The Applications of Mitoxantrone and Its Liposome in Adult Acute Myeloid Leukemia

Acute myeloid leukemia (AML), a rapidly progressing hematopoietic malignancy, can only be cured hopefully by hematopoietic stem cells transplantation (HSCT). Before HSCT, we usually exert effects by attempting certain regimens to induce these tumor cells to death. Administered in AML patients, the classic “3 + 7” intensive induction regimen including anthracyclines and cytarabine is recommended by guidelines worldwide. However, conventional regimens consist of anthracyclines, a category of drug limited by cumulative, dose-related, progressive myocardial damage and congestive heart failure occurs when its total doses break through the cut-off. Based on this background, mitoxantrone (MIT), an anthraquinone, was developed to a new form to reduce cardiotoxicity. Meanwhile, the nanomedicine, mitoxantrone liposome (Lipo-MIT), was characterized by improved bioavailability and limited toxicity. This drug has great therapeutic potential, but different side effects. We conclude the overall history and development of MIT and Lipo-MIT, which show controversial efficacy of MIT compared to doxorubicin and therapeutic potential of Lipo-MIT. This article reviewed the application of MIT and liposome forms in adult AML patients. .

Study on the anticarcinogenic effect and acutetoxicity of liver-targeting mitoxantrone-nanoparticles

AIM To study the anticarcinogenic effect and acute toxicity of liver targeting mitoxantrone nanospheres. METHODS The anticarcinogenic effect of mitoxantrone polybutylcyanoacrylate nanoparticles (DHAQ PBCA NP) was investigated by using heterotopic and orthotopic transplantation models of human hepatocellular carcinoma (HCC) in nude mice and was compared with mitoxantrone (DHAQ) and doxorubicin (ADR). The acute toxicity of DHAQ PBCA NP lyophilized injection in mice was also studied. RESULTS The tumor inhibition rates of ADR, DHAQ, DHAQ PBCA NP to orthotopically transplanted HCC were 60 07%, 67 49% and 99 44%, respectively, but regard to heterotopically transplanted HCC, these were 80 03%, 86 18% and 92 90%, which were concordant with the results acquired by mitosis counting and proliferating cell nuclear antigen (PCNA). After iv administration to mice with DHAQ PBCA NP, the LD 50 was 16 9*!mg/*!kg ± 3 9*!mg/*!kg , no obvious local irritation was observed and there was no significant damage to the structure of liver cells, and that of the heart, spleen and kidneys. CONCLUSION The effect of DHAQ PBCA NP was significantly higher than that of DHAQ and ADR in the anti orthotopically transplanted HCC and the acute toxicity was relatively low.

Comparison of Mitoxantrone in Combination with Intermediate-dose Cytarabine versus High-dose Cytarabine as Consolidation Therapies for Young Non-APL Acute Myeloid Leukemia Patients with Favorable and Intermediate Cytogenetics

In this study,we compared the efficacy of mitoxantrone in combination with intermediate-dose cytarabine（HAM） with that of high-dose cytarabine alone（Hi DAC） as consolidation regimens in non-acute promyelocytic leukemia（APL） acute myeloid leukemia patients with favorable and intermediate cytogenetics.A total of 62 patients from Shenzhen People＇s Hospital were enrolled in this study.All patients enrolled received standard induction chemotherapy and achieved the first complete remission（CR1）.In these patients,24 received Hi DAC and 38 received HAM as consolidation.The median relapse free survival（RFS） and overall survival（OS） were similar between these two consolidation regimens.Even in subgroup analysis according to risk stratification,the combination regimen conferred no benefit in longterm outcome in patients with favorable or intermediate cytogenetics.However,in patients receiving HAM regimen,the lowest neutrophil count was lower,neutropenic period longer,neutropenic fever rate higher,and more platelet transfusion support was required.HAM group also tended to have higher rate of sepsis than Hi DAC group.According to our results,we suggest that combination treatment with mitoxantrone and intermediate-dose cytarabine has limited value as compared to Hi DAC,even in young non-APL AML patients with favorable and intermediate cytogenetics.

Sensitive Voltammetric Determination of Mitoxantrone by Using CS-Dispersed Graphene Modified Glassy Carbon Electrodes

A novel CS-dispersed graphene modified glassy carbon electrode was fabricated. Study electrochemical characteristics of mitoxantrone in the CS-dispersed graphene modified electrode by cyclic voltammetry and other methods, by selecting and optimizing the various parameters to create a new electrochemical method for the determination of mitoxantrone. The linear range of the oxidation peak current is from 6×10–10 to 1 ×10–6 mol/l in this method, after 2.5 mins open-circuit accumulation, the limit of detection is 2×10–10 mol/l. After 10 parallel determinations, the relative standard deviation was 3.7% that the concentration of mitoxantrone was 1×10–8 mol/l. The modified electrode has been successfully applied for the assay of mitoxantrone in human urine samples.

The synthesis of potential anticancer drugs related to mitoxantrone

ABSTRACT In an attempt at a rational design for anticancer drugs, two new potential anticancer compounds related to mitoxantrone were prepared. Compounds 4. 1.4-dihydroxy-6-aminoethyl-9.10-anthracenedione was synthesized in 6 steps starting with 4-methyl-phthalic acid, and compound 5, 2(4-aminobutyl)-l 4-dihvdroxv-9,10-anthracenedione was synthesized in 5 steps from N-3-bromopropylphthalimide.

Electrochemical Behavior of Mitoxantrone and Its Determination at a Pt/C Implanted Modified Microelectrode

In a 0.02 mol/L Na_2HPO_4-KH_2PO_4(PBS) buffer solution(pH=6.82), the electrochemical behavior of mitoxantrone was studied by linear-sweep voltammetry and cyclic voltammetry at a Pt/C ion implantation modified microelectrode. A sensitive reduction peak was observed. The peak potential was \{-0.72 V\}(vs.SCE), the peak current was proportional to the concentration of mitoxantrone within the ranges of 7.0×10 -8—9.0×10 -7 mol/L and 1.0×10 -6—2.4×10 -5 mol/L, with a detection limit of 4.0×10 -8 mol/L. The linear correlation coefficients were 0.9994 and 0.9992, respectively. This method has been applied to the direct determination of mitoxantrone in simulated urine. The recoveries were in the range from 96.2% to 105.9%. The reduction process was a quasi-reversible one with adsorptive characteristics at the Pt/C microelectrode. The electrode reaction rate constant k_s and the electron transfer coefficient α of the system were determined to be 4.5 and 0.65 s -1, respectively. The experiments showed that Pt element had surely been implanted into the surface of the carbon fiber, and the atomic Pt improved the electrocatalytic activity. The Pt/C microelectrode had a good stability and reproducibility.

Interaction Between Mitoxantrone Metal Complex and Titan Yellow by Resonance Rayleigh Scattering Spectra and Its Analytical Application

In a pH 2.4 Britton-Robinson buffer medium, the anthracycline antibiotics mitoxantrone（MXT） could react with metal ions such as Pd（Ⅱ）, Co（Ⅱ） and Cu（Ⅱ） to form 1：2（molar ratio） cationic chelates, which further reacted with the anionic dye titan yellow to form 1：2 ternary ion-association complexes by electrostatic interaction. As a result, the intensity of resonance Rayleigh scattering（RRS） was enhanced greatly. These RRS spectral characteristics of various metal ion systems were similar, and the maximum RRS wavelengths were all located at 454 nm. But the increments of RRS intensities were different in the series of Pd（Ⅱ）〉Co（Ⅱ）〉Cu（Ⅱ）. The enhanced RRS intensities were proportional to the concentration of MXT in a range of 0.03-2.4μg/mL and the detection limit（3σ） was 0.009μg/mL for the Pd（Ⅱ） system. In this study, the optimum conditions of the reactions and the effects of foreign substances were investigated, in addition, the composition and reaction mechanism of ion-association complexes were discussed. Thus a highly sensitive, simple and rapid method is proposed for the determination of MXT in urine and serum samples.

