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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 -
Cancer Mar 2006Docetaxel and mitoxantrone are considered first-line chemotherapeutic options in patients with hormone-refractory prostate cancer (HRPC), but their clinical... (Clinical Trial)
Clinical Trial
BACKGROUND
Docetaxel and mitoxantrone are considered first-line chemotherapeutic options in patients with hormone-refractory prostate cancer (HRPC), but their clinical effectiveness in a second-line setting is unknown. Therefore, the authors conducted a population-based retrospective study to establish activity and tolerability of second-line docetaxel or mitoxantrone in HRPC.
METHODS
The study included 68 patients who had failed androgen ablation therapy and who received docetaxel and mitoxantrone in either sequence. Clinical efficacy in terms of median overall survival (OS), progression-free survival (PFS), posttreatment prostate-specific antigen (PSA) decline of > or = 50% and treatment-related toxicity were evaluated.
RESULTS
Of 68 patients, 35 received docetaxel followed by mitoxantrone, and 33 received mitoxantrone followed by docetaxel. Both groups were comparable for recognized pretreatment prognostic factors. Patients who received docetaxel first-line had a trend toward longer median OS compared with patients treated with second-line docetaxel after mitoxantrone failure (22 mos, 95% confidence interval [CI], 17.2-26.8 mos vs. 15 mos, 95% CI, 10.4-19.6 mos). Median number of second-line chemotherapy cycles was 3 and median PFS survival was 2-3 months in both groups. Second-line docetaxel produced a higher PSA response compared with mitoxantrone (38% vs. 12%, P = 0.012), but this did not translate to a survival benefit. Both second-line docetaxel and mitoxantrone were associated with a high frequency of treatment-related adverse events that resulted in dose reduction, delay, or discontinuation (64% and 46% of patients, respectively).
CONCLUSIONS
Study results favored docetaxel given up-front for patients with HRPC considered suitable for further chemotherapy. Second-line docetaxel or mitoxantrone had limited efficacy and tolerability. Patients who are candidates for second-line chemotherapy, should be enrolled into clinical trials.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Humans; Male; Middle Aged; Mitoxantrone; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Survival Analysis; Taxoids; Treatment Outcome
PubMed: 16456811
DOI: 10.1002/cncr.21695 -
The Journal of Pharmacology and... Aug 2009P-glycoprotein (Pgp), a member of the ATP-binding cassette transporter family, is one of the major causes for multidrug resistance (MDR). We report using confocal... (Comparative Study)
Comparative Study
P-glycoprotein (Pgp), a member of the ATP-binding cassette transporter family, is one of the major causes for multidrug resistance (MDR). We report using confocal microscopy to study the roles of Pgp in mediating the efflux of the anticancer agent mitoxantrone and the reversal of MDR by the specific Pgp inhibitor valspodar (PSC833). The net uptake and efflux of mitoxantrone and the effect of PSC833 were quantified and compared in Pgp-expressing human cancer MDA-MB-435 (MDR) cells and in parental wild-type cells. The MDR cells, transduced with the human Pgp-encoding gene MDR1 construct, were approximately 8-fold more resistant to mitoxantrone than the wild-type cells. Mitoxantrone accumulation in the MDR cells was 3-fold lower than that in the wild-type cells. The net uptake of mitoxantrone in the nuclei and cytoplasm of MDR cells was only 58 and 67% of that in the same intracellular compartment of the wild-type cells. Pretreatment with PSC833 increased the accumulation of mitoxantrone in the MDR cells to 85% of that in the wild-type cells. In living animals, the accumulation of mitoxantrone in MDA-MB-435mdr xenograft tumors was 61% of that in the wild-type tumors. Administration of PSC833 to animals before mitoxantrone treatment increased the accumulation of mitoxantrone in the MDR tumors to 94% of that in the wild-type tumors. These studies have added direct in vitro and in vivo visual information on how Pgp processes anticancer compounds and how Pgp inhibitors modulate MDR in resistant cancer cells.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Cell Line, Tumor; Cyclosporins; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Mice; Mice, Nude; Mitoxantrone; Xenograft Model Antitumor Assays
PubMed: 19423841
DOI: 10.1124/jpet.109.153551 -
Journal of Clinical Oncology : Official... Jun 2009Mitoxantrone plus prednisone and ixabepilone each have modest activity as second-line chemotherapy in docetaxel-refractory castration-resistant prostate cancer (CRPC)...
