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Onkologie Oct 1990Iodo-doxorubicin belongs to the group of doxorubicin analogs with modifications at the 4'-position of the daunosamine sugar moiety. Epirubicin is the archetype of the... (Review)
Review
Iodo-doxorubicin belongs to the group of doxorubicin analogs with modifications at the 4'-position of the daunosamine sugar moiety. Epirubicin is the archetype of the analogs created by configurational changes at the sugar. In case of EPI, the hydroxy group at the 4'-position is equatorial instead axial. In case of I-DOX, the hydroxy group has been replaced by an iodine-atom. This exchange has a great influence on the basicity of the amino group at the 3'-position. The physico-chemical properties of I-DOX are markedly different from those of DOX and EPI. I-DOX is unprotonated at physiological pH and much more lipophilic than DOX. The preclinical screening showed greater potency of I-DOX in different tumor cell systems. Cardiotoxicity and tissue toxicity after extravasation were significantly reduced in case of I-DOX. The substance was evaluated within three phase-I-studies in Europe during 1988 to 1990. The most prominent toxicity observed was myelotoxicity. This type of toxicity was dose-dependent and reversible. Alopecia, stomatitis/mucositis were not seen at all. There was only minor nausea without vomiting. The measured thyroid parameters were not affected by administration of an iodine-containing drug, but long-term effects cannot be ruled out. No acute cardiotoxicity was observed. The pharmacokinetics and metabolism of I-DOX differ from those of DOX and EPI. The terminal half-life of I-DOX is shorter, the plasma clearance higher than of DOX. One major difference is the formation of iodo-doxorubicinol, which is much larger in case of I-DOX compared to DOX and EPI. This cytostatic metabolite has a long terminal half-life.
Topics: Animals; Cell Line; Doxorubicin; Drug Resistance; Humans; Neoplasms; Tumor Cells, Cultured
PubMed: 2082229
DOI: 10.1159/000216794 -
Canadian Journal of Physiology and... Feb 2021Doxorubicin is an anticancer agent that is commonly used to treat a number of tumors and is associated with acute and chronic changes of the cardiovascular system....
Doxorubicin is an anticancer agent that is commonly used to treat a number of tumors and is associated with acute and chronic changes of the cardiovascular system. Ellagic acid has strong free radical scavenging capacity, neuroprotective and hepatoprotective effects, and is known to protect against changes occurring due to diabetes, cardiovascular diseases, and cancer. Twenty-four Wistar rats were divided in four groups: control group received saline, doxorubicin group received doxorubicin in a single dose of 20 mg/kg, ellagic acid group received ellagic acid in a dose of 4 mg/kg, and doxorubicin + ellagic acid group received doxorubicin and ellagic acid in same doses as in previous groups. The effect of ellagic acid treatment, alone or in combination with doxorubicin, was studied on isolated heart frequency and strength of the contraction, and on thoracic aorta contractile responses. Application of ellagic acid to rats pre-treated with doxorubicin significantly prevented functional changes occurring in the heart, but not in the thoracic aorta tissue. Ellagic acid statistically significantly ( < 0.001) prevented doxorubicin-induced increase in heart rate, while at the same time increased single contraction force ( < 0.001) and attenuated morphological changes on heart tissue induced by doxorubicin. We can conclude that ellagic acid has potential to prevent doxorubicin-induced changes of the cardiovascular system.
Topics: Animals; Cytoprotection; Dose-Response Relationship, Drug; Doxorubicin; Ellagic Acid; Heart; Male; Rats; Rats, Wistar
PubMed: 33509026
DOI: 10.1139/cjpp-2020-0404 -
Small (Weinheim An Der Bergstrasse,... Feb 2023Osteosarcoma (OS) is the most serious bone malignancy, and the survival rate has not significantly improved in the past 40 years. Thus, it is urgent to develop a new...
