DNA binding studies on several new anthracycline antitumor antibiotics II. The importance of the carbomethoxy-group as position-10 of the class II anthracycline molecule.
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Animals↗
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Exercise for the mitigation of cancer therapy-related cardiac dysfunction in breast cancer patients treated with anthracyclines: a systematic review and meta-analysis.
PURPOSE: Cancer therapy-related cardiac dysfunction (CTRCD) is a significant concern for breast cancer patients undergoing anthracycline-based chemotherapy. Although exercise has been proposed as a cardioprotective strategy, existing reviews have largely examined heterogeneous cancer populations receiving varied treatments, leaving a gap in the evidence base focused exclusively on anthracycline-induced CTRCD. This systematic review and meta-analysis aimed to address that gap by evaluating the effects of long-term exercise on key CTRCD markers in breast cancer patients treated exclusively with anthracyclines. METHODS: A comprehensive search of PubMed, Scopus, Cochrane Central Register of Controlled Trials, and Web of Science was conducted for randomized controlled trials including breast cancer patients undergoing anthracycline-based chemotherapy, receiving long-term exercise interventions (≥ 12 weeks, ≥ 1 session/week) compared to usual cancer care, and reporting at least one of the following outcomes: left ventricular ejection fraction, global longitudinal strain, cardiac troponin I, cardiac troponin T, or N-terminal prohormone of brain natriuretic peptide. RESULTS: Six randomized controlled trials involving 360 participants were included. Exercise significantly attenuated cardiac troponin I elevation compared to controls (SMD = -0.50; 95% CI, -0.93 to -0.06; p = 0.02). No statistically significant between-group differences were observed for left ventricular ejection fraction, global longitudinal strain, cardiac troponin T, or N-terminal prohormone of brain natriuretic peptide. CONCLUSION: The cardioprotective role of exercise during anthracycline treatment remains uncertain, though the attenuation of cardiac troponin I elevation suggests a potential protective signal warranting further investigation through larger, standardized trials employing advanced assessment modalities and longer follow-up periods.
Humans↗
Diet modulates cardiac metabolic stress during anthracycline treatment.
Diet is a modifiable determinant of cardiovascular risk and may influence tolerance to cancer therapies. The mechanisms by which specific dietary components affect cardiac metabolism during anthracycline treatment remain poorly defined, limiting the incorporation of dietary recommendations into treatment guidelines. Here, we integrated heart proteomics data from patients treated with or without anthracyclines with a genome-scale reconstruction of human cardiac metabolism (CardioNet). Using constraint-based flux analysis, we conducted >30,000 in silico simulations of diet scenarios generated from chemical profiles of ∼500 foods curated in the Periodic Table of Food Initiative. These simulations revealed that diets enriched in rapidly absorbable sugars and depleted of essential fatty acids impair cardiac metabolic efficiency, increasing reactive oxygen species production and the demand for purine salvage fluxes. These predicted metabolic patterns were consistent with plasma metabolomics from patients treated with anthracyclines, validating our findings. Computational modeling of 39 recipes across six cuisines revealed cardiometabolic effects of omnivorous versus vegan diets in patients. Modeling of a healthy vegan diet increased cardiometabolic efficiency compared with a healthy omnivorous diet in patients treated with anthracyclines, independent of the culinary background. Our approach demonstrates that integrating the molecular composition of food with genome-scale metabolic models enables systematic analysis of diet patterns for translational testing. Ultimately, these in silico studies provide a framework for trials and may inform dietary recommendations for improving cardiometabolic health.NEW & NOTEWORTHY We developed a systems biology framework to predict how diet influences cardiac metabolism during cancer therapy. Across >30,000 in silico diet simulations, we identified nutrient patterns that either exacerbate or mitigate anthracycline-induced metabolic stress. These findings demonstrate how computational modeling can uncover diet-metabolism interactions driving cardiotoxicity and guide dietary interventions.
Humans↗
Clinical and cytokinetic aspects of remission induction of childhood acute lymphoblastic leukemia (ALL): addition of an anthracycline to vincristine and prednisone.
