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Cell Cycle (Georgetown, Tex.) Aug 2013Although chemically non-reactive, inert noble gases may influence multiple physiological and pathological processes via hitherto uncharacterized physical effects. Here...
Although chemically non-reactive, inert noble gases may influence multiple physiological and pathological processes via hitherto uncharacterized physical effects. Here we report a cell-based detection system for assessing the effects of pre-defined gas mixtures on the induction of apoptotic cell death. In this setting, the conventional atmosphere for cell culture was substituted with gas combinations, including the same amount of oxygen (20%) and carbon dioxide (5%) but 75% helium, neon, argon, krypton, or xenon instead of nitrogen. The replacement of nitrogen with noble gases per se had no effects on the viability of cultured human osteosarcoma cells in vitro. Conversely, argon and xenon (but not helium, neon, and krypton) significantly limited cell loss induced by the broad-spectrum tyrosine kinase inhibitor staurosporine, the DNA-damaging agent mitoxantrone and several mitochondrial toxins. Such cytoprotective effects were coupled to the maintenance of mitochondrial integrity, as demonstrated by means of a mitochondrial transmembrane potential-sensitive dye and by assessing the release of cytochrome c into the cytosol. In line with this notion, argon and xenon inhibited the apoptotic activation of caspase-3, as determined by immunofluorescence microscopy coupled to automated image analysis. The antiapoptotic activity of argon and xenon may explain their clinically relevant cytoprotective effects.
Topics: Apoptosis; Argon; Cell Culture Techniques; Cell Line, Tumor; Cell Survival; Cytochromes c; Cytoprotection; Humans; Microscopy, Fluorescence; Mitoxantrone; Staurosporine; Xenon
PubMed: 23907115
DOI: 10.4161/cc.25650 -
European Review For Medical and... Dec 2021Mitoxantrone (MTX)- induced cardiotoxicity is a clinical concern that is limiting its use. The aim of this paper, therefore, was to investigate the subchronic...
OBJECTIVE
Mitoxantrone (MTX)- induced cardiotoxicity is a clinical concern that is limiting its use. The aim of this paper, therefore, was to investigate the subchronic administration of MTX plus nonspecific/specific inhibitors of CYP450/2E1, to assess the extent of oxidative-induced injury by measuring levels of oxidative cardiac and injury biomarkers in mice and to evaluate the effects of CYP2E1 on caspase 3 activity and nuclear factor erythroid 2-related factor-2 (NRF-2).
MATERIALS AND METHODS
Mice (n = 32) were divided into four treatment groups of eight: control, MTX, MTX + 4-methlypyrazole (4MP) and MTX + disulfiram (Disf). After 6 weeks of treatments, blood and heart samples were collected.
RESULTS
Liquid chromatography-mass spectrometry (LCMS) analysis of MTX-treated plasma samples revealed several metabolites with different retention times. Cardiac antioxidant enzymes and creatine kinase (CK) levels were not significantly different among the groups. However, cardiac troponin and caspase 3 activity were significantly raised, with increased CYP2E1 expressions and reduced NRF-2 expression. Tissue damage was observed in all the treatment groups, including MTX, leading to the conclusion that MTX-induced cardiotoxicity was mediated by CYP2E1 activity, which initiated caspase 3 production, and decreased NRF-2 expression.
CONCLUSIONS
Therefore, agents that inhibit CPY2E1 expression might attenuate MTX-induced cardiotoxicity by increasing NRF-2 expression.
Topics: Animals; Antineoplastic Agents; Cardiotoxicity; Caspase 3; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP2E1 Inhibitors; Disulfiram; Female; Fomepizole; Male; Mice, Inbred BALB C; Mitoxantrone; Myocardium; NF-E2-Related Factor 2; Troponin I; Mice
PubMed: 34982442
DOI: 10.26355/eurrev_202112_27627 -
International Journal of Nanomedicine 2018A previous study developed a novel luteinizing hormone-releasing hormone (LHRH) receptor-targeted liposome. The aim of this study was to further assess the...
BACKGROUND
A previous study developed a novel luteinizing hormone-releasing hormone (LHRH) receptor-targeted liposome. The aim of this study was to further assess the pharmacokinetics, biodistribution, and anti-tumor efficacy of LHRH receptor-targeted liposomes loaded with the anticancer drug mitoxantrone (MTO).