Interactions of Mitoxantrone-Modified Superparamagnetic Iron Oxide Nanoparticles with Biomimetic Membranes and Cells

We report on the formation of conjugates of superparamagnetic iron nanoparticles(NPs)with the chemotherapeutic agent mitroxantrone(MTX).The NPs are synthesized from mixed iron oxides and are ca.15 nm in diameter.Decoration of the NP surface with MTX is accomplished with standard coupling chemistry techniques using sebacic acid as the coupling agent.The resulting NP-MTX conjugate is characterized thermogravimetrically,spectroscopically and electrochemically.The interactions of the NP-MTX conjugate with a model lipid layer formed as a Langmuir-Blodgett(LB)film reveal that the nanoparticle exhibits a significant perturbative effect on the layer,as seen from translational diffusion(FRAP)measurements.Evaluation of the cytotoxicity of the conjugate relative to that of free MTX demonstrates that the NP-MTX conjugate is more toxic than free MTX for both normal and malignant cell lines.These results underscore the importance of targeted delivery in the administration of chemotherapeutic agents.

Effects of pirarubicin and mitoxantrone for bladder cancer perfusion chemotherapy on the expression of malignant molecules in serum and lavage fluid

Objective: To study the effects of pirarubicin and mitoxantrone for bladder cancer perfusion chemotherapy on the expression of malignant molecules in serum and lavage fluid. Methods:Patients with advanced bladder cancer who underwent bladder cancer perfusion chemotherapy in our hospital between March 2015 and December 2017 were selected and randomly divided into the THP group who accepted pirarubicin perfusion chemotherapy and the MTZ group who accepted mitoxantrone perfusion chemotherapy. The serum was collected before and after chemotherapy to determine the contents of tumor markers in serum;the lavage liquid was collected after chemotherapy to determine the contents of malignant molecules. Results:Compared with those of same group before chemotherapy, CXCL5, VEGF, CYFRA21-1, DKK1 and DKK3 contents in serum of both group of patients decreased chemotherapy, and CXCL5, VEGF, CYFRA21-1, DKK1 and DKK3 contents in serum of MTZ group after chemotherapy were lower than those of THP group;ILP-2, CyclinD1, Twist, EpCAM and MMP2 contents in lavage liquid of MTZ group were significantly lower than those of THP group whereas Bad, Bax, TRAIL, FasL, E-cadherin and TIMP4 contents were significantly higher than those of THP group. Conclusion: Mitoxantrone for bladder cancer perfusion chemotherapy can be more effectively than pirarubicin to regulate the expression of malignant molecules.

Mitoxantrone-Mediated Apoptotic B16-F1 Cells Induce Specific Anti-tumor Immune Response

In the process of cell apoptosis induced by specific reagents,calreticulin(CRT)in endoplasmic reticulum is transferred and coated onto the cell membrane.As a sort of specific ligand,the CRT on the surface of apoptotic cells could mediate recognition and clearance of apoptotic cells by phagocytes.In this research we discovered that mitoxantrone could induce apoptosis of mouse melonoma B16-F1 tumor cells,accompanied by the membrane translocation and coating of CRT.When mitoxantrone-treated B16-F1 cells were used as antigen to inoculate mice,the mice acquired an ability to suppress proliferation of homologous tumor cells.Splenocytes from these mice showed an increased cytolytic effect on homologous B16-F1 cells but no such effect on non-homologous H22 tumor cells.All these results suggested that mitoxantrone-treated apoptotic B16-F1 cells could be used as a sort of cell vaccine to initiate effective anti-tumor immunoresponse in mice.

