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European Journal of Medical Research Jun 2024Multiple Sclerosis (MS) is a complex autoimmune disorder that significantly impacts the central nervous system, leading to a range of complications. While intracranial... (Review)
Review
Multiple Sclerosis (MS) is a complex autoimmune disorder that significantly impacts the central nervous system, leading to a range of complications. While intracranial haemorrhage (ICH) is a rare but highly morbid complication, more common CNS complications include progressive multifocal leukoencephalopathy (PML) and other CNS infections. This severe form of stroke, known for its high morbidity and mortality rates, presents a critical challenge in the management of MS. The use of disease-modifying drugs (DMDs) in treating MS introduces a nuanced aspect to patient care, with certain medications like Dimethyl Fumarate and Fingolimod showing potential in reducing the risk of ICH, while others such as Alemtuzumab and Mitoxantrone are associated with an increased risk. Understanding the intricate relationship between these DMDs, the pathophysiological mechanisms of ICH, and the individualised aspects of each patient's condition is paramount. Factors such as genetic predispositions, existing comorbidities, and lifestyle choices play a crucial role in tailoring treatment approaches, emphasising the importance of a personalised, vigilant therapeutic strategy. The necessity for ongoing and detailed research cannot be overstated. It is crucial to explore the long-term effects of DMDs on ICH occurrence and prognosis in MS patients, aiming to refine clinical practices and promote patient-centric, informed therapeutic decisions. This approach ensures that the management of MS is not only comprehensive but also adaptable to the evolving understanding of the disease and its treatments.
Topics: Humans; Multiple Sclerosis; Cerebral Hemorrhage; Immunosuppressive Agents; Mitoxantrone; Fingolimod Hydrochloride; Dimethyl Fumarate
PubMed: 38918831
DOI: 10.1186/s40001-024-01945-x -
MicroPublication Biology 2024Pixantrone and mitoxantrone are structurally related anticancer drugs which have been shown to generate covalent conjugates at apurinic/apyrimidinic (AP) sites in DNA....
Pixantrone and mitoxantrone are structurally related anticancer drugs which have been shown to generate covalent conjugates at apurinic/apyrimidinic (AP) sites in DNA. Mitoxantrone binding to AP sites induces DNA strand cleavage and inhibits the endonuclease activity of human AP endonuclease 1 (APE1). Here, pixantrone was demonstrated to have similar properties, but relative to mitoxantrone, it was significantly less potent in both DNA incision and APE1 inhibition. Consistent with these observations, pixantrone had ~ 15-fold lower affinity for DNA containing an AP site analogue, tetrahydrofuran, as measured by a Thiazole Orange (ThO) displacement assay.
PubMed: 38911437
DOI: 10.17912/micropub.biology.001207 -
European Journal of Clinical... Jun 2024This study is aimed at investigating the pharmacokinetic (PK) characteristics of pegylated liposomal mitoxantrone (PLM) in patients with relapsed/refractory lymphoma or...
OBJECTIVE
This study is aimed at investigating the pharmacokinetic (PK) characteristics of pegylated liposomal mitoxantrone (PLM) in patients with relapsed/refractory lymphoma or small cell lung cancer (SCLC) by constructing population pharmacokinetic (popPK) models for both liposome-encapsulated mitoxantrone and free mitoxantrone.
METHODS
A total of 23 patients with relapsed/refractory lymphoma and 42 patients with SCLC were included. A popPK model was simultaneously developed utilizing a non-linear mixed effects model (NONMEM) to explore the PK profiles of liposome-encapsulated mitoxantrone and free mitoxantrone. Clearance (CL) and distribution volume (V) were calculated, and covariate analysis was employed to evaluate the influence of patient disease type, demographic information, and biochemical indicators of liver and kidney function on PK parameters.
RESULTS
The concentration-time profiles for both liposome-encapsulated mitoxantrone and free mitoxantrone were described by a one-compartment model. The release (Rel) of liposome-encapsulated mitoxantrone to free mitoxantrone was determined to be 0.0191 L/h, and the V of liposome-encapsulated mitoxantrone was 2.32 L. The apparent CL of free mitoxantrone was estimated at 1.66 L/h. The apparent V of free mitoxantrone was 35.8 L in patients with relapsed/refractory lymphoma and 22.2 L for patients with SCLC. In patients with relapsed/refractory lymphoma, lower maximum concentration (C) and higher apparent V of free mitoxantrone were observed compared with patients with SCLC.