METHODS
Plasma and tissue distribution profiles of LHRH receptor-targeted MTO-loaded liposomes (LHRH-MTO-LIPs) were quantified in healthy mice or a xenograft tumor nude mouse model of MCF-7 breast cancer, and were compared with non-targeted liposomes and a free-drug solution.
RESULTS
The LHRH-MTO-LIPs demonstrated a superior pharmacokinetic profile relative to free MTO. The first target site of accumulation is the kidney, followed by the liver, and then the tumor; maximal tumor accumulation occurs at 4 h post-administration. Moreover, the LHRH-MTO-LIPs exhibited enhanced inhibition of MCF-7 breast cancer cell growth in vivo compared with non-targeted MTO-loaded liposomes (MTO-LIPs) and free MTO.
CONCLUSION
The novel LHRH receptor-targeted liposome may become a viable platform for the future targeted treatment of cancer.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Female; Humans; Liposomes; MCF-7 Cells; Mice, Inbred BALB C; Mice, Nude; Mitoxantrone; Peptides; Receptors, LHRH; Time Factors; Tissue Distribution; Treatment Outcome
PubMed: 29520138
DOI: 10.2147/IJN.S150512 -
BMC Cancer Mar 2011In patients with advanced hepatocellular carcinoma (HCC), combination chemotherapy using 5- fluorouracil, cisplatin, and mitoxantrone (FMP) could achieve a response rate... (Comparative Study)
Comparative Study
Retrospective comparison between a regular and a split-dose protocol of 5-fluorouracil, cisplatin, and mitoxantrone for the treatment of far advanced hepatocellular carcinoma.
BACKGROUND
In patients with advanced hepatocellular carcinoma (HCC), combination chemotherapy using 5- fluorouracil, cisplatin, and mitoxantrone (FMP) could achieve a response rate > 20%, but the beneficial effect was compromised by formidable adverse events. Chemotherapy given in a split-dose manner was associated with reduced toxicities. In this retrospective study, we compared the efficacies and side effects between a regular and a split-dose FMP protocol approved in our medical center.
METHODS
From 2005 to 2008, the clinical data of 84 patients with far advanced HCC, who had either main portal vein thrombosis and/or extrahepatic metastasis, were reviewed. Of them, 65 were treated by either regular (n = 27) or split-dose (n = 38) FMP and had completed at least one therapeutic course. The remaining 19 patients were untreated. Clinical parameters, therapeutic responses, survivals and adverse events were compared.
RESULTS
The median overall survival was 6.0, 5.2, and 1.5 months, respectively, in patients receiving regular FMP, split-dose FMP, and no treatment (regular versus split-dose group, P = 0.447; regular or split-dose versus untreated group; P < 0.0001). Patients receiving split-dose treatment had a significantly lower risk of grade 3/4 neutropenia (51.9 versus 10.5%, P = 0.0005). When the two treated groups were combined, the median overall survival was 10.6 and 3.8 months respectively for patients achieving disease control and progressive disease (P < 0.001). Cox proportion hazard model identified Child-Pugh stage B (hazard ratio [HR], 2.216; P = 0.006), presence of extrahepatic metastasis (HR, 0.574; P = 0.048), and achievement of disease control (HR, 0.228; P < 0.001) as independent factors associated with overall survival. Logistic regression analysis revealed that anti-hepatitis C virus antibody (odds ratio [OR], 9.219; P = 0.002) tumor size (OR, 0.816; P = 0.036), and previous anti-cancer therapy (OR, 0.195; P = 0.017) were significantly associated with successful disease control.
CONCLUSIONS
Comparable overall survival was observed between patients receiving regular and split-dose FMP therapies. Patients receiving split-dose therapy had a significantly lower risk of grade 3/4 neutropenia. Positive anti-hepatitis C virus antibody, smaller tumor size, and absence of previous anti-cancer therapy were independent predictors for successful disease control.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Clinical Protocols; Disease Progression; Female; Fluorouracil; Humans; Liver Neoplasms; Male; Middle Aged; Mitoxantrone; Retrospective Studies; Survival Analysis
PubMed: 21453495
DOI: 10.1186/1471-2407-11-117 -
Cancer Biology & Therapy May 2016Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has tremendous promise in treating various forms of cancers. However, many cancer cells exhibit or...