Osteosarcoma (OS) is the most serious bone malignancy, and the survival rate has not significantly improved in the past 40 years. Thus, it is urgent to develop a new strategy for OS treatment. Chemodynamic therapy (CDT) as a novel therapeutic method can destroy cancer cells by converting endogenous hydrogen peroxide (H O ) into highly toxic hydroxyl radicals (·OH). However, the therapeutic efficacy of CDT is severely limited by the low catalytic efficiency and overexpressed glutathione (GSH). Herein, an excellent nanocatalytic platform is constructed via a simple solvothermal method using F127 as a soft template to form the hollow copper ferrite (HCF) nanoparticle, followed by the coating of polydopamine on the surface and the loading of doxorubicin (DOX). The Fe and Cu released from HCF@polydopamine (HCFP) can deplete GSH through the redox reactions, and then trigger the H O to generate ·OH by Fenton/Fenton-like reaction, resulting in enhanced CDT efficacy. Impressively, the photothermal effect of HCFP can further enhance the efficiency of CDT and accelerate the release of DOX. Both in vitro and in vivo experiments reveal that the synergistic chemodynamic/photothermal/chemo-therapy exhibits a significantly enhanced anti-OS effect. This work provides a promising strategy for OS treatment.
Topics: Humans; Copper; Cell Line, Tumor; Doxorubicin; Nanoparticles; Hydrogen Peroxide; Neoplasms; Glutathione; Tumor Microenvironment
PubMed: 36504423
DOI: 10.1002/smll.202205414 -
Nanoscale Mar 2022We demonstrate the use of water-soluble C-β-cyclodextrin conjugates to encapsulate and deliver doxorubicin to the cell nucleus. The behaviour of the fullerene...
We demonstrate the use of water-soluble C-β-cyclodextrin conjugates to encapsulate and deliver doxorubicin to the cell nucleus. The behaviour of the fullerene aggregates inside cells is dictated by the functionalization of the C cage. While both the C conjugates are taken up by lysosomes upon cellular entry, only the one with a hydroxylated cage rapidly escaped the lysosome. The drug delivery system (DDS) with a hydroxylated C cage showed significantly enhanced doxorubicin delivery to the cell nucleus, whereas the DDS with a hydrophobic C cage was trapped in the lysosome for a longer time and showed significantly reduced doxorubicin delivery to the nucleus. This study opens new paths towards advanced fullerene-based DDSs for small molecule drugs.
Topics: Cell Nucleus; Doxorubicin; Drug Delivery Systems; Fullerenes; beta-Cyclodextrins
PubMed: 35262142
DOI: 10.1039/d2nr00777k -
Expert Opinion on Investigational Drugs Jun 2007The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates... (Review)
Review
The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats and dogs, including significantly reduced cardiotoxicity. After intravenous administration, DOXO-EMCH binds rapidly to the Cys-34 position of circulating albumin and accumulates in solid tumors due to passive targeting. In a clinical Phase I study, the dose of doxorubicin could be increased by a factor of 4.5-340 mg/m(2) when 75 mg/m(2) of free doxorubicin is considered to be the dose that can be administered as a single agent concomitant with the typical spectrum of side effects (i.e., myelotoxicity and mucositis). DOXO-EMCH was able to induce tumor regressions in anthracycline-sensitive tumors (i.e., breast cancer, small cell lung cancer and sarcoma). Phase II studies will be initiated at the beginning of 2007.
Topics: Albumins; Animals; Antibiotics, Antineoplastic; Clinical Trials as Topic; Doxorubicin; Humans; Hydrazones; Neoplasms; Prodrugs
PubMed: 17501697
DOI: 10.1517/13543784.16.6.855 -
BMC Pharmacology & Toxicology Oct 2023Complications and fata toxicity induced by chemotherapy are the main challenge for clinical management of osteosarcoma. The identification of agents that can augment the...
