Efficacy and safety of mitoxantrone hydrochloride liposome injection in treatment of peripheral T-cell lymphomas: a multicenter, non-interventional, ambispective cohort, real-world study (MOMENT) / 白血病·淋巴瘤

Objective:To evaluate the efficacy and safety of mitoxantrone hydrochloride liposome injection in the treatment of peripheral T-cell lymphoma (PTCL) in a real-world setting.Methods:This was a real-world ambispective cohort study (MOMENT study) (Chinese clinical trial registry number: ChiCTR2200062067). Clinical data were collected from 198 patients who received mitoxantrone hydrochloride liposome injection as monotherapy or combination therapy at 37 hospitals from January 2022 to January 2023, including 166 patients in the retrospective cohort and 32 patients in the prospective cohort; 10 patients in the treatment-na?ve group and 188 patients in the relapsed/refractory group. Clinical characteristics, efficacy and adverse events were summarized, and the overall survival (OS) and progression-free survival (PFS) were analyzed.Results:All 198 patients were treated with mitoxantrone hydrochloride liposome injection for a median of 3 cycles (range 1-7 cycles); 28 cases were treated with mitoxantrone hydrochloride liposome injection as monotherapy, and 170 cases were treated with the combination regimen. Among 188 relapsed/refractory patients, 45 cases (23.9%) were in complete remission (CR), 82 cases (43.6%) were in partial remission (PR), and 28 cases (14.9%) were in disease stabilization (SD), and 33 cases (17.6%) were in disease progression (PD), with an objective remission rate (ORR) of 67.6% (127/188). Among 10 treatment-na?ve patients, 4 cases (40.0%) were in CR, 5 cases (50.0%) were in PR, and 1 case (10.0%) was in PD, with an ORR of 90.0% (9/10). The median follow-up time was 2.9 months (95% CI 2.4-3.7 months), and the median PFS and OS of patients in relapsed/refractory and treatment-na?ve groups were not reached. In relapsed/refractory patients, the difference in ORR between patients with different number of treatment lines of mitoxantrone hydrochloride liposome injection [ORR of the second-line, the third-line and ≥the forth-line treatment was 74.4% (67/90), 73.9% (34/46) and 50.0% (26/52)] was statistically significant ( P = 0.008). Of the 198 PTCL patients, 182 cases (91.9%) experienced at least 1 time of treatment-related adverse events, and the incidence rate of ≥grade 3 adverse events was 66.7% (132/198), which was mainly characterized by hematologic adverse events. The ≥ grade 3 hematologic adverse events mainly included decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, and anemia; non-hematologic adverse events were mostly grade 1-2, mainly including pigmentation disorders and upper respiratory tract infection. Conclusions:The use of mitoxantrone hydrochloride liposome injection-containing regimen in the treatment of PTCL has definite efficacy and is well tolerated, and it is a new therapeutic option for PTCL patients.

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.

G-quadruplex forming region within WT1 promoter is selectively targeted by daunorubicin and mitoxantrone: A possible mechanism for anti-leukemic effect of drugs

Wilms tumor 1 (WT1) has long been overexpressed in acute myeloid leukemia and has a prognostic value in its diagnosis.Lately, the formation of G-quadruplexes in oncogenic promoters like WT1 has been widely investigated since stabilizationof these structures leads to transcriptional inhibition of the oncogene. Daunorubicin and mitoxantrone considered as crucialcomponents of almost all standard acute myeloid leukemia induction regimens. Herein we have proposed a probablemolecular mechanism of action through which the drugs may stabilize WT1 promoter G-quadruplexes. Differential pulsevoltammetry, circular dichroism, and polyacrylamide gel electrophoresis, electrophoretic mobility shifts assay, polymerasechain reaction (PCR) stop assays, and quantitative RT-PCR were performed in order to better understanding the nature ofinteractions between the drugs and G-quadruplexes. Data revealed that both drugs had potential to stabilize G-quadruplexesand down-regulate WT1 transcription but daunorubicin exposed more silencing impact. The results illustrated the therapeutic association of these two commercial FDA-approved drugs in WT1 transcriptional down-regulation. Since WT1 hasknown as a transcriptional regulator of at least 137 target genes, so the new data are significant for the development of newapproaches to regulating WT1 and other target genes by employing special drugs in cancer treatment.