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has tremendous promise in treating various forms of cancers. However, many cancer cells exhibit or develop resistance to TRAIL. Interestingly, many studies have identified several secondary agents that can overcome TRAIL resistance. To expand on these studies, we conducted an extensive drug-re-profiling screen to identify FDA-approved compounds that can be used clinically as TRAIL-sensitizing agents in a very malignant type of brain cancer, Glioblastoma Multiforme (GBM). Using selected isogenic GBM cell pairs with differential levels of TRAIL sensitivity, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective as single agents. Cardiac glycosides constituted a large group of TRAIL-sensitizing compounds, and they were also effective on GBM cells as single agents. We then explored a second class of TRAIL-sensitizing drugs, which were enhancers of TRAIL response without any effect on their own. One such drug, Mitoxantrone, a DNA-damaging agent, did not cause toxicity to non-malignant cells at the doses that synergized with TRAIL on tumor cells. We investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptors (DR4 and DR5) expression was upregulated, and pro-apoptotic and anti-apoptotic gene expression patterns were altered in favor of apoptosis. Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients.
Topics: Antineoplastic Agents; Glioblastoma; Humans; Mitoxantrone
PubMed: 27029345
DOI: 10.1080/15384047.2016.1167292 -
Genes Apr 2023Occurrence of non-canonical G-quadruplex (G4) DNA structures in the genome have been recognized as key factors in gene regulation and several other cellular processes....
Occurrence of non-canonical G-quadruplex (G4) DNA structures in the genome have been recognized as key factors in gene regulation and several other cellular processes. The and involved in pathways of oxidation sensing regulation and ATP generation, respectively, make () bacteria responsible for oxidative stress inside host macrophage cells. Circular Dichroism spectra demonstrate stable hybrid G4 DNA conformations of / DNA sequences. Real-time binding of mitoxantrone to G4 DNA with an affinity constant ~10-10 M, leads to hypochromism with a red shift of ~18 nm, followed by hyperchromism in the absorption spectra. The corresponding fluorescence is quenched with a red shift ~15 nm followed by an increase in intensity. A change in conformation of the G4 DNA accompanies the formation of multiple stoichiometric complexes with a dual binding mode. The external binding of mitoxantrone with a partial stacking with G-quartets and/or groove binding induces significant thermal stabilization, ~20-29 °C in G4 DNA. The interaction leads to a two/four-fold downregulation of transcriptomes of / genes apart from the suppression of DNA replication by polymerase enzyme, establishing the role of mitoxantrone in targeting G4 DNA, as an alternate strategy for effective anti-tuberculosis action in view of deadly multi-drug resistant tuberculosis disease causing bacterial strains t that arise from existing therapeutic treatments.
Topics: Mitoxantrone; Mycobacterium tuberculosis; DNA; G-Quadruplexes; Base Sequence
PubMed: 37239338
DOI: 10.3390/genes14050978 -
Annals of Oncology : Official Journal... Dec 2000A great number of clinical research studies have been reported in the field of chemotherapy for advanced androgen-independent prostate cancer during the last ten years.... (Review)
Review
BACKGROUND AND PURPOSE
A great number of clinical research studies have been reported in the field of chemotherapy for advanced androgen-independent prostate cancer during the last ten years. The aims of the present review were to assess their impact on management of the disease and on survival of patients.
METHODS
The review of full published reports was facilited by the use of a MEDLINE computer search.
RESULTS
Clinical research studies have focused on defining guidelines for eligibility criteria and accurate endpoints for patients to be enrolled onto clinical trials and developing new agents or combination of drugs including estramustine phosphate. Any combination of current chemotherapy has no impact on overall survival of patients. Among drugs in development, only the promising activity observed with docetaxel deserves randomized trials to assess its impact on survival. The major innovative advance of the 90s is the demonstration of the impact of chemotherapy (mitoxantrone + prednisone) on quality of life as compared to prednisone alone. A greater and longer-lasting improvement in quality of life along with a concomitant decrease in costs was observed.
CONCLUSIONS
At the present time, chemotherapy should be considered as a palliative treatment in patients with symptomatic androgen-independent disease. The enrollment of patients into clinical trials dealing with quality of life as primary endpoint is strongly solicited. A standard methodology should be used in phase II trials with a primary goal of selection of agents which should progress to randomized trials using survival as an endpoint. Hopefully new specific strategies targeted to reverse the molecular changes that underlie prostate tumorigenesis should rapidly impact the multimodality management of AIPC in the third millenium.
Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Mitoxantrone; Neoplasm Metastasis; Paclitaxel; Palliative Care; Prednisolone; Prostatic Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Taxoids
PubMed: 11205458
DOI: 10.1023/a:1008394823889 -
Bulletin Du Cancer May 2005Until now, mitoxantrone was the standard drug for hormone resistant prostate cancer (HRPC). Docetaxel has shown more than 50% of biological response rate in HRPC in... (Review)
Review
Until now, mitoxantrone was the standard drug for hormone resistant prostate cancer (HRPC). Docetaxel has shown more than 50% of biological response rate in HRPC in several phase II studies. Recently, two phase III studies comparing mitoxantrone and docetaxel were reported. In the view of the results of these studies, it is likely that we will change the usual treatment policy. First one , TAX 327, compared docetaxel 75 mg/m2 every 3 weeks, docetaxel 35 mg/m2 weekly and mitoxantrone 12 mg/m2 every 3 weeks. 1,006 patients were included, overall survival was better in the docetaxel arm than in the mitoxantrone arm (18.7 vs. 16.9 months; p = 0.009). The SWOG study compared docetaxel-estramustine and mitoxantrone-prednisone. 770 patients were included, the difference in overall survival was significantly in favor of the docetaxel arm (17.5 vs. 15.6 months; p = 0.02). These results shows that docetaxel is now the standard treatment of HRPC and the standard arm for future studies in this disease.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Docetaxel; Estramustine; Humans; Male; Mitoxantrone; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids
PubMed: 15932803
DOI: No ID Found -
Neurology India 2009Mitoxantrone is an approved disease modifying agent for treatment of multiple sclerosis (MS). The aim of the study was to assess its efficacy and safety in Indian MS... (Clinical Trial)
Clinical Trial
BACKGROUND AND PURPOSE
Mitoxantrone is an approved disease modifying agent for treatment of multiple sclerosis (MS). The aim of the study was to assess its efficacy and safety in Indian MS patients.
MATERIALS AND METHODS
A total of 23 patients with clinically definite MS (Poser criteria) were enrolled in an open label study. Of which, 21 satisfied the McDonald's criteria for MS and two satisfied the diagnostic criteria of neuromyelitis optica (NMO). The numbers of relapses and expanded disability status scale (EDSS) score were used as primary and secondary outcome measures. The patients were monitored for the adverse effects.
RESULTS
In 17 (15 MS and two NMO) patients who completed one year of therapy, there was significant difference in the mean annual relapse rates [before 0.879+/-0.58; on mitoxantrone 0.091+/-0.17, (P=0.003)]. Of the 17 patients, ten (MS 9 and NMO 1) completed therapy for two years. Annual relapse rates [before (1.024+/-0.59), on therapy (0.155+/-0.21), (P=0.0054)] and EDSS score [before start of therapy 5.3, at the end of therapy 2.4, (P=0.001)] showed significant benefit in the ten patients who completed two years therapy. This benefit persisted during the mean follow-up period of two and a half years after completion of therapy. The adverse events noted in the entire cohort were leucopenia in four patients and asymptomatic reversible decrease in cardiac ejection fraction in one patient. Leucopenia was severe in two patients requiring discontinuation of the therapy and mitoxantrone was also discontinued in the patient with cardiotoxicity.
CONCLUSIONS
Mitoxantrone, as an initial therapy, decreases clinical exacerbations and disability progression, and has a reasonable safety profile in Indian patients with MS and NMO.
Topics: Adolescent; Adult; Analgesics; Cohort Studies; Disability Evaluation; Female; Humans; India; Male; Middle Aged; Mitoxantrone; Multiple Sclerosis; Retrospective Studies; Young Adult
PubMed: 19770542
DOI: 10.4103/0028-3886.55611 -
Clinical Evidence Dec 2004
Review
Topics: Amantadine; Exercise Therapy; Glatiramer Acetate; Humans; Interferon-beta; Mitoxantrone; Multiple Sclerosis; Peptides; Secondary Prevention
PubMed: 15865753
DOI: No ID Found