Phase I study of ixabepilone, mitoxantrone, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy: a study of the department of defense prostate cancer clinical trials consortium.
PURPOSE
Mitoxantrone plus prednisone and ixabepilone each have modest activity as second-line chemotherapy in docetaxel-refractory castration-resistant prostate cancer (CRPC) patients. Clinical noncrossresistance was previously observed.
PATIENTS AND METHODS
Metastatic CRPC patients progressing during or after taxane-based chemotherapy enrolled in a phase I multicenter study of ixabepilone and mitoxantrone administered every 21 days along with prednisone. Ixabepilone and mitoxantrone doses were alternately escalated in a standard 3 + 3 design. Patients were evaluated for toxicity and disease response. Dose-limiting toxicities (DLTs) were defined as treatment related, occurring during cycle 1, and included grade 4 prolonged or febrile neutropenia, thrombocytopenia (grade 4 or grade 3 with bleeding), or > or = grade 3 nonhematologic toxicity.
RESULTS
Thirty-six patients were treated; 59% of patients experienced grade 3/4 neutropenia. DLTs included grade 3 diarrhea (n = 1), prolonged grade 4 neutropenia (n = 4), and grade 5 neutropenic infection (n = 1). Due to prolonged neutropenia, the highest dose levels were repeated with pegfilgrastim on day 2 of each cycle. The maximum tolerated dose in combination with pegfilgrastim was not exceeded. The recommended phase II dose is mitoxantrone 12 mg/m2 and ixabepilone 35 mg/m2 every 21 days, pegfilgrastim 6 mg subcutaneously day 2, and continuous prednisone 5 mg twice per day. Thirty-one percent of patients have experienced > or = 50% prostate-specific antigen (PSA) declines, and two experienced objective responses. Of 21 patients treated with mitoxantrone 12 mg/m2 plus ixabepilone > or = 30 mg/m2, nine (43%) experienced > or = 50% PSA declines (95% CI, 22% to 66%).
CONCLUSION
These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Castration; Docetaxel; Epothilones; Humans; Infusions, Subcutaneous; Male; Middle Aged; Military Personnel; Mitoxantrone; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids
PubMed: 19349545
DOI: 10.1200/JCO.2008.19.8002 -
Scientific Reports Apr 2022Spike-mediated entry of SARS-CoV-2 into human airway epithelial cells is an attractive therapeutic target for COVID-19. In addition to protein receptors, the SARS-CoV-2...
Spike-mediated entry of SARS-CoV-2 into human airway epithelial cells is an attractive therapeutic target for COVID-19. In addition to protein receptors, the SARS-CoV-2 spike (S) protein also interacts with heparan sulfate, a negatively charged glycosaminoglycan (GAG) attached to certain membrane proteins on the cell surface. This interaction facilitates the engagement of spike with a downstream receptor to promote viral entry. Here, we show that Mitoxantrone, an FDA-approved topoisomerase inhibitor, targets a heparan sulfate-spike complex to compromise the fusogenic function of spike in viral entry. As a single agent, Mitoxantrone inhibits the infection of an authentic SARS-CoV-2 strain in a cell-based model and in human lung EpiAirway 3D tissues. Gene expression profiling supports the plasma membrane as a major target of Mitoxantrone but also underscores an undesired activity targeting nucleosome dynamics. We propose that Mitoxantrone analogs bearing similar heparan sulfate-binding activities but with reduced affinity for DNA topoisomerases may offer an alternative therapy to overcome breakthrough infections in the post-vaccine era.