CONCLUSION
The popPK characteristics of both liposome-encapsulated and free mitoxantrone in patients with relapsed/refractory lymphoma or SCLC were effectively described by a one-compartment model.
PubMed: 38904799
DOI: 10.1007/s00228-024-03711-8 -
Multiple Sclerosis and Related Disorders Jun 2024Neurofilament light chain (NFL) is a biomarker for monitoring disease activity and treatment response in multiple sclerosis (MS). However, while most agree that NFL...
BACKGROUND
Neurofilament light chain (NFL) is a biomarker for monitoring disease activity and treatment response in multiple sclerosis (MS). However, while most agree that NFL levels predict disease activity and worsening, the predictive value of NFL on future relapse risk remains uncertain.
OBJECTIVE
The primary aim was to evaluate the predictive value of age-corrected serum NFL (sNFL) ratio on relapse risk in highly active relapsing-remitting MS patients (RRMS) treated with natalizumab. A secondary aim was to investigate the predictive value of sNFL ratios for MRI activity.
METHODS
From January 1, 2006, to December 31, 2010, 355 patients initiated natalizumab treatment at the Danish Multiple Sclerosis Center. 305 patients were anti-natalizumab antibodies negative and had at least one blood sample available for sNFL analysis using single molecule array analysis at baseline, three, six, or 12 months. The patients were either treatment-naïve (n = 8), switching from interferon-β or glatiramer acetate (n = 253), or switching from mitoxantrone (n = 44). An age-corrected ratio was calculated for sNFL. Time to first relapse was calculated from baseline and after re-baseline at 90 days. Data were collected from baseline until the two-year follow-up or end of treatment and included disease duration, expanded disability status scale, previous treatments, relapses 12 months prior to natalizumab initiation, smoking intensity, body mass index, and body weight. In addition, the patients underwent annual MRI of the brain.
RESULTS
The sNFL ratio was increased in 173 of 287 samples (60.3 %) at baseline, in 119 of 246 samples (48.8 %) at month three, in 109 of 287 samples (38.0 %) at month six, and in 82 of 270 samples (30.4 %) at month 12. The sNFL ratio continuously declined over 12 months with significant decreases for every measuring timepoint: baseline vs. three months p = 3.0 × 10; three months vs. six months p = 3.2 × 10; six months vs. 12 months p = 0.002. Univariate Cox regression analysis showed that time to first relapse from 1) natalizumab initiation and from 2) re-baseline was associated with the number of relapses in the previous 12 months (hazard ratio 1.31 per relapse, 95 % CI = 1.2-1.5, p = 2.0 × 10; and 1.21 per relapse, 95 % CI = 1.1-1.4, p = 0.002, respectively). sNFL ratio at re-baseline was negatively associated with relapse risk (hazard ratio 0.82 per unit; 95 % CI = 0.7-1.0; p = 0.049). A multivariable Cox regression analysis of relapse risk from re-baseline showed that the number of relapses in the 12 months prior to natalizumab treatment (hazard ratio 1.29; 95 % CI = 1.1-1.5; p = 6.0 × 10) and smoking (hazard ratio 1.51 per 20 cigarettes per day; 95 % CI = 1.0-2.2; p = 0.030) were associated with increased risk of relapse; sNFL ratio was associated with a lower risk of relapse (hazard ratio = 0.736 per unit; 95 % CI = 0.6-0.9 p = 0.007). In univariate logistic regression analyses, the sNFL ratio at 12 months and values above the 75th and the 90th percentile predicted MRI activity in the following year (odds ratio [OR] = 2.0, 95 % CI = 1.2-3.6, p = 0.012; OR = 2.2, 95 % CI = 1.2-4.1, p = 0.014; and OR = 2.8, 95 % CI = 1.1-6.7, p = 0.026).
CONCLUSION
In this highly active RRMS cohort, high sNFL ratios reflected previous relapse activity and decreased after initiation of treatment but were not associated with increased relapse risk in the following two years. Pre-treatment relapses and smoking on treatment were predictors of relapse risk after re-baselining at 90 days. MRI activity in year two was predicted by sNFL ratios at month 12.
PubMed: 38889559
DOI: 10.1016/j.msard.2024.105701 -
Translational Oncology Aug 2024Following infection or exposure to therapeutic agents, an aggressive immune response may result, termed cytokine storm (CS) or cytokine release syndrome. Here the innate...
