2 atom of cytosine of the adjacent G.C base-pair.
Topics: Antibiotics, Antineoplastic; Deoxyribonucleotides; Hydroxyquinolines; Intercalating Agents; Magnetic Resonance Spectroscopy; Protein Conformation; Quinolines
PubMed: 2719658
DOI: 10.1042/bj2590433 -
Drug Design, Development and Therapy 2020Doxorubicin is an anthracycline antibiotic used as an anticancer agent. Long-term use of this anticancer agent could accumulate its metabolite, doxorubicinol, and cause...
INTRODUCTION
Doxorubicin is an anthracycline antibiotic used as an anticancer agent. Long-term use of this anticancer agent could accumulate its metabolite, doxorubicinol, and cause cardiomyopathy, due to its cardiotoxicity. This cardiotoxic effect depends on the amount of doxorubicin and doxorubicinol accumulated in the body. This study aimed to analyze doxorubicin and doxorubicinol levels in the blood plasma of breast cancer patients.
METHODS
Participants of this study were 30 breast cancer patients who had received doxorubicin in their therapy regimen. The samples were analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), with the Acquity UPLC BEH C18 Waters chromatography column (2.1 x 100 mm : 1.7 μm). Plasma (250 μL) samples were prepared by protein precipitation, using methanol. The mobile phase consisted of 0.1% acetic acid (eluent A) and acetonitrile (eluent B), with gradient elution; the flow rate was 0.15 mL/min and runtime, 7 min.
RESULTS AND DISCUSSION
This method was linear in the range of 1-1000 ng/mL for doxorubicin and 0.5-500 ng/mL for doxorubicinol. This method was successfully used to analyze doxorubicin and doxorubicinol, simultaneously, using hexamethylphosphoramide as the internal standard, in the plasma of breast cancer patients. Results showed that the measured concentrations of doxorubicin and doxorubicinol ranged between 12.54-620.01 ng/mL and 1.10-27.00 ng/mL, respectively. The measured cumulative doses of doxorubicin ranged between 48.76 and 319.01 mg/m; thus, the risk of cardiomyopathy in the surveyed patients was under 4%, according to literature.
Topics: Adult; Aged; Antibiotics, Antineoplastic; Breast Neoplasms; Doxorubicin; Female; Humans; Middle Aged
PubMed: 32921983
DOI: 10.2147/DDDT.S251144 -
The Journal of Antibiotics Aug 1982A novel antibiotic, prothracarcin was isolated from the culture broth of Streptomyces umbrosus subsp. raffinophilus DO-62. The antibiotic has the molecular formula of...
A novel antibiotic, prothracarcin was isolated from the culture broth of Streptomyces umbrosus subsp. raffinophilus DO-62. The antibiotic has the molecular formula of C14H14N2O and belongs to the pyrrolo [1,4]benzodiazepine antibiotics. Its structure has been elucidated by mass and NMR spectra. It is active against Gram-positive and Gram-negative bacteria and experimental murine tumor sarcoma 180 and leukemia P388.
Topics: Animals; Antibiotics, Antineoplastic; Benzodiazepines; Chemical Phenomena; Chemistry; Fermentation; Mice; Neoplasms, Experimental; Streptomyces
PubMed: 7142014
DOI: 10.7164/antibiotics.35.972 -
The Journal of Antibiotics May 1983WF-3161 is an antitumor antibiotic produced by a strain of fungus, Petriella guttulata. The antibiotic was purified by solvent extraction and a combination of silica gel...
WF-3161 is an antitumor antibiotic produced by a strain of fungus, Petriella guttulata. The antibiotic was purified by solvent extraction and a combination of silica gel and reverse phase column chromatography. The chemical structure of the antibiotic (C31H44N4O6, mp 181-183 degrees C) was found to be a cyclic tetrapeptide consisting of phenylalanine, leucine, pipecolinic acid and 2-amino-8-oxo-9,10-epoxydecanoic acid. WF-3161 inhibited the growth of Trichophyton asteroides. It prolonged survival period of mice bearing leukemia P-388 with a high therapeutic index.
Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Chemical Phenomena; Chemistry; Leukemia P388; Magnetic Resonance Spectroscopy; Mice; Peptides; Peptides, Cyclic; Xylariales
PubMed: 6860430
DOI: 10.7164/antibiotics.36.478