Synthesis and Quality Evaluation of Mitoxantrone / 中国药房

OBJECTIVE： To synthetize the synthesis of mitoxantrone and evaluate its quality. METHODS： Crude product of mitoxantrone was prepared by slow oxidation of 1，4，5，8-tetrahydro-anthraquinone with N-（2-hydroxyethyl） ethylenediamine in water bath at 50 ℃ for 2 h under argon protection and in dry air for 4 h. The crude product was crystallized by ethanol-n-hexane  （4 ∶ 1，V/V） mixture solution， which was cooled overnight and then washed by ethanol-n-hexane mixture for many times. The melting range， pH value of solution， ultraviolet-visible absorption spectrum， infrared structural characteristics， drying weight loss （water loss rate） and critical relative humidity （CRH） of the purified products （4 batches） were investigated. HPLC method was used to determine the contents of mitoxantrone. RESULTS： The mitoxantrone was prepared successfully， and synthetic yield of mitoxantrone was 34.3％； the melting point ranged from 159.1-163.6 ℃. The aqueous solution was alkaline （pH 7.63-9.54）； there was a maximum ultraviolet absorption peak at 235-245 nm； there was a maximum absorption peak of visible light at 590-600 nm； the infrared characteristics were consistent with those described of mitoxantrone in the 2015 edition of the Infrared Spectrum Collection of Drugs； water loss rate were －0.83％-2.36％； CRH value was 54.7％， and the average content of the product was 78.1％（n＝4） by HPLC method. CONCLUSIONS： The mitoxantrone is synthesized under mild， non-toxic and harmless experiment conditions. The synthesis step is simple， the cost is low and the yield is high. The quality of products meets the quality requirements.

Blood Concentration Determination and Pharmacokinetic Study of Mitoxantrone in Rats / 中国药房

OBJECTIVE： To extablish the method for blood concentration determination of mitoxantrone in rats， and to study the pharamokinetics of mitoxantrone in rats. METHODS： Totally 6 SD rats were collected and given mitoxantrone 5 mg/kg via tail vein. The blood samples 0.3 mL were collected before medication and 5， 10， 20， 40， 60， 120， 240， 480， 720 min after medication. Blood samples were placed in heparinized EP tube， and the plasma was centrifuged and separated. After adding silica gel， the plasma were ground and mixed well， then added into methanol solution containing 0.5 mol/L hydrochloric acid to precipitate protein. After grinding and mixing， the supernatant was centrifuged and dried with nitrogen and then dissolved with mobile phase. HPLC method was adopted to determine the plasma concentration of mitoxantrone. The determination was performed on ZORBAX SB-C18 column with mobile phase consisted of 20 mmol/L ammonium acetate （pH adjusted to 2.0 with hydrochloric acid）-methanol （65 ∶ 35， V/V） at the flow rate of 1.0 mL/min. The detection wavelength was set at 244 nm， and column temperature was 30 ℃. The sample size was 20 μL. Pharmacokinetic parameters were calculated with DAS 3.0 software. RESULTS： The linear range of mitoxantrone were 200-10 000 μg/L （r＝0.999 6， n＝6）. The lower limit of quantitation was 200   μg/L， and the limit of detection was 150 μg/L， respectively. RSDs of intra-day and inter-day precision and stability were all lower than 8.0％ （n＝5， 3， 6， respectively）. The extraction recoveries were （85.64±3.93）％-（92.31±1.68）％ （n＝3）. The recoveries of accuracy test were （93.58±1.42）％-（113.92±2.74）％ （n＝3）. The pharmacokinetic parameters of mitoxantrone were as follows as AUC0-720 min was （5 247.1±474.6.0） μg·h/L； t1 /2z was （24.88±6.94） h； CLZ was （0.46±0.09） L/（h·kg）； Vz was （11.07±2.64） L/kg. CONCLUSIONS： The method has recovery and good repeatability， and is suitable for the determination of blood concentration of mitoxantrone and its pharmacokinetic research.