Fifty-six untreated patients with childhood with acute lymphoblastic leukemia (ALL) were randomized to receive one of three remission induction regimens: vincristine and prednisone (VP), vincristine, prednisone and daunorubicin (VPD), or vincristine, prednisone and adriamycin (VPA). The complete remission rate was similar for all three groups. Although the anthracycline regimens caused somewhat more rapid leukemic cell reduction than the VP only group, this difference was not significant. Labeling index reduction between study days 1 and 5 was significantly greater (p less than 0.001) with an anthracycline than for the VP group, but there was no difference between the two anthracyclines. Granulocytopenia during induction was significantly increased (p less than 0.05) in both the VPD and VPA groups as compared with VP alone. A significantly higher rate of infectious morbidity (p less than 0.01) was associated with the addition of either anthracycline, but to date no significant differences in remission duration or survival have been observed. The addition of anthracyclines to VP for remission induction in childhood ALL has theoretical advantages, but may be undesirable because of increased morbidity.
Child, Preschool↗
Deoxyribonucleic acid binding studies on several new anthracycline antitumor antibiotics. Sequence preference and structure--activity relationships of marcellomycin and its analogues as compared to adriamycin.
The deoxyribonucleic acid (DNA) binding characteristics of adriamycin and several new anthracycline glycosides, including marcellomycin, aclacinomycin, rudolfomycin, musettamycin, and pyrromycin, have been studied. The fluorescence spectra were determined for all six anthracyclines, and the fluorescence quenching effects caused by interactions with the natural DNAs poly(dAdT)--poly(dAdT) and poly(dGdC) were characterized. Binding parameters were determined by Scatchard analyses of results obtained by spectrofluorometric titrations of anthracyclines with DNA. Consistent with earlier structure--activity relationship studies of nucleic acid synthesis inhibitory effects, the results demonstrate a correlation between the length of the glycosidic side chain and DNA binding affinity. In addition, the sugar residue 2-deoxyfucose appears to confer greater DNA binding ability than do the sugars rednosamine and cinerulose when present in the terminal position of the glycosidic side chain, also in agreement with earlier studies. The sequence preference of anthracycline--DNA interaction has been examined by using DNAs of varying GC content, including the naturally occurring calf thymus DNA (43% GC), Clostridium perfringens DNA (28% GC), and Micrococcus luteus DNA (72% GC) and the synthetic double-stranded copolymers poly(dGdC)--poly(dGdC) and poly(dAdT)--POLY(DAdT). The results demonstrate that although adriamycin shows an absolute requirement for GC sequences for DNA binding, marcellomycin and its analogues showed no such sequence requirement. Furthermore, an AT preference for DNA binding was demonstrated with marcellomycin and its analogues.
Aclarubicin↗
Anthracyclines attenuate Nrf1-dependent proteolytic pathways and potentiate proteasome inhibitor cytotoxicity.
Proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib are FDA-approved treatments for multiple myeloma, but resistance frequently limits their effectiveness. The transcription factor Nrf1 (NFE2L1) upregulates proteasome and autophagy genes upon proteasome inhibition, contributing to adaptive resistance. In this study, we identified anthracyclines, including doxorubicin, as suppressors of the Nrf1-driven transcriptional response. Mechanistically, doxorubicin impaired Nrf1 binding to antioxidant response elements (AREs) within promoter regions of target genes without affecting Nrf1 processing or nuclear localization. Importantly, aclarubicin, a non-DNA-damaging anthracycline, also attenuated Nrf1 transcriptional activity, indicating that DNA damage is not required for this inhibition. Doxorubicin cotreatment delayed proteasome recovery after pulse inhibition and partially restored sensitivity to carfilzomib in bortezomib-resistant U266 myeloma cells, consistent with genetic knockout of Nrf1. These findings identify a DNA-damage-independent mechanism by which anthracyclines directly obstruct Nrf1-mediated transcriptional induction. Thus, anthracyclines serve as chemical tools to probe the molecular control of proteostasis and suggest a strategy to mitigate Nrf1-driven adaptive response to proteasome inhibition.
Humans↗
Anthracycline cardiomyopathy in children: report of two cases.
Two children with leukemia are presented, each demonstrating an unusual aspect of anthracycline-induced cardiomyopathy. In the first patient (a 7-month-old female with acute monocytic leukemia) extremely young age and previous chemotherapy with a podophyllotoxin derivative, VP-16, may have prediposed the patient to fatal congestive heart failure at a total Daunorubicin dose of only 225 mg/m2. In the second patient, a delay of 4 1/2 years was not sufficient in preventing congestive heart failure resulting from the administration of additional anthracycline chemotherapy. We conclude that extremely young age and, possibly, prior therapy with VP-16 may be addition risk factors in the development of anthracycline cardiomyopathy. Also, we suggest that once an anthracycline agent has reached a toxic threshold for the myocardium, the heart may always be at risk to injury from additional Adriamycin or Daunorubicin therapy.
Child↗
Model systems for cardiotoxic effects of anthracyclines.
The use of anthracycline antibiotics in cancer chemotherapy is limited by their cardiotoxic qualities. For the evaluation of new derivatives animal model systems are required. Cardiomyopathy can be induced in rabbits and monkeys, but these models are too expensive for screening purposes. In rats, anthracycline antibiotics cause morphologic lesions of the heart muscle, but these are more difficult to demonstrate than in larger animals. However, significant changes of the heart function (electrocardiogram (ECG), cardiac output), the function of heart mitochondria (inhibition of electron transfer, uncoupling of oxidative phosphorylation and inhibition of Ca translocation) occur in a dose-related manner. Intraventricular conduction defect demonstrated in the ECG is one of the earliest and most consistent expressions of the cardiotoxic properties of anthracyclines. It was therefore used as primary screening parameter. The results of the screening of over 50 new anthracyclines has shown that the cardiotoxic properties vary considerably and that they are not closely related to the chemotherapeutic and the hematotoxic properties. Interesting structure-activity relationships were observed in a series of rubidazone derivatives substituted at the benzhydrazone part of the molecule.
Animals↗
Growth and production of anthracyclines in wild-type and mutant strains of Streptomyces galilaeus.
The course of growth curves with respect to the biosynthesis of anthracyclines was followed in the wild low-producing strain Streptomyces galilaeus JA 3043 and in its mutants G-167 (producing increased quantities of glycosides of epsilon-pyrromycinone) and J-14 (accumulating free epsilon-pyrromycinone). A two-phase type of fermentation (growth phase, production phase) was observed in strains JA 3043 and J-14. The maximum production of anthracyclines occurred only after the end of intense growth of the culture. Two phases of rapid growth separated by a phase of stagnation were observed in strain G-167. The second growth phase proceeded only during late hours of cultivation and was (as compared with the first phase) associated with an intensive biosynthesis of anthracyclines.
Anti-Bacterial Agents↗
Intra- and interspecific cosynthetic activity of mutants of Streptomyces coeruleorubidus and Streptomyces galilaeus impaired in the biosynthesis of anthracyclines.
Cosynthesis of anthracycline compounds was followed in five phenotypic groups of mutants of Streptomyces coeruleorubidus (A--E), blocked in the biosynthesis of the daunomycine complex, and in two mutant types of Streptomyces galilaeus (F, G) blocked in the biosynthesis of glycosides of epsilon-pyrromycinone and aklavinone. Glycosides of daunomycinone and 13-dihydrodaunomycinone were produced in combinations A+B, A+C, A+D, A+E and A+F, epsilon-rhodomycinone was synthesized in combinations A+E, A+F, B+E and B+F. During the cultivation of types B--E with type G or F non-anthracycline compounds, typical of S. galilaeus, were cosynthesized. No cosynthesis could be observed in other combinations of the mutant types. Negative results were also obtained with combinations of mutants of the same group and during cultivation of all mutant types with streptomycetes not producing anthracyclines. A scheme illustrating metabolic pathways leading to the biosynthesis of daunomycinone, aklavinone, epsilon-rhodomycinone in S. coeruleorubidus and S. galilaeus was constructed.
Daunorubicin↗
The inhibition of Rauscher leukemia virus and avian myeloblastosis virus DNA polymerases by anthracycline compounds.