Topics: Heparin; Heparitin Sulfate; Humans; Mitoxantrone; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; COVID-19 Drug Treatment
PubMed: 35440680
DOI: 10.1038/s41598-022-10293-x -
Biomedicine & Pharmacotherapy =... Sep 2022Lysosomes, now known to take part in multiple cellular functions, also respond to various stress stimuli. These include biogenesis in response to nanomolar...
Lysosomes, now known to take part in multiple cellular functions, also respond to various stress stimuli. These include biogenesis in response to nanomolar concentrations of hydrophobic weak-base anticancer drugs. However, since lysosomal stress mediated by accumulation of weak-base drugs at such concentrations has never been proven and these drugs have diverse effects on malignant cells, we investigated whether the interpretation of the data was true. We found that lysosomal accumulation of the drugs daunorubicin, doxorubicin, mitoxantrone, symadex, chloroquine, clomipramine and sunitinib alone, was insufficient to induce lysosomal alkalization i.e., lysosomal stress-mediated biogenesis at nanomolar concentrations. Instead, we found that some of the drugs used induced G2 phase arrest and lysosomal biogenesis that is associated with activation of transcription factor EB (TFEB). Similarly, cantharidin, a control compound that does not belong to the weak base drugs, induced cell cycle arrest in the G2 phase associated with TFEB-driven lysosomal biogenesis. Overall none of the tested drugs caused stress-induced lysosomal biogenesis at nanomolar concentrations. However, daunorubicin, doxorubicin, mitoxantrone, symadex and cantharidin induced a massive block in the G2 phase of the cell cycle which is naturally associated with TFEB-driven lysosomal biogenesis.
Topics: Autophagy; Cantharidin; Cell Cycle; Doxorubicin; Lysosomes; Mitoxantrone
PubMed: 35785701
DOI: 10.1016/j.biopha.2022.113328 -
Kardiologia Polska 2016Mitoxanthrone (MTX) is a synthetic anthracycline antibiotic that has been used for several years in the treatment of patients with primary progressive, secondary...
BACKGROUND
Mitoxanthrone (MTX) is a synthetic anthracycline antibiotic that has been used for several years in the treatment of patients with primary progressive, secondary progressive, and relapsing remitting multiple sclerosis (MS) who do not respond to other drugs. MTX has antineoplastic, immunomodulatory, and antibacterial properties. The most common adverse effects of MTX include nausea and vomiting, hair loss, increased risk of urinary and respiratory tract infections, and amenorrhea. Less frequent problems include leukopenia, thrombocytopenia, anaemia, and an increase in hepatic enzyme and bilirubin levels. Other severe sequelae of MTX treatment are drug cardiotoxicity and a potential to induce leukaemia. Drug toxicity results from its affinity to iron ions. The resulting complex strongly induces formation of free oxygen radicals and increases lipid peroxidation. Asymptomatic reduction in left ventricular ejection fraction (LVEF) by two-dimensional (2D) echocardiography, cardiomyopathy, and congestive heart failure have been observed in patients with MS at a rate of about 2.6-5%. Few studies evaluated cardiotoxicity of MTX in MS patients. Most previous studies were performed in small groups of cancer patients and cardiac evaluation was limited to physical examination.
AIM
To evaluate the effect of MTX treatment on LVEF by 2D echocardiography.
METHODS
We studied 72 MS patients aged 25-63 years who were treated with MTX in 2002-2014. The diagnosis of MS was made using the 2001 McDonald criteria updated in 2005. The study group included primary progressive MS in 40 (56%) patients, secondary progressive MS in 5 (7%) patients, and relapsing remitting MS in 27 (37%) patients. MTX was administered at 12 mg/m2 of body surface area every 3 months (up to the total dose of 140 mg/m2). MTX treatment was initiated in patients with no signs of heart failure on physical examination, normal electrocardiogram (ECG), normal LVEF by 2D echocardiography, and normal laboratory test findings including complete blood count and hepatic and renal function parameters. Each MTX administration was preceded by 2D echocardiography with LVEF measurement, ECG, and physical examination of the cardiovascular system. The effect of MTX treatment on LVEF was evaluated by comparing baseline LVEF with LVEF measurements before the last MTX dose. Statistical analysis was performed using the Student t test.