Effect of baicalein on reversal of multidrug resistance in MCF-7/MX cells in vitro and its mechanisms / 中国药理学通报

Aim To investigate the effect of baicalein on the reversal of multidrug resistance ( MDR) media-ted by breast cancer resistance protein ( BCRP) in hu-man breast cancer MCF-7/MX cells, and explore the possible mechanisms. Methods MTT assay was per-formed to determine the cytotoxicity of baicalein and susceptibility of chemotherapeutic drugs. The protein expression levels of BCRP, p-p38 MAPK and NF-κB p65 were determined by Western blot. Results MCF-7/MX cells were not only resistant to MX but cross-re-sistant to 5-FU and DDP, and the resistance index was 70. 45, 6. 68 and 21. 47, respectively. 2. 5, 5μmol· L-1 of baicalein could increase the sensitivity to above chemotherapeutic agents and decrease the expression levels of BCRP, p-p38 MAPK and NF-κB p65 in MCF-7/MX cells. Conclusion Baicalein can effec-tively reverse MDR of MCF-7/MX by down-regulating BCRP expression through p38/MAPK and NF-κB path-ways.

The effect of mitoxantrone on prostate cancer and analysis of pain relief / 中国生化药物杂志

Objective To investigate the therapeutic effect of mitoxantrone on prostate cancer and the effect of relieving pain of patients.MethodsRetrospective analysis of clinical data of patients with bone pain in April 2010 to May 2016 year in our hospital for treatment of prostate cancer, according to their treatment divided into control group and observation group, the control group was 40 cases given docetaxel treatment, the observation group was 30 cases treated with mitoxantrone.Compared the pain relief, sleep quality, tumor markers and the incidence of adverse reactions of the two groups.ResultsAfter treatment, the observation group pain control rate was 96.67%, significantly higher than the control group, the difference was statistically significant (P<0.05);the observation group sleep quality was significantly better than the control group, the difference was statistically significant (P<0.05);the observation group cPSA and CEA were lower than those of control group, the difference was statistically significant (P<0.05).Two groups of patients with bone marrow suppression, nausea and vomiting, rash and liquid retention rate had no significant difference (χ2=0.648, P=0.421).ConclusionMitoxantrone has better therapeutic effect on prostate cancer, can significantly relieve the situation and quality of sleep in patients with bone pain.

Preparation and antitumor activity of mitoxantrone conjugated D-α-tocopherylpolyethylene glycol 1000 succinate prodrug micelle / 中国药科大学学报

@#To improve the theraputic effect of chemotherapeutic drugs, D-α-tocopheryl polyethylene glycol 1000 succinate(TPGS)was employed as a carrier of mitoxantrone(MTO). MTO was successfully conjugated to TPGS via succinic anhydride to prepare TPGS-MTO prodrug. The prodrug was then self-assembled into TPGS-MTO micelle, with the particle size of(25. 61±0. 92)nm, the polydispersity of 0. 22±0. 04 and the Zeta potential of -(3. 98±0. 09)mV. The micelle was homogeneous spheres under the observation of transmission electron microscope(TEM). The drug loading capacity(DLC)was(18. 61±0. 24)% by HPLC. Meanwhile, the particle size of TPGS-MTO micelle remained stable in 24 h. TPGS-MTO showed a controlled drug release profile with only 9. 04% MTO being detected in 24 h in neutral conditions, and faster release was achieved by decreasing pH in media. Cellular uptake experiments showed that micelle was 1. 18 times more effective than parent drug after 6 h incubation on MCF-7 cells. The cytotoxicity of micelle on MCF-7 and MCF-7/MDR cells was detected by MTT, both with anti-tumor activity, especially on MCF-7/MDR cells. In conclusion, TPGS-MTO prodrug micelle could be a potential formulation of higher therapeutic effects and fewer side-effects than MTO itself.