Following infection or exposure to therapeutic agents, an aggressive immune response may result, termed cytokine storm (CS) or cytokine release syndrome. Here the innate immune system becomes uncontrolled, leading to serious consequences including possible death. Patients surviving CS are at greater risk for de novo tumorigenesis, but it is unclear if any specific cytokines are directly responsible for this outcome. De novo tumorigenesis has been observed in donated cells exposed to CS following haematopoietic stem cell transplant (HSCT). Modelling HSCT, we firstly demonstrated the release of CS levels from the HS-5 human bone marrow stromal cell line, post-exposure to chemotherapy. We then exposed the TK6 lymphoblast cell line to healthy and storm doses of IL-6 and measured increased genotoxicity via the micronucleus assay. During HSCT, haematopoietic cells are exposed to a complex mix of cytokines, so to determine if IL-6 was integral in a chemotherapy-induced bystander effect, we attempted to inhibit IL-6 from HS-5 cells using resatorvid or siRNA, treated with chlorambucil or mitoxantrone, and then co-cultured with bystander TK6 cells. Whilst resatorvid did not reduce IL-6 and did not reduce micronuclei in the bystander TK6 cells, siRNA inhibition reduced IL-6 to healthy in vivo levels, and micronuclei aligned with untreated controls. Our data suggests that exposure to high IL-6 (in the absence of inflammatory cells) has potential to induce genetic damage and may contribute to de novo tumorigenesis post-CS. We suggest that for individuals with a pro-inflammatory profile, anti-IL-6 therapy may be an appropriate intervention to prevent complications post-CS.
PubMed: 38870677
DOI: 10.1016/j.tranon.2024.102030 -
Blood Advances Jun 2024β-thalassemia is a condition characterized by reduced or absent synthesis of β-globin resulting from genetic mutations, leading to expanded and ineffective...
β-thalassemia is a condition characterized by reduced or absent synthesis of β-globin resulting from genetic mutations, leading to expanded and ineffective erythropoiesis. Mitoxantrone has been widely used clinically as an antitumor agent in light of its ability to inhibit cell proliferation. However, its therapeutic effect on expanded and ineffective erythropoiesis in β-thalassemia is untested. We found that mitoxantrone decreased α-globin precipitates and ameliorated anemia, splenomegaly and ineffective erythropoiesis in the HbbTh3/+ mouse model of β-thalassemia intermedia. The partially reversed ineffective erythropoiesis is a consequence of effects on autophagy as mitochondrial retention and protein levels of mTOR, P62 and LC3 in reticulocytes decreased in mitoxantrone-treated HbbTh3/+ mice. These data provide significant pre-clinical evidence for targeting autophagy as a novel therapeutic approach for β-thalassemia.
PubMed: 38861356
DOI: 10.1182/bloodadvances.2024012679 -
Frontiers in Pharmacology 2024Colorectal cancer is a common malignant tumor with high mortality, for which chemotherapy resistance is one of the main reasons. The high expression of ABCG2 in the...
Colorectal cancer is a common malignant tumor with high mortality, for which chemotherapy resistance is one of the main reasons. The high expression of ABCG2 in the cancer cells and expulsion of anticancer drugs directly cause multidrug resistance (MDR). Therefore, the development of new ABCG2 inhibitors that block the active causes of MDR may provide a strategy for the treatment of colorectal cancer. In this study, we find that dorsomorphin (also known as compound C or BML-275) potently inhibits the transporter activity of ABCG2, thereby preserving the chemotherapeutic agents mitoxantrone and doxorubicin to antagonize MDR in ABCG2-overexpressing colorectal cancer cells. Additionally, dorsomorphin does not alter ABCG2 protein expression. The results of molecular docking studies show that dorsomorphin is bound stably to the ABCG2-binding pocket, suggesting that dorsomorphin is a potent ABCG2 inhibitor that attenuates ABCG2-mediated MDR in colorectal cancer.
PubMed: 38855753
DOI: 10.3389/fphar.2024.1393693 -
Frontiers in Medicine 2024Acute lymphoblastic leukemia (ALL) represents a malignancy involving early-stage differentiated lymphoid cells that invade the bone marrow, blood, and extramedullary...
Liposomal mitoxantrone-based multidrug chemotherapy as a bridge to allogeneic hematopoietic stem cell transplantation in relapsed/refractory acute lymphoblastic leukemia (ALL) after immunotherapy failure: a case report.
Acute lymphoblastic leukemia (ALL) represents a malignancy involving early-stage differentiated lymphoid cells that invade the bone marrow, blood, and extramedullary sites. First-line treatment spans 2-3 years with induction, consolidation, intensification, and long-term maintenance phases. Relapsed/refractory (R/R) ALL typically carries an adverse prognosis, and there is currently no standard of care for this disease. Here, we present a case of R/R ALL that responded effectively to liposomal mitoxantrone-based multidrug chemotherapy, resulting in a rapid complete response after 35 days of therapy. Subsequently, the patient was successfully treated with allo-HSCT. At 5 months follow-up, the patient was alive and leukemia-free. Additionally, no severe adverse events were recorded during liposomal mitoxantrone treatment or hospitalization for allo-HSCT. Given the encouraging efficacy and the manageable adverse events observed in our case, liposomal mitoxantrone-based multidrug chemotherapy should be further explored as a bridge to allo-HSCT in patients with R/R ALL.
PubMed: 38854665
DOI: 10.3389/fmed.2024.1383288 -
Biomedicine & Pharmacotherapy =... Jul 2024Mitoxantrone resistant variant of SW620 line was developed, characterized and subsequently used as a model system to determine oncostatin M ability to modulate MDR...
Mitoxantrone resistant variant of SW620 line was developed, characterized and subsequently used as a model system to determine oncostatin M ability to modulate MDR phenomenon. The selection regimen allowed for overexpression of ABCG2 and ABCB1 both at the RNA and protein level, which was further confirmed by functional assays. Oncostatin M supplementation resulted in partial reversal of MDR phenotype by decreasing overexpression of ABCG2 demonstrating for the first time the ability of this cytokine for selective down-regulation of one of MDR proteins.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Mitoxantrone; Drug Resistance, Neoplasm; Humans; Neoplasm Proteins; Oncostatin M; Cell Line, Tumor; Drug Resistance, Multiple; ATP Binding Cassette Transporter, Subfamily B
PubMed: 38850649
DOI: 10.1016/j.biopha.2024.116861 -
Journal of Controlled Release :... Jul 2024Hypoimmunogenicity and the immunosuppressive microenvironment of ovarian cancer severely restrict the capability of immune-mediated tumor killing. Immunogenic cell death...
Hypoimmunogenicity and the immunosuppressive microenvironment of ovarian cancer severely restrict the capability of immune-mediated tumor killing. Immunogenic cell death (ICD) introduces a theoretical principle for antitumor immunity by increasing antigen exposure and presentation. Despite recent research progress, the currently available ICD inducers are still very limited, and many of them can hardly induce sufficient ICD based on traditional endoplasmic reticulum (ER) stress. Accumulating evidence indicates that inducing mitochondrial stress usually shows a higher efficiency in evoking large-scale ICD than that via ER stress. Inspired by this, herein, a mitochondria-targeted polyprodrug nanoparticle (named Mito-CMPN) serves as a much superior ICD inducer, effectively inducing chemo-photodynamic therapy-caused mitochondrial stress in tumor cells. The rationally designed stimuli-responsive polyprodrugs, which can self-assemble into nanoparticles, were functionalized with rhodamine B for mitochondrial targeting, cisplatin and mitoxantrone (MTO) for synergistic chemo-immunotherapy, and MTO also serves as a photosensitizer for photodynamic immunotherapy. The effectiveness and robustness of Mito-CMPNs in reversing the immunosuppressive microenvironment is verified in both an ovarian cancer subcutaneous model and a high-grade serous ovarian cancer model. Our results support that the induction of abundant ICD by focused mitochondrial stress is a highly effective strategy to improve the therapeutic efficacy of immunosuppressive ovarian cancer.
Topics: Female; Ovarian Neoplasms; Mitochondria; Photochemotherapy; Nanoparticles; Animals; Humans; Cell Line, Tumor; Photosensitizing Agents; Antineoplastic Agents; Prodrugs; Immunogenic Cell Death; Mice, Inbred BALB C; Cisplatin; Immunotherapy; Tumor Microenvironment
PubMed: 38849094
DOI: 10.1016/j.jconrel.2024.06.014