Studies by other investigators have shown that adriamycin and daunorubicin exhibit antitumor and antiviral activity. A possible antiviral mechanism for the anthracycline compounds is the potent inhibition of viral DNA polymerases. Five anthracycline compounds were tested against purified Rauscher leukemia virus and avian myeloblastosis virus DNA polymerases. All compounds were found to be potent inhibitors of viral DNA polymerase activity. Inhibition was found to be primarily due to the planar ring structure (daunomycinone) common to all of these compounds. The degree of inhibition was dependent on the templates used: activated DNA, synthetic hybrids, poly(rA).dT12-18 and poly(rC).dG12-18, and the synthetic copolymer, poly(DA-dT). Alteration of the group substituent on the planar ring affected the degree of viral DNA polymerase inhibition. The inhibitory effects by anthracycline compounds appear to be relatively specific for viral polymerases.
Anthracenes↗
[Anthracycline antibiotic, beromycin. The formation of complexes with DNA and the suppresion of nucleic acid biosynthesis].
Beromycin, an antitumor anthracycline antibiotic formed in vitro complexes with native and denaturated DNA and ribosomal RNA. Beromycin had a comparatively low constant of DNA binding and to a less extent increased the melting temperature and viscosity of DNA than the other anthracycline antibiotics. A peculiar property of beromycin was very slow binding with DNA, the complex formation was completed in 60 minutes. Beromycin had a selective inhibitory effect on synthesis of nucleic acids in bacterial and tumor cells. Beromycin inhibited synthesis of RNA in the DNA-dependent RNA-polymerase reaction when both the native and denaturated DNA were used as the template. A lower biological activity of beromycin as compared to the other anthracycline antibiotics, such as rubomycin or carminomycin may be explained by lower affinity of this antibiotic to DNA.
Animals↗
Quantitative models for growth inhibition of human leukemia cells by antitumor anthracycline derivatives.
A batch elution method with hydroxylapatite was developed to assay DNA damage by a set of antitumor anthracycline derivatives and was standardized with respect to the kinetics of unwinding, size of the alkaline unwinding unit, and fidelity of selective elution of single and double-stranded DNA. The method was applied to a study of a set of 10 antitumor anthracycline derivatives which inhibit growth of CCRF-CEM human leukemia cells over a range of potencies exceeding four orders of magnitude. The derivatives, including Adriamycin, daunorubicin, and carminomycin, vary in structure at C-4 and C-13, with substitutions at C-14 and N and stereochemical differences at C-4'. In a static model (fixed drug concentrations and incubation times), the potency [1/ID37 (concentration of agent that inhibits cell growth by 37%)] of nine of the ten derivatives may be expressed as functions of DNA damage (n), inhibition of thymidine incorporation (l), and drug retention (r): ID37 = Ka(r/l . n)kb, with a coefficient of correlation of greater than 0.99. A kinetic model with 4-demethoxydaunorubicin (varying concentrations and incubation times) was also described. Following initial uptake and a period of rapid loss after cells are washed free of excess drug, the change in agent concentration in the cells follows first-order kinetics. The cell index (cell number after 50 hr in drug-free growth medium/cell number after initial 2-hr exposure with drug) may be expressed linearly in terms of the kinetics of drug loss (coefficient of correlation, greater than 0.98), or as functions of 1/n (coefficient of correlation, greater than 0.958), 1/l . n (coefficient of correlation, greater than 0.963, or r/l . n (coefficient of correlation, greater than 0.963). These studies may be used to define a class of similarly acting anthracycline agents and to give some insight into the mechanism of action of the agents that fall within the class.
Antibiotics, Antineoplastic↗
Effect of aeration efficiency and carbon source on the production of anthracyclines in Streptomyces galilaeus.
Biosynthesis of anthracyclines in Streptomyces galilaeus during submerged cultivation is considerably influenced by aeration and by the concentration of glucose in the medium. At higher values of oxygen absorption rate both the production of epsilon-pyrromycinone glycosides in the wild strain JA 3043 and its production mutant G-167 and accumulation of free epsilon-pyrromycinone in the blocked mutant G-162 were found to be higher; the production of 7-deoxyaglycones was lower in all strains. The studied strains differed in the rate of glucose consumption and in the ability to utilize starch for the biosynthesis of anthracyclines. A two-fold concentration of glucose in the medium resulted in the G-162 strain in an increase of the yield of epsilon-pyrromycinone by 120%. The production of glycosides in strain G-167 increased even after exhaustion of glucose from the medium and the amount of 7-deoxyaglycones simultaneously decreased.