Cardiotoxicity of Mitoxantrone Treatment in a German Cohort of 639 Multiple Sclerosis Patients

BACKGROUND AND PURPOSE: The aim of this study was to elucidate the role of therapy-related cardiotoxicity in multiple sclerosis (MS) patients treated with mitoxantrone and to identify potential predictors for individual risk assessment. METHODS: Within a multicenter retrospective cohort design, cardiac side effects attributed to mitoxantrone were analyzed in 639 MS patients at 2 MS centers in Germany. Demographic, disease, treatment, and follow-up data were collected from hospital records. Patients regularly received cardiac monitoring during the treatment phase. RESULTS: None of the patients developed symptomatic congestive heart failure. However, the frequency of patients experiencing cardiac dysfunction of milder forms after mitoxantrone therapy was 4.1% (26 patients) among all patients. Analyses of the risk for cardiotoxicity revealed that cumulative dose exposure was the only statistically relevant risk factor associated with cardiac dysfunction. CONCLUSIONS: The number of patients developing subclinical cardiac dysfunction below the maximum recommended cumulative dose is higher than was initially assumed. Interestingly, a subgroup of patients was identified who experienced cardiac dysfunction shortly after initiation of mitoxantrone and who received a low cumulative dose. Therefore, each administration of mitoxantrone should include monitoring of cardiac function to enhance the treatment safety for patients and to allow for early detection of any side effects, especially in potential high-risk subgroups (as determined genetically).

Leucemia promielocítica aguda: Resultados del protocolo terapéutico LPA2000, Programa Nacional de Cáncer del Adulto (PANDA), Ministerio de Salud, Chile / Acute promyelocytic leukemia: Results of the Chilean protocol LPA2000

Background: The current recommendations for treatment of patients with newly diagnosed acute promyelocytic leukemia (APL) include all-trans-retinoic acid (ATRA) and anthracycline based chemotherapy. Aim: To evaluate the results of the Chilean protocol following the LPA99 regimen of the Spanish PETHEMA group, except for the replacement of Idarubicin by Daunorubicin. Patients and Methods: Induction consisted of Daunorubicin 45 mg/m² on days 2, 4, 6 and 8 plus ATRA 45 mg/m² daily until complete remission. Patients in complete remission (CR) received three monthly chemotherapy courses: Daunorubicin 45 mg/m²/d/4days i.v. and ATRA 45 mg/m²/d/15 days p.o. (course no. 1); Mitoxantrone 10 mg/m²/d/5 days i.v. and ATRA 45 mg/m²/d/15 days p.o. (course no. 2); Daunorubicin 60 mg/m²/d/ day 1 i.v. in the low risk group, and 1 and 2 in the intermediate-high risk groups and ATRA 45 mg/m²/d/15 days p.o. (course no. 3). Maintenance therapy consisted of mercaptopurine 90 mg/m²/d p.o., methotrexate 15 mg/m²/wk p.o. and, ATRA intermittently, 45 mg/m²/d p.o. for 15 days every three months. Results: Between January 2000 and December 2005, 56 patients with newly diagnosed APL from 10 centers were enrolled. A total of 46 patients achieved CR (85%), 8 (15%) died of early complications, seven patients relapsed, with a 16% relapse risk at three years. The 5-year Kaplan-Meier estimates of overall survival and relapse-free survival were 64% and 84% respectively. Conclusions: These data indicate that this protocol has a good antileukemic effect but further reduction of early death and relapse, especially in the high risk group is needed.

Preparation of mitoxantrone hydrochloride-loaded liposomes and investigation of pharmacodynamics and pharmacokinetics / 中国药学杂志

OBJECTIVE: To prepare mitoxantrone-loaded liposomes using copper ion gradient method and compare the pharmacodynamics (PD) and pharmacokinetics (PK) of liposomal mitoxantrone (Mit-lipo) with free mitoxantrone (Mit-free). METHODS: Orthogonal design was adopted to screen the preparation process and formulation of Mit-lipo, using encapsulation efficiency (EE) as the evaluation index. The antineoplastic effect of Mit-lipo was evaluated in L1210/BDF1 ascites tumor model. The PK study of Mit-lipo and Mit-free was performed in KM mice followed a single intravenous injection. RESULTS: The optimal preparation process and formulation were as follows; the weight proportion of mitoxantrone to HSPC was 1:10. Mit-lipo was prepared by copper ion gradient method using 0.3 mol · L-1 copper sulfate (pH 7.5) as the inner phase solution. The drug loading process was performed at 60°C for 30 min. The particle size of Mit-lipo was (99.5±1.9) nm, and the EE was (95.0±0.6)%. The PK study showed that the AUC and t1/2 values of Mit-lipo were higher than those of Mit-free in KM mice, suggesting Mit-lipo had a long circulation characteristic. The PD study showed that Mit-lipo could significantly prolong the survival time of tumor-bearing mice with lower toxicity than Mit-free. CONCLUSION: The developed preparation method for Mit-lipo has a high EE. The PK of Mit-lipo changes obviously compared to Mit-free, resulting in an increase of the therapeutic index.