Mitochondrion targeting peptide-modified magnetic graphene oxide delivering mitoxantrone for impairment of tumor mitochondrial functions

In this study,we prepared mitochondrion targeting peptide-grafted magnetic graphene oxide(GO)nanocarriers for efficient impairment of the tumor mitochondria.The two-dimensional GOMNP-MitP nanosheets were synthesized by grafting magnetic y-Fe_(2)O_(3)to the surface of GO,followed by covalent modification of mitochondrion targeting peptide(MitP).GOMNP-MitP exhibited the high capacity of loading the anticancer drug mitoxantrone(MTX),and preferentially targeted the tumor mitochondria.With the aid of alternating magnetic field(AMF),the MTX-loading GOMNP-MitP released MTX to the mitochondria,severely impairing mitochondrial functions,including attenuation of ATP production,decrease in mitochondrial membrane potential(MMP),and further leading to activation of apoptosis.This study realized high-efficient mitochondrion-ta rgeting drug delivery for anticancer therapy by twodimensional nanoplatforms.

FMD/R-FMD方案治疗老年复发NHL17例报告

目的观察FMD/R-FMD方案治疗老年复发NHL的疗效和不良反应。方法复治的老年NHL患者17例,采用FMD(fludarabine,mitoxantroneanddexamethasone)方案治疗14例,采用Rituximab(美罗华)-FMD方案治疗3例。结果17例NHL中可评价疗效的有16例,有效率为81.3%,完全缓解率为25%(4/16)。主要不良反应为骨髓抑制和轻度胃肠道反应。结论FMDR-FMD方案治疗老年复发NHL效果好,不良反应轻,值得进一步研究。

Chemotherapy and its evolving role in the management of advanced prostate cancer

Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer （CRPC）. Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing ＇level-1 evidence＇ that docetaxel-based chemotherapy led to prolongation in overall survival （OS）. This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents （e.g. abiraterone and enzalutamide） have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include： how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.

A tactical nanomissile mobilizing antitumor immunity enables neoadjuvant chemo-immunotherapy to minimize postsurgical tumor metastasis and recurrence

Neoadjuvant chemotherapy has become an indispensable weapon against high-risk resectable cancers,which benefits from tumor downstaging.However,the utility of chemotherapeutics alone as a neoadjuvant agent is incapable of generating durable therapeutic benefits to prevent postsurgical tumor metastasis and recurrence.Herein,a tactical nanomissile(TALE),equipped with a guidance system(PD-L1 monoclonal antibody),ammunition(mitoxantrone,Mit),and projectile bodies(tertiary amines modified azobenzene derivatives),is designed as a neoadjuvant chemo-immunotherapy setting,which aims at targeting tumor cells,and fast-releasing Mit owing to the intracellular azoreductase,thereby inducing immunogenic tumor cells death,and forming an in situ tumor vaccine containing damage-associated molecular patterns and multiple tumor antigen epitopes to mobilize the immune system.The formed in situ tumor vaccine can recruit and activate antigen-presenting cells,and ultimately increase the infiltration of CD8^(+)T cells while reversing the immunosuppression microenvironment.Moreover,this approach provokes a robust systemic immune response and immunological memory,as evidenced by preventing 83.3%of mice from postsurgical metastasis or recurrence in the B16-F10 tumor mouse model.Collectively,our results highlight the potential of TALE as a neoadjuvant chemo-immunotherapy paradigm that can not only debulk tumors but generate a long-term immunosurveillance to maximize the durable benefits of neoadjuvant chemotherapy.

Electrochemical Method to Characterize Multidrug Resistance

Multidrug resistance（MDR） is a main factor to make the failure of chemotherapy. It is closely related to the over-expression of P-glycoprotein（P-gp）, multidrug resistance protein（MRP） and breast cancer resistance protein（BCRP）. Herein we reported a novel method to characterize MDR, taking advantage of the electrochemical properry of chemotherapeutic drugs. Meanwhile, the definition of accumulation phase and retention phase has been improved. Furthermore, with specific modulators introduced to inhibit the relevant efflux pumps, the exact protein that mainly works in the cells employed in this study can be identified.