Two-step Enzymatic Synthesis of Guanine Arabinoside

The chemical synthesis of Guanine arabinoside （ara-G） is extremely complex, time-consuming, and seriously polluted. A two-step enzymatic synthesis process was developed to acquire ara-G easily. 2,6-Diaminopurine arabinoside （ara-DA） was first synthesized with purine nucleoside phosphorylase and pyrimidine nucleoside phosphorylase produced by Enterobacter aerogenes DGW-07. The conversion yield of ara-DA could reach above 90% when the reaction liquid contained 30 mmol·L^-1 uracil arabinoside as arabinose donor, 10 mmol·L^- 1 2,6-diaminopurine as arabinose acceptor in pH 7.0 20 mmol·L^-1 phosphate buffer, and reacted at 60℃ for 48h. Then, ara-DA was effectively transformed into ara-G with adenylate deaminase produced by Aspergillus oryzae DAW-01. The total process had no complex separation and purification.

Mitoxantrone Ethylcellulose Microspheres for Liver Arte-rial Embolization

Herein,the orthogonal test was used to optimize the preparation conditions and technique of mitoxantrone ethylcellulose microsphere fDHAQ-EC-MS)for liver arterial embolization.The dynamic dialysis method was used to study the drug release characteristics ofthe DRAQ-EC-MS.The suspension of DHAQ-EC-MS for clinical liver arterial embolization was prepared.The results show that the DHAQ-EC-MS is regular in morphology with a mean diameter of 110.24 ± 38.19μm and 86.5% of them within the range of 40-150μm,The drug loading is 12.5% and the embedding ratio is 55.6%. The release characteristics were in accordance with the single exponential model.The drug release equation is log(Y∞-Y)=-0.116t-1.198 × 10￣(-3)(r=0.9992,t(50)=2.6h).The suspension is ofstable physical and chemical properties and is suitable for clinical use.

Targeting Effect Study of ￣(3) H-Mitoxantrone Nanosphereson Hepatocellular Carcinoma(HCC) Model in Nude Mice

The distribution of ￣(3)H-mitoxantrone polybutyl cyanoacrylate nanospheres(￣(3)H-DHAQ-PBCA-NS)in the viscera,muscle and tumors of human hepatocellular carcinoma (HCC)model in nude mice was studied with liquid scintillation counting techniique. The results showed that the ￣(3)H-DHAQ-PBCA-NS had remarkable liver targeting effect. The content of ￣(3)H-DHAQ-PBCA-NSin liver and heterotopic liver tumor was found to be 71.31±10. 49% of total amount of drug in animal body. It was also found that the content of ￣(3)H-DHAQ-PBCA-NS in liver was higher than that in liver tissue, and the content of ￣(3)H-DHAQ-PBCA-NS in annpit tumor was higher than that in armpit muscle tissue,but had no significant difference;It provides an ideal preparation for the DHAQ admini-stration.

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.

Preparation and functional characterization of tumor-targeted folic acid-chitosan conjugated nanoparticles loaded with mitoxantrone

Folic acid conjugated chitosan was prepared by cross-linking reaction with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride(EDC), and then used as a template to prepare folic acid-chitosan(FA-CS) conjugated nanoparticles and load mitoxantrone nanoparticles(FA-CSNP/MTX). Drug dissolution testing, CCK-8 method, and confocal microscopy were used to detect their controlled-release capability in different situations and the specific uptake by HONE1 cells. The experimental results show that the nanoparticles have uniform size distribution of 48-58 nm. The highest encapsulation rate of the particles on mitoxantrone hydrochloride(MTX) is(77.5±1.9)%, and the drug loading efficiency is(18.4±0.4)%. The sustained release effect, cell growth inhibition activity and targeting effect of the FA-CS/MTX nanoparticles are good in artificial gastric fluid and intestinal fluid. It is demonstrated that the FA-CSNP system is a potentially useful system for the targeted delivery of anticancer drug MTX.

Induction of nucleoside phosphorylase in Enterobacter aerogenes and enzymatic synthesis of adenine arabinoside

Nucleoside phosphorylases (NPases) were found to be induced in Enterobacter aerogenes DGO-04, and cytidine and cytidine 5′-monophosphate (CMP) were the best inducers. Five mmol/L to fifteen mmol/L cytidine or CMP could distinctly increase the activities of purine nucleoside phosphorylase (PNPase), uridine phosphorylase (UPase) and thymidine phosphorylase (TPase) when they were added into medium from 0 to 8 h. In the process of enzymatic synthesis of adenine arabinoside from adenine and uracil arabinoside with wet cells of Enterobacter aerogenes DGO-04 induced by cytidine or CMP, the reaction time could be shortened from 36 to 6 h. After enzymatic reaction the activity of NPase in the cells induced remained higher than that in the cells uninduced.

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.