Treatment of neuromyelitis optica: an evidence based review / Tratamento da neuromielite óptica: uma revisão baseada em evidências

Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system characterized by severe optic neuritis and transverse myelitis, usually with a relapsing course. Aquaporin-4 antibody is positive in a high percentage of NMO patients and it is directed against this water channel richly expressed on foot processes of astrocytes. Due to the severity of NMO attacks and the high risk for disability, treatment should be instituted as soon as the diagnosis is confirmed. There is increasing evidence that NMO patients respond differently from patients with multiple sclerosis (MS), and, therefore, treatments for MS may not be suitable for NMO. Acute NMO attacks usually are treated with high dose intravenous corticosteroid pulse and plasmapheresis. Maintenance therapy is also required to avoid further attacks and it is based on low-dose oral corticosteroids and non-specific immunosuppressant drugs, like azathioprine and mycophenolate mofetil. New therapy strategies using monoclonal antibodies like rituximab have been tested in NMO, with positive results in open label studies. However, there is no controlled randomized trial to confirm the safety and efficacy for the drugs currently used in NMO.

Neuromielite óptica (NMO) é uma doença inflamatória do sistema nervoso central caracterizada por grave neurite óptica e mielite transversa, com um curso usualmente recorrente. O anticorpo contra aquaporina-4 é positivo em grande porcentagem dos pacientes com NMO e se liga a este canal de água altamente expresso nos processos pediosos dos astrócitos. Devido à gravidade dos ataques de NMO e ao elevado risco de incapacidade, o tratamento deve ser instituído tão logo o diagnostico seja confirmado. Existem evidências crescentes de que pacientes com NMO respondem de forma diferente dos pacientes com esclerose múltipla (EM) e, portanto, os tratamentos utilizados na EM podem não ser adequados para NMO. Os quadros agudos de NMO são tratados com pulsos de corticosteroides em altas doses e plasmaférese. O tratamento de manutenção também deve ser instituído para evitar ataques subsequentes e é baseado em corticosteroides orais em baixas doses ou imunossupressores, como a azatioprina e o micofenolato mofetil. Novas estratégias de tratamento utilizando anticorpos monoclonais como rituximab têm sido avaliadas para NMO, com resultados positivos em estudos abertos. Entretanto, não existem estudos clínicos controlados, randomizados, para confirmar a segurança e eficácia dos tratamentos atualmente utilizados na NMO.

Efficacy and toxicity of mitoxantrone and oral etoposide in the treatment of hormone-refractory prostate cancer: pilot study / Eficácia e toxicidade da mitoxantrona e etoposídeo oral no tratamento de câncer de próstata hormônio-refratário: estudo piloto

Objective: To evaluate the efficacy and toxicity of the association of mitoxantrone and oral etoposide. Methods: Twelve consecutive patients with metastatic hormone-refractory prostate cancer were treated with mitoxantrone and oral etoposide. Toxicity, response rate and response duration were assessed. Results: Partial response was observed in two patients (response duration of seven and four months) and one patient had stable disease (during four months). Mitoxantrone and oral Etoposide were well tolerated and did not affect tolerability to subsequent chemotherapy. Conclusion: Mitoxantrone and oral etoposide association is an active and well-tolerated regimen in hormone-refractory prostate cancer.

