OBJECTIVE: To investigate the complications and clinical outcome of children with acute myeloid leukemia (AML) undergoing mitoxantrone-cytarabine-etoposide (MAE) induction therapy. METHODS: A total of 170 children with AML were given MAE induction therapy, and the complications and remission rate were analyzed after treatment. RESULTS: The male/female ratio was 1.33:1 and the mean age was 7.4 years (range 1-15 years). Leukocyte count at diagnosis was 29.52×10/L [range (0.77-351)×10/L]. Of all children, 2 had M0-AML, 24 had M2-AML, 2 had M4-AML, 48 had M5-AML, 3 had M6-AML, 7 had M7-AML, 69 had AML with t(8;21)(q22;q22), and 15 had AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22). The most common complication was infection (158/170, 92.9%). Among these 158 patients, 22 (13.9%) had agranulocytosis with pyrexia (with no definite focus of infection), and 136 (86.1%) had definite focus of infection (including bloodstream infection). Other complications included non-infectious diarrhea, bleeding, and drug-induced hepatitis. Treatment-related mortality was observed in 10 children, among whom 8 had severe infection, 1 had multiple organ failure, and 1 had respiratory failure. Remission rate was evaluated for 156 children and the results showed a complete remission rate of 85.3%, a partial remission rate of 4.5%, and a non-remission rate of 10.3%. CONCLUSIONS Induction therapy with the MAE regimen helps to achieve a good remission rate in children with AML after one course of treatment. Infection is the main complication and a major cause of treatment-related mortality.
Adolescent ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Child ; Child, Preschool ; Cytarabine ; Drug Administration Schedule ; Etoposide ; Female ; Humans ; Infant ; Leukemia, Myeloid, Acute ; drug therapy ; Male ; Mitoxantrone ; Remission Induction

OBJECTIVETo investigate the efficacy and safety of MA (mitoxantrone and cytarabine) regimen chemotherapy combined with granulocyte-colony stimulating factor (G-CSF)-mobilized family related HLA-haploidentical donor peripheral blood hematopoietic stem cell (G-PBHSC) infusion for the treatment of acute myeloid leukemia (AML) patients aged over 80 years.

METHODSFour elderly patients with AML were treated in Chinese Second Artillery General Hospital from August 2008 to September 2013. The proportion of male to female was 1 : 3 and the median age 83 (80-85) years. All patients received programmed infusions of G-PBHSC after MA regimen chemotherapy without graft-versus-host disease (GVHD) prophylaxis. After complete remission (CR), patients only received G-PBHSC infusion without chemotherapy.

RESULTSThree cases achieved CR and their disease free survival (DFS) time was 18, 8, 6 months, respectively. 1 case did not reach remission after 2 cycles chemotherapy. The median overall survival (OS) time was 10 (3-20) months. No GVHD was observed in any of the patients during treatment. Concludsion: The combination of chemotherapy and programmed haploidentical G-PBHSC infusion is an alternative approach for AML patients aged over 80 years.

Aged, 80 and over ; Combined Modality Therapy ; Cytarabine ; Disease-Free Survival ; Female ; Graft vs Host Disease ; Granulocyte Colony-Stimulating Factor ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells ; Humans ; Leukemia, Myeloid, Acute ; Male ; Mitoxantrone ; Remission Induction

OBJECTIVE: To study the effect of MDR1 (P-gp) and ABCG2 on the drug resistance in Hep 2 cells. METHOD: Flow cytometry was used to detect the variations of the antitumor drugs accumulation and discharging, and activity variations when MDR1 and ABCG2 inhibitors were used in Hep-2. RESULT: The accumulation and discharging of mitoxantrone was significantly higher than the control group when ABCG2 inhibitor FTC was used in Hep-2 (P<0. 05). In contrast, P-gp did not appear similar case; To the mitoxantrone and cisplatin, there was no statistical correlation about activity of Hep-2 between P-gp or ABCG2 antagonist and the control; To the doxorubicin, combining FTC and P-gp, the activity of Hep-2 was higher than the control and difference was significant (P<. 05), In contrast, FTC and P-gp did not appear similar case when used alone; To the 5-FU, when PGP used, the activity of Hep-2 was higher than that in the control and difference was significant (P<0. 05), In con- trast, FTC and FTC+P-gp did not appear similar case; To the paclitaxel, when P-gp or FTC+P-gp used, the activity of Hep-2 was higher than that in the control and difference was significant(P<0. 05). CONCLUSION ABCG2 may lead to drug resistance mainly by changing the ability of cell in accumulating and discharging chemotherapy drugs. P-gp has other way. P-gp and ABCG2 play different roles in different drug resistance.
ATP Binding Cassette Transporter, Subfamily B ; metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters ; metabolism ; Cell Line, Tumor ; Cisplatin ; pharmacology ; Doxorubicin ; pharmacology ; Drug Resistance, Neoplasm ; Humans ; Mitoxantrone ; pharmacology ; Neoplasm Proteins ; metabolism ; Paclitaxel ; pharmacology