RESULTS
The mean LVEF before administration of the first MTX dose was 65 ± 3.3%. The lowest LVEF at the final 2D echo-cardiographic examination was 60 ± 2.1%. We did not find a significant LVEF reduction during MTX treatment in MS patients compared to baseline values. Severe myocardial dysfunction manifesting with significant LVEF reduction by 2D echocardiography or clinical evidence of heart failure was not noted in any patient in the study group.
CONCLUSIONS
Our study showed no significant LVEF reduction during MTX monotherapy in MS patients without a history of a cardiac disease and with normal echocardiographic findings at baseline. Long-term cardiac effects of MTX require further studies.
Topics: Adult; Echocardiography; Female; Heart; Humans; Male; Middle Aged; Mitoxantrone; Multiple Sclerosis; Ventricular Function, Left
PubMed: 26412472
DOI: 10.5603/KP.a2015.0195 -
ACS Nano Aug 2018In desmoplastic melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the...
In desmoplastic melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death. Here, we show that when effectively co-delivered to the tumor site at their optimal ratio by a TME-responsive nanocarrier, the 5:1 combination of MIT and CEL significantly triggered immunogenic tumor apoptosis and recovered tumor antigen recognition, thus eliciting overall antitumor immunity. Furthermore, the strong synergy benefitted the host in reduced drug exposure and side effects. Collectively, the nanocarrier-mediated chemo-immunotherapy successfully remodeled fibrotic and immunosuppressive TME, arrested cancer progression, and further inhibited tumor metastasis to major organs. The affected tumors remained dormant long after dosing stopped, resulting in a prolonged progression-free survival and sustained immune surveillance of the host bearing desmoplastic melanoma.
Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Cell Proliferation; Disease Progression; Drug Carriers; Drug Delivery Systems; Drug Screening Assays, Antitumor; Immunosenescence; Immunotherapy; Melanoma; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitoxantrone; NIH 3T3 Cells; Nanoparticles; Pentacyclic Triterpenes; Skin Neoplasms; Triterpenes; Tumor Microenvironment
PubMed: 30016071
DOI: 10.1021/acsnano.8b01890 -
Nature Communications May 2020ABCG2 is an ABC transporter that extrudes a variety of compounds from cells, and presents an obstacle in treating chemotherapy-resistant cancers. Despite recent...
ABCG2 is an ABC transporter that extrudes a variety of compounds from cells, and presents an obstacle in treating chemotherapy-resistant cancers. Despite recent structural insights, no anticancer drug bound to ABCG2 has been resolved, and the mechanisms of multidrug transport remain obscure. Such a gap of knowledge limits the development of novel compounds that block or evade this critical molecular pump. Here we present single-particle cryo-EM studies of ABCG2 in the apo state, and bound to the three structurally distinct chemotherapeutics. Without the binding of conformation-selective antibody fragments or inhibitors, the resting ABCG2 adopts a closed conformation. Our cryo-EM, biochemical, and functional analyses reveal the binding mode of three chemotherapeutic compounds, demonstrate how these molecules open the closed conformation of the transporter, and establish that imatinib is particularly effective in stabilizing the inward facing conformation of ABCG2. Together these studies reveal the previously unrecognized conformational cycle of ABCG2.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Antineoplastic Agents; Biological Transport; Disulfides; HEK293 Cells; Humans; Imatinib Mesylate; Ligands; Mitoxantrone; Models, Biological; Protein Structure, Secondary
PubMed: 32385283
DOI: 10.1038/s41467-020-16155-2