Objetivo: Avaliar a eficácia e toxicidade da associação mitoxantrona e etoposídeo oral. Métodos: Doze pacientes consecutivos com câncer de próstata metastático e refratário a tratamento hormonal foram tratados com mitoxantrona e etoposídeo oral. Avaliaram-se toxicidade, taxa de resposta e duração de resposta. Resultados: resposta parcial foi observada em dois pacientes (com duração de sete e quatro meses) e um paciente teve estabilização da doença (por quatro meses). Mitoxantrona e etoposídeo oral foram bem tolerados e não afetaram tolerabilidade à quimioterapia subsequente. Conclusão: A associação mitoxantrona e etoposídeo oral é um tratamento ativo e bem tolerado por pacientes com câncer de próstata metastático refratário à hormonioterapia.

Enhancing cytotoxicity of Mitoxantrone on human breast cancer cell with microbubble contrast during low-frequency ultrasound exposure / 中国医学影像技术

Objective To investigate the antitumor effect and its mechanism of microbubble contrast combined with Mitoxantrone exposed to low-frequency ultrasound on human breast cancer cell MCF-7. Methods MTT method was applied to examine the growth inhibition of MCF-7 treated with Mitoxantrone. MCF-7 cells were randomly divided into 4 groups:Mitoxantrone group (group D), ultrasound+Mitoxantrone group (group U+D), ultrasound+microbuble +Mitoxantrone group (group U+M+D) and control group (group C). The cytoactive of each group was examined with MTT. The intracellular drug content in each group was measured with high performance liquid chromatography. The morphology of MCF-7 cells apoptosis was observed with transmission electron microscopy (TEM). Results The IC_(50) of Mitoxantrone was 2.87 μg/ml. The differences of cytoactive among all groups were significant (P<0.05). The intracellular drug content of group U+M+D was higher than that of group U+D, and the latter was higher than that of group D. The morphological changes of apoptosis were observed with TEM. Conclusion Low-frequency ultrasound can promote intracellular drug content as to enhance the sensitivity of chemotherapy drugs on tumor cells, and this effect can be enhanced by microbubble contrast exposure to low-frequency ultrasound.

Analysis of outcome and prognosis-related factors of MA regimen for acute myeloid leukemia / 白血病·淋巴瘤

Objective To analyze the outcome and prognosis-related factors of MA (mitoxantrone+cytarabine) regimen for acute myeloid leukemia(AML). Methods 102 untreated AML patients were treated with MA. All patients were divided into two groups according to age, blood white cell count(WBC), FrenchAmerican-British (FAB) morphology, level of lactate dehydrogenase (LDH) and immunophynotype respectively.Analyze the prognosis-related factors. Results The complete remission (CR), partial remission (PR), nonresponse (NR) rate, and remission rate (CR+PR) of all the 102 cases were 63.73 % (65/102), 17.65 % (18/102), 18.62 % (419/102)and 81.38 % (83/102) respectively. The patients younger than 60 years old, WBC＜100×109/L, LDH≤600 U/L, FAB-M2 morphology group had higher CR and remission rate. The CR rate of patients with CD7 positive had statistical difference from that of patients with CD7 negative (P ＜0.05), but the remission rate not. However, the CR and remission rate of patients with CD19 positive had no statistical difference from that of patients with CD19 negative (P ＞0.05). Conclusion These results suggest that use of MA regimen was effective and safe for AML. Age, WBC, FAB morphology, level of LDH and CD7 expression are prognosis-related factors for clinical outcome.

Mitoxantrone inhibits growth of melanoma by increasing expression of calreticulin / 中国肿瘤生物治疗杂志