Complications and fata toxicity induced by chemotherapy are the main challenge for clinical management of osteosarcoma. The identification of agents that can augment the efficacy of chemotherapy at lower doses may represent an alternative therapeutic strategy. Narasin is a polyether antibiotic widely used in veterinary medicine. In this study, we show that narasin is active against osteosarcoma cells at the same concentrations that are less toxic to normal cells. This effect is achieved by growth inhibition and apoptosis induction, which is mediated by oxidative stress and damage, and mitochondrial dysfunction. The antioxidant N-acetyl-l-cysteine (NAC) abolishes the anti-osteosarcoma activity. Importantly, narasin significantly augments doxorubicin's efficacy in both osteosarcoma cell culturing system and subcutaneous implantation mouse model. The combination of narasin and doxorubicin at non-toxic doses completely arrests osteosarcoma growth in mice. Our results suggest that the concurrent administration of doxorubicin and narasin could present a viable alternative therapeutic approach for osteosarcoma.
Topics: Animals; Mice; Osteosarcoma; Doxorubicin; Oxidative Stress; Bone Neoplasms; Cell Line, Tumor; Apoptosis
PubMed: 37864240
DOI: 10.1186/s40360-023-00695-6 -
Cellular and Molecular Life Sciences :... Feb 2019Doxorubicin is one of the most effective drugs for the first-line treatment of high-grade osteosarcoma. Several studies have demonstrated that the major cause for...
Doxorubicin is one of the most effective drugs for the first-line treatment of high-grade osteosarcoma. Several studies have demonstrated that the major cause for doxorubicin resistance in osteosarcoma is the increased expression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). We recently identified a library of HS-releasing doxorubicins (Sdox) that were more effective than doxorubicin against resistant osteosarcoma cells. Here we investigated the molecular mechanisms of the higher efficacy of Sdox in human osteosarcoma cells with increasing resistance to doxorubicin. Differently from doxorubicin, Sdox preferentially accumulated within the endoplasmic reticulum (ER), and its accumulation was only modestly reduced in Pgp-expressing osteosarcoma cells. The increase in doxorubicin resistance was paralleled by the progressive down-regulation of genes of ER-associated protein degradation/ER-quality control (ERAD/ERQC), two processes that remove misfolded proteins and protect cell from ER stress-triggered apoptosis. Sdox, that sulfhydrated ER-associated proteins and promoted their subsequent ubiquitination, up-regulated ERAD/ERQC genes. This up-regulation, however, was insufficient to protect cells, since Sdox activated ER stress-dependent apoptotic pathways, e.g., the C/EBP-β LIP/CHOP/PUMA/caspases 12-7-3 axis. Sdox also promoted the sulfhydration of Pgp that was subsequently ubiquitinated: this process further enhanced Sdox retention and toxicity in resistant cells. Our work suggests that Sdox overcomes doxorubicin resistance in osteosarcoma cells by at least two mechanisms: it induces the degradation of Pgp following its sulfhydration and produces a huge misfolding of ER-associated proteins, triggering ER-dependent apoptosis. Sdox may represent the prototype of innovative anthracyclines, effective against doxorubicin-resistant/Pgp-expressing osteosarcoma cells by perturbing the ER functions.
Topics: Antibiotics, Antineoplastic; Apoptosis; Cell Survival; DNA Damage; Doxorubicin; Drug Delivery Systems; Drug Resistance, Neoplasm; Endoplasmic Reticulum; Humans; Immunoblotting; Inhibitory Concentration 50; Osteosarcoma; Polymerase Chain Reaction
PubMed: 30430199
DOI: 10.1007/s00018-018-2967-9 -
Carbohydrate Research Jan 2022An array of self-assembled biocompatible doxorubicin (DOX) loaded heparin--cyclodextrin supramolecular hydrogels (DOX@HGs) with highly encapsulated efficiency was...
An array of self-assembled biocompatible doxorubicin (DOX) loaded heparin--cyclodextrin supramolecular hydrogels (DOX@HGs) with highly encapsulated efficiency was constructed using heparin-β-cyclodextrin derivatives (Hep-β-CD), α-cyclodextrin (α-CD), pluronic F-127 and DOX via the synergy of host-guest and multiple hydrogen bonding interactions. These hydrogels were characterized by GPC measurements (GPC), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Size and zeta potential determinations, X-ray diffraction (XRD), and rheological characteristics; the data confirmed successful formation of the hydrogels. Furthermore, these hydrogels demonstrated distinctive thixotropy, indicating rapid self-repairing after continuously oscillatory shear stress. Variable release of DOX from DOX @HGs was obtained at various pH after 84 h depending on the strength of the hydrogels. At pH 7.4, cumulative DOX release was approximately 49.07% for DOX@HG 1, 32.15% for DOX@HG 2, and 27.12% for DOX@HG 3. While at pH 5.5, release of DOX was increased to 59.08% for DOX@HG 1 and to 43.2% for DOX@HG 3 after 84 h (P < 0.05). This information demonstrated that a higher DOX release rate was observed under a lower pH due to strong charge expansion of CDs and weakening of electrostatic interactions between heparin and DOX. Additionally, cytotoxicity of free DOX and DOX@HGs in ovarian cancer SKOV-3 cells was studied at various exposure durations. The results revealed that cytotoxicity of DOX@HG 1-3 toward ovarian cancer SKOV-3 cells was lower than that of free DOX (P < 0.05), suggesting prolonged DOX release from the hydrogels in SKOV-3 cells.
Topics: Doxorubicin; Drug Carriers; Drug Delivery Systems; Heparin; Hydrogels; Hydrogen-Ion Concentration; Micelles
PubMed: 34741880
DOI: 10.1016/j.carres.2021.108464 -
Nanoscale Jun 2022The supramolecular organization of Doxorubicin (DOX) within the standard Doxoves® liposomal formulation (DOX®) is investigated using visible light and phasor approach...
The supramolecular organization of Doxorubicin (DOX) within the standard Doxoves® liposomal formulation (DOX®) is investigated using visible light and phasor approach to fluorescence lifetime imaging (phasor-FLIM). First, the phasor-FLIM signature of DOX® is resolved into the contribution of three co-existing fluorescent species, each with its characteristic mono-exponential lifetime, namely: crystallized DOX (DOX, 0.2 ns), free DOX (DOX, 1.0 ns), and DOX bound to the liposomal membrane (DOX, 4.5 ns). Then, the exact molar fractions of the three species are determined by combining phasor-FLIM with quantitative absorption/fluorescence spectroscopy on DOX, DOX, and DOX pure standards. The final picture on DOX® comprises most of the drug in the crystallized form (∼98%), with the remaining fractions divided between free (∼1.4%) and membrane-bound drug (∼0.7%). Finally, phasor-FLIM in the presence of a DOX dynamic quencher allows us to suggest that DOX is both encapsulated and non-encapsulated, and that DOX is present on both liposome-membrane leaflets. We argue that the present experimental protocol can be applied to the investigation of the supramolecular organization of encapsulated luminescent drugs/molecules all the way from the production phase to their state within living matter.
Topics: Doxorubicin; Liposomes; Microscopy, Fluorescence; Polyethylene Glycols
PubMed: 35719059
DOI: 10.1039/d2nr00311b -
Journal of Nanoscience and... Sep 2019The magnetic resonance imaging diagnosis and high-efficiency tumor targeting treatment are of notable importance for cancer therapy. In this study, starch-octanoic acid...
The magnetic resonance imaging diagnosis and high-efficiency tumor targeting treatment are of notable importance for cancer therapy. In this study, starch-octanoic acid (ST-OA) micelles were successfully prepared to co-encapsulate the anti-tumor drug doxorubicin (DOX) and superparamagnetic iron oxide nanoparticles (SPIONs), taking advantage of the hydrophobic core of the core-shell micellar structure. Size distribution, morphology and release behaviors of micelles were investigated. In addition, magnetic properties and the anti-tumor theranostic performance were confirmed by conducting the cellular uptake, imaging and anti-tumor activity experiments. Therefore, co-encapsulation and specific delivery of the chemotherapeutic drug and contrast agent into tumor cells can realize the diagnosis and treatment of malignant tumor at the same time.
Topics: Doxorubicin; Drug Delivery Systems; Humans; Magnetic Iron Oxide Nanoparticles; Magnetic Resonance Imaging; Micelles; Neoplasms; Starch
PubMed: 30961696
DOI: 10.1166/jnn.2019.16548