INHIBITION OF NF-κB ACTIVITY ENHANCED CYTOSINE ARABINOSIDE INDUCED APOPTOSIS IN LEUKEMIC CELL LINE HL60-N

Objective: To explore the effects of dexamethasone (DXM) and vincristine (VCR) on cytosine arabinoside (Ara-C) induced apoptosis and activation of nuclear factor-k-gene binding (NF-kB) in leukemic cell line HL60-n. Methods: Apoptosis of HL60-n cells was analysed by TdT-mediated X-dUTP nick and end labeling (TUNEL) and DNA electrophoresis. NF-kB activity of HL60-n cells was detected by electrophoretic mobility shift assay (EMSA). Results: There was slight activation of NF-kB in HL60-n cells without drug induction. Ara-C at 1 mmol/L significantly enhanced the activation of NF-kB in HL60-n cells. The level of NF-kB activation induced by DXM at 1 mmol/L or VCR at 0.1 mmol/L had no significant difference compared with that of the control group. However, in HL60-n cells pre-treated with 1 mmol/L of DXM or 0.1 mmol/L of VCR, the activation of NF-kB induced by 1 mmol/L of Ara-C was significantly suppressed with inhibition rates of 31.0% and 47.0%, respectively. The apoptosis rates of HL60-n cells induced by 1.0 mmol/L, 10 mmol/L and 100 mmot/L Ara-C were 45.003.16%, 61.883.40% and 77.624.75%, respectively. The apoptotic rates of HL60-n cells induced by DXM at 1 mmol/L or VCR at 0.1 mmol/L were similar to that of the control group. However, either DXM at 1 mmol/L or VCR at 0.l mmol/L could enhance the apoptosis of HL60-n cells induced by Ara-C at 1 mmol/L with rates of 39.1% and 59.2%, respectively. Conclusion: Ara-C can induce apoptosis and activation of NF-kB in HL60-n cells. The mechanism of increased apoptosis of HL60-n cells by DXM or VCR may be related to suppression of NF-kB activation.

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.

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.

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. .

Clinical Observation of FMD Regimen:Fludarabine,Mitoxantrone,Dexamethasone,in Treatment of Non-Hodgkin's Lymphoma

OBJECTIVE To evaluate the clinical effectivity and toxicity of the regimen FMD （fludarabine, mitoxantrone, dexamethasone） in patients with non-Hodgkin＇s lymphoma. METHODS Thirty-two patients, twenty-four of whom had indolent B-cell lymphoma, 6 peripheral T-cell lymphoma, two diffuse large B-cell lymphoma, received FMD. Treatment comprised： fludarabine 25-30 mg/m^2 days 1-3, mitoxantrone 8-10 mg/m^2 day 1, and dexamethasone 20-30 mg/m^2 days 1-5. At the same time, patients received prophylaxis against conditional infection with trimethoprim-sulfamethoxazole, fluconazole, acyclovir and immunoglobulin. RESULTS Of the thirty-two patients treated, the complete response （CR） rate, partial response （PR） rate and overall response （OR） rate were 56.3%, 21.9% and 78.2% respectively. The CR and OR rate of 24 patients with indolent B-cell lymphoma were 66.7% and 88.3% respectively. Two of six patients with peripheral T-cell lymphoma were of complete response type and one was of partial response type. One of two patients with diffuse large B-cell lymphoma was partial response. The dominating toxicity was myelotoxicity and immunotoxicity. There was no treatment associated death in all patients treated with FMD. Grade 3-4 neutropenia occurred in 43.8% patients, 12.5% patients had infections and 9.3% developed grade 3-4 thrombocytopenia. At a median follow-up of 24 （5-54） months, the 2-year overall-survival rate and progression-free survival rate were （87.5 ± 1.4）% and （83.3 ± 1.6）% respectively. The 2-year OS and PFS rates of the indolent group were （93.75 ± 6.25）% and （87.5 ± 8.54）%. CONCLUSION FMD regimen was highly effective with low toxicity in the treatment of non-Hodgkin＇s lymphoma, especially in indolent B-cell lymphoma. It also helps to improve the prognosis even in some aggressive lymphoma, such as peripheral T cell lymphoma.

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.

New Octadecanoyl Diterpenoid Arabinoside from Conyza blinii

A new octadecanoyl diterpenoid glycoside,（E）-8α,15-dihydroxy-15-（3S-hydroxy-octadecanoyl）-13-labdene-8-O-α-L-arabinopyranoside（1）,was isolated from the aerial parts of Conyza blinii,and the structure was identified on the basis of a detailed spectroscopic analysis,including 2D NMR spectrometry and HRESI-MS.

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.

C_(19)-Diterpenoid alkaloid arabinosides from an aqueous extract of the lateral root of Aconitum carmichaelii and their analgesic activities

Eight new C_(19)-diterpenoid alkaloid arabinosides, named aconicarmichosides E–L(1–8), were isolated from an aqueous extract of the lateral roots of Aconitum carmichaelii(Fu Zi). Their structures were determined by spectroscopic and chemical methods including 2D NMR experiments and acid hydrolysis. Compounds 1–8, together with the previously reported four neoline 14-O-arabinosides from the same plant, represent the only examples of glycosidic diterpenoid alkaloids so far. At a dose of 1.0 mg/kg(i.p.), as compared with the black control, compounds 1, 2, and 4–6 exhibited analgesic effects with 465.6% inhibitions against acetic acid-induced writhing of mice. Structure–activity relationship was also discussed.