Objective: To investigate the effect of mitoxantrone (MIT) on calreticulin (CRT) expression in B16 cells, and to observe the immune effect of B16-membrane antigen vaccine highly expressing CRT on B16 tumor-bearing mice. Methods: The expression of CRT on membrane of B16 cells was detected by immunofluorescence after treatment with different concentrations of MIT. B16-implanted mouse model was established, and the growth of B16-implanted tumors and CRT expression in B16-implanted tumor tissues were observed after treatment with different concentrations of MIT. Membrane antigen vaccines from both normal B16 cells and MIT-treated B16 cells were prepared, and mice were immunized before B16 cell implantation. The infiltration of immune cells into B16 tumor tissues and the ratios of CD4~+ and CD8~+ T cells in the spleen of B16 tumor-bearing mice were examined by immunohistochemistry and flow cytometry, respectively. Results: Flow cytometry results showed that MIT dose-dependently increased CRT expression on B16 cell membrane, with CRT expression in control and high dosage MIT groups being (29.40±3.57)% and (72.20±2.94)% (P<0.05), respectively. MIT also increased CRT expression in B16 tumor tissues, with those in the control and high dosage MIT groups being 3.21±1.37 and 9.17±1.06 (P<0.05), respectively. MIT effectively inhibited the growth of B16 tumors (P<0.05). Compared with normal B16 cell membrane antigen vaccine, the vaccine highly expressing CRT increased the numbers of DCs and T cells in B16 tumors tissues and the ratios of CD4~+ and CD8(+) T cells in the spleen (P<0.05). Conclusion: MIT can increase CRT expression on membrane of B16 cells. B16-membrane antigen vaccine highly expressing CRT can enhance the infiltration of DCs and T cells in melanoma, thus improving the immune effect of B16-membrane antigen vaccine.

Cellular uptake study of CAP/GPC-MPEG nanoparticle in breast cancer cells / 中国癌症杂志

Background and purpose:A pressing obstacle in clinical chemotherapy is drug resistance in breast cancer.A nano-delivery system,which has many advantages as a drug carrier,such as carrying anticancer drugs,can be used effectively to overcome drug resistance in tumors.This paper examined a new nano-delivery system,called calcium phosphate and glycerophosphocholine-mPEG(CAP/GPC-MPEG)composite nanoparticle and its influence on the cellular drug uptake of BCRP-over expressing mitoxantrone(MIT)-resistant breast cancer cell MCF-7/MIT.This paper will also examine its effect on overcoming drug resistance in the MCF-7/MIT cells.Methods:After the calcium phosphate and GPC-mPEG composite nanoparticles were designed and prepared,the entrapment efficiency and in vitro drug release of mitoxantrone-loaded nanoparticles were investigated.Quantitative comparisons were made between cellular uptake of drug-loaded nanoparticles and free drugs.Finally,a confocal laser scanning microscopy Was used to compare the subcellular distribution of drug-loaded nanoparticles and the free drugs.Results:Calcium phosphate and GPC-mPEG composite nanoparticles were nanoporous spherical particles with diameters between 50-100 mn.The MIT-loaded nanoparticles have an entrapment efficiency of(89.45±0.05)%.Although the drug-loaded nanoparticles showed an initial burst of drug release,it was followed by a more sustained release.The concentration of mitoxantrone was 1.89 times treated with MIT-loaded nanoparticles for 1 h compared to that treated with free mitoxantrone for 1 h in MCF-7/MIT cells.and which was 2.33 times in MCF-7 cells.Fluorescent red mitoxantrone appeared in the cytoplasm and nucleus of the MCF-7 and MCF-7,MIT cells treated with MlT-loaded nanoparticles whereas it is almost undetected in both cells treated with free mitoxantrone.Conclusion:Calcium phosphate and GPC-mPEG composite nanoparticles Can promote the cellular uptake and entering of mitoxantrone to the nucleus in MCF-7 and its corresponding BCRP-over expressing MIT-resistant MCF-7/MIT breast cancer cell lines.This nanoparticle is a potential nano-carrier for overcoming drug resistance in tumors.

Diverse effects of two kinds of PI3K inhibitors on drug-resistant human breast cancer MCF-7/MIT cells / 肿瘤

Objective:To investigate the reversing effect of phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002(LY) and wortmannin (Wort), on the drug resistance of mitoxantrone (MIT)-resistant human breast cancer MCF-7/MIT cells. Methods:Drug-resistant MCF-7/MIT cells were treated with LY or Wort combined with MIT. Cell viability and proliferation were measured using the MTT assay and morphological changes were recorded by microscopy. Intracellular accumulation of MIT in MCF-7/MIT cells was detected by flow cytometry. Mitochondrial membrane potential was determined by rhodamine 123 staining. Cell cycle was examined by propidium iodide staining. Results:LY significantly enhanced the cytotoxicity of MIT to MCF-7/MIT cells. In LY and MIT cotreated cells, the percentage of cells arrested at S and G2/M phases and the mitochondrial membrane potential decreased significantly compared with single LY- or MIT-treated cells. The mechanism was related with increased accumulation of MIT in MCF-7/MIT cells induced by LY. While Wort, another PI3K inhibitor, did not significantly enhance the cytotoxic effects of MIT.Conclusion: The PI3K inhibitor significantly enhances the sensitivity of MCF-7/MIT cells to MIT.