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).
Cohort Studies* ; Follow-Up Studies ; Germany ; Heart Failure ; Hospital Records ; Humans ; Mitoxantrone* ; Multiple Sclerosis* ; Retrospective Studies ; Risk Assessment ; Risk Factors

To investigate whether accelerated blood clearance (ABC) phenomenon could be induced after repeated injection of mitoxantrone thermosensitive liposomes, LC-MS/MS and enzyme linked immunosorbent assay (ELISA) were used to measure the concentration of mitoxantrone and the anti-polyethylene glycol (PEG) IgM levels in rat plasma, separately. The drug was rapidly cleared away after the second administration. The anti-PEG IgM was detected after the first dose which was neutralized quickly after the second dose. It is proved that repeated administration of mitoxantrone thermosensitive liposomes in rat caused the ABC phenomenon.
Animals ; Antineoplastic Agents ; administration & dosage ; blood ; pharmacokinetics ; Chromatography, High Pressure Liquid ; Immunoglobulin M ; blood ; Liposomes ; administration & dosage ; blood ; pharmacokinetics ; Male ; Metabolic Clearance Rate ; Mitoxantrone ; administration & dosage ; blood ; pharmacokinetics ; Polyethylene Glycols ; administration & dosage ; chemistry ; pharmacokinetics ; Rats ; Rats, Wistar ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry

This study was aimed to investigate the effects of mitoxantrone on proliferation and apoptosis of human multiple myeloma cell line RPMI-8226 and its mechanism. The inhibitory rate of RPMI8226 cells proliferation was assayed by MTT, the morphological changes of RPMI-8226 cells were observed by inverted flurescent microscopy and transmission electron microscopy, the apoptosis rate and the cell cycle distribution of RPMI-8226 cells were detected by flow cytometry. The effects of mitoxantrone on the expression of BCL-2, BAX, caspase-3 mRNA were detected by RT-PCR, the BCL-2, BAX, caspase-3 protein expression of RPMI-8226 cells was analyzed by Western blot. The results showed that mitoxantrone could inhibit the proliferation of RPMI-8226 cells in time- and dose-dependent manners. Light microscopy showed that the cell number in mitoxantrone group was significantly less than that in control group and the cell growth arrangement was irregular, apoptotic cells could be seen. Under electron microscope, typical apoptotic morphological and ultrastructural changes could be observed, these results confirmed that the mitoxantrone could induce apoptosis of RPMI-8226 cells, the difference have statistical significance (P < 0.05). The 1.0 µg/ml low concentration of mitoxantrone mainly arrested RPMI-8226 cells in the G2/M phase(P < 0.05), and the 2.0 µg/ml high concentration of mitoxantrone mainly arrested RPMI-8226 cells in the S phase (P < 0.05). The expression of BCL-2 mRNA decreased (P < 0.05),while the expression of BAX, caspase-3 mRNA increased (P < 0.05). Western blot indicated that BCL-2 protein expression also decreased (P < 0.05) and BAX, caspase-3 protein expression increased. It is concluded that the mitoxantrone can inhibit the proliferation of RPMI-8226 cells by inducing cell apoptosis. Activation of the mitochondrial and death receptor pathways of apoptosis may be involved in the mitoxantrone-induced apoptosis, the cell cycle arrest may also play an important role in the apoptosis mechanism.
Apoptosis ; drug effects ; Caspase 3 ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Humans ; Mitoxantrone ; pharmacology ; Multiple Myeloma ; pathology ; Proto-Oncogene Proteins c-bcl-2

S1-M1-80 cells, derived from human colon carcinoma S1 cells, are mitoxantrone-selected ABCG2-overexpressing cells and are widely used in in vitro studies of multidrug resistance(MDR). In this study, S1-M1-80 cell xenografts were established to investigate whether the MDR phenotype and cell biological properties were maintained in vivo. Our results showed that the proliferation, cell cycle, and ABCG2 expression level in S1-M1-80 cells were similar to those in cells isolated from S1-M1-80 cell xenografts (named xS1-M1-80 cells). Consistently, xS1-M1-80 cells exhibited high levels of resistance to ABCG2 substrates such as mitoxantrone and topotecan, but remained sensitive to the non-ABCG2 substrate cisplatin. Furthermore, the specific ABCG2 inhibitor Ko143 potently sensitized xS1-M1-80 cells to mitoxantrone and topotecan. These results suggest that S1-M1-80 cell xenografts in nude mice retain their original cytological characteristics at 9 weeks. Thus, this model could serve as a good system for further investigation of ABCG2-mediated MDR.
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; antagonists & inhibitors ; metabolism ; Adenosine ; analogs & derivatives ; pharmacology ; Animals ; Antineoplastic Agents ; pharmacology ; Cell Cycle ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; drug effects ; Cisplatin ; pharmacology ; Colonic Neoplasms ; metabolism ; pathology ; Diketopiperazines ; Doxorubicin ; metabolism ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Female ; Heterocyclic Compounds, 4 or More Rings ; Humans ; Inhibitory Concentration 50 ; KB Cells ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitoxantrone ; pharmacology ; Neoplasm Proteins ; antagonists & inhibitors ; metabolism ; Neoplasm Transplantation ; Rhodamine 123 ; metabolism ; Topotecan ; pharmacology