Anti-Bacterial Agents↗
Absence of anthracycline-induced degradation of nuclear DNA in Ehrlich ascites tumour cells.
The in vivo effects of anthracycline antibiotics on the integrity of Ehrlich ascites tumour cell DNA have been studied by sedimentation analysis of nuclear structures containing superhelical DNA in neutral sucrose gradients. These fast-sedimenting protein-DNA complexes may be released by gently lysing cells in solution containing non-ionic detergents and high NaCl concentrations (1.95 M). The supercoiled structure of DNA in these protein-DNA complexes is suggested by the characteristic sedimentation in the presence of intercalating agents. Apparently, no DNA damage could be detected in Ehrlich cells from 7-day-old tumours within 3 h after various doses of daunomycin (0.5--10 mg/kg of body wt.) were administered i.p. to mice. Sedimentation anomalies could not be observed even 15 or 30 h after administration of rtherapeutic doses of daunomycin or adriamycin. In contrast, at 30 min after administration to mice, therapeutic doses of bleomycin (2--8 mg/kg) caused extensive fragmentation of tumour cell DNA, which could be monitored as slowly sedimenting DNA structures (compared with the the control). Similarly, DNA damage could be induced by procarbazine at therapeutic doses. Exposure to bleomycin or procarbazine abolished the characteristic biphasic response to ethidium bromide. The absence of anthracycline-induced degradation of Ehrlich ascites tumour cell DNA is apparently in contrast with the DNA damage observed in L1210 tumour cells. These observations suggest that DNA damage is not a necessary condition for antitumour activity.
Animals↗
Laser flow cytometry and cancer chemotherapy: detection of intracellular anthracyclines by flow cytometry.
The intracellular distribution of important chemotherapeutic antibiotics belonging to the anthracycline group (e.g. adriamycin) can be detected by laser flow cytometry. The indirect method is based on the interference of these compounds with the binding of propidium iodide to the nuclear DNA. While in the direct method, the intracellular fluorescence of these antibiotics is excited and detected with a laser beam in a flow system. The present report demonstrates the use of these two methods for intracellular detection and quantitation of a number of important anthracyclines.
Animals↗
Comparative ultrastructural studies of nucleoli of tumor cells treated with adriamycin and the newer anthracyclines, carminomycin and marcellomycin.
This study was designed to determine the effects of several antitimor anthracyclines, including Adriamycin and its analogs, carminomycin and marcellomycin, on the ultrastructure of nucleoli of Novikoff hepatoma cells. Adriamycin and carminomycin, which are structurally related, induce nucleolar segregation following the formation of conspicuous fibrillar centers. Marcellomycin did not induce formation of nucleolar fibrillar centers. Instead, numerous microspherules formed following treatment with marcellomycin; later complete nucleolar segregation developed. The microspherules were observed to be in various stages of extrusion from the nucleolar body. This microspherule "migration" appeared to be both time and drug concentration dependent. These results show that the rate and extent of nucleolar ultrastructural aberration may be related to structural differences of the various anthracyclines.
Animals↗
Biochemical parameters of growth inhibition of human leukemia cells by antitumor anthracycline agents.
Ten antitumor anthracycline derivatives used in this study inhibit growth of a human leukemia cell line over a range of potencies exceeding four orders of magnitude. The agents vary from each other at C-4 and C-13, with stereochemical differences at C-4' and substitutions at C-14 and N. Drug retention, DNA damage, and inhibition of DNA synthesia are parameters used to express potency of the agents in a mathematic model. Estimates of DNA damage are sufficient, however, to describe growth inhibition by a single agent (4-demethoxydaunorubicin). It may be possible now to attempt to extend the model to predict therapeutic responses to a number of anthracyclines, thereby enhancing the clinical utility of this important class of agents.
Antibiotics, Antineoplastic↗