A Systematic Review of MA versus DA Regimen for Patients with Acute Myelogenous Leukemia / 医学研究杂志

Objective To assess the safety and efficacy of patients with acute myelogenous leukemia treated with mitoxantrone/arabinosylcytosin versus daunorubicin/arabinosylcytosin.Methods We searched Pubmed,Embase,the Cochrane Library,Chinese biomedicine literature database,Chinese Scientific Journals full-text database,and Chinese Journal full-text database for randomized controlled trials comparing MA regimen with DA regimen.We manually searched key Chinese magazines of related fields.The quality of included studies was evaluated and graded according to Cochrane Reviewer's Handbook.Results Nine randomized controlled trials totaling 608 patients were included.Meta-analysis results were as follows:There was significant difference between MA regimen and DA regimen in total complete remission rate [RR=1.24,95%CI(1.10,1.40)]and effective rate[RR =1.22,95%CI(1.09,1.36)] after the second course of treatment.There was significant difference between MA regimen and DA regimen in heart toxicity incidence [RR=0.54,95%CI(0.29,0.99)],infection incidence [RR=1.56,95%CI(1.29,1.94)],agranulocytosis time [RR=2.70,95%CI(2.09,3.31)].There was no significant difference in nausea and vomitting [RR=0.96,95%CI(0.87,1.07)].Conclusion Current clinical studies might confirm that MA regimen is superior to DA regimen in complete remission rate and effective rate in treating the patient with initial treatment acute myelogenous leukemia.Fewer patients receiving MA regimen experienced heart toxicity incidence compared with patients receiving DA regimen,but more experienced infection and agranulocytosis.They still need to be confirmed by large sample,high quality randomized controlled trials.

Preparation of LEM-GM-CSF and its inhibition effect on HL60/ADM cells in vitro / 第三军医大学学报

Objective To prepare liposome-entrapped mitoxantrone (LEM)-GM-CSF and observe the cytotoxicity of HL-60/ADM cells treated with LEM-GM-CSF, LEM and dihydroxyanthraquinone (DHAQ) in vitro. Methods LEM was prepared by reverse phase evaporation (REV). High speed centrifugation was applied to separate LEM and dissociate DHAQ. Colorimetry was employed to determine encapsulation efficiency. The liposome structure and particle size were determined by transmission electron microscopy. GM-CSF was coupled to LEM by glutaraldehyde method. UV-spectrophotometric analysis was applied to measure the coupled efficiency. Flow cytometry was applied to determine the immunoconjugate retained efficiency. The cytotoxicity of HL60/ADM cells and interdiction efficiency of GM-CSF were investigated by MTT test. Results The encapsulation efficiency of LEM was 80%. Most liposomes were monolayer, and the particle size was 170-220 nm. Its coupled efficiency with GM-CSF was 42.3%, and the immunoconjugate retained efficiency was 74.6%. All LEM-GM-CSF, LEM and DHAQ had cytotoxicity on HL60/ADM, their cytotoxic power in decrement sequence: LEM-GM-CSF, LEM, DHAQ. After treated with LEM-GM-CSF, LEM and DHAQ for 24 h, the IC50 of HL-60/ADM was 8.73, 12.42, 27.31 ?g/ml respectively and for 48 h the IC50 were 0.62, 8.25, 12.44 ?g/ml. The inhibition rate increased in a dose-dependent manner. Conclusion The encapsulation efficiency, the coupled efficiency and the immunoconjugate retained efficiency of LEM-GM-CSF prepared by our method were satisfying. LEM-GM-CSF representing anti-leukaemia efficiency in vitro had cytotoxicity on HL60/ADM cells.