To establish a pig kidney cell line LLC-PK1/BCRP in which human breast cancer resistance protein was highly expressed, the expression vector pcDNA3.1(+)-BCRP which contained BCRP gene was constructed and transfected into LLC-PKI cells via liposomes. After selecting with G418, population doubling time, flow cytometry and Western blotting analysis were used to evaluate the cell line. MTT assays were employed to determine the drug resistance index of mitoxantrone and doxorubicin. Invert fluorescent microscope was used to observe the efflux of fluorescence dye Hoechst 33342 by BCRP, furthermore, the BCRP's inhibitor GF120918 was applied to reverse the efflux of Hoechst 33342. The experiment results showed that the expression of BCRP protein increased in LLC-PK1/BCRP cell. The population doubling time of LLC-PK1/BCRP cell was a little longer than that of the parental cell LLC-PK1. The resistance indexes to mitoxantrone and doxorubicin were 51.95 and 6.09 times, respectively, higher than LLC-PK1 cell. The efflux of Hoechst 33342 was significantly enhanced and could be reversed by GF120918. So a LLC-PK1/BCRP cell line was established, which highly expressed BCRP protein successfully. This cell line could be a valuable model to further investigate the biological profile of BCRP and select the substrate and inhibitor of BCRP.
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; genetics ; metabolism ; Acridines ; pharmacology ; Animals ; Benzimidazoles ; metabolism ; Cell Cycle ; Cell Proliferation ; Doxorubicin ; pharmacology ; Drug Resistance, Multiple ; Genetic Vectors ; LLC-PK1 Cells ; cytology ; metabolism ; Mitoxantrone ; pharmacology ; Neoplasm Proteins ; genetics ; metabolism ; Plasmids ; Swine ; Tetrahydroisoquinolines ; pharmacology ; Transfection

OBJECTIVETo compare docetaxel plus prednisone with mitoxantrone plus prednisone as first-line chemotherapy for metastatic hormone-refractory prostate cancer (mHRPC).

METHODSFrom January 2007 through August 2010, 62 patients with mHRPC received 5 mg of prednisone twice daily were randomly assigned to receive mitoxantrone 12 mg/m² every three weeks (group A) or 75 mg/m² every three weeks (group B). The cycles of each regimen were less than 10 times. The primary end point was overall survival. The secondary end points were the prostate-specific antigen (PSA) response rate, the duration of PSA response and the objective tumor response rate (ORR). All the t test, χ² test and Fisher's exact test were performed between 2 groups.

RESULTSThirty-one patients enrolled in group A received a median 4 cycles of regimen (range 1 - 10), whereas 30 patients enrolled in group B received a median of 7 cycles of regimen (range 2 - 10). There were 45.2% patients in group A and 70.0% in group B had PSA response (χ² = 3.85, P < 0.05). The duration time of PSA response was 121 days (range 20-323 days) in group A and 168 days (range 42 - 447 days) in group B, respectively. The ORR was 15.0(3/20) in group A and 10.3% (3/29) in group B, respectively. The median survival was 511 days (95%CI: 357 - 665 days) in group A and 833 days (95%CI: 634 - 1032 days) in group B, respectively (χ² = 4.20, P = 0.040). The incidence of thrombocytopenia in group A was higher than group B (χ² = 5.60, P = 0.018); the incidences of nausea and vomiting (χ² = 4.32, P = 0.038), diarrhea (P = 0.024), fatigue (χ² = 5.90, P = 0.015), and alopecia (χ² = 5.42, P = 0.020) in group B were higher than group A.

CONCLUSIONDocetaxel plus prednisone can lead to superior overall survival and PSA response rate in patients with mHRPC.

Aged ; Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; therapeutic use ; Humans ; Male ; Middle Aged ; Mitoxantrone ; administration & dosage ; Neoplasm Metastasis ; Prednisone ; administration & dosage ; Prospective Studies ; Prostatic Neoplasms, Castration-Resistant ; drug therapy ; secondary ; Taxoids ; administration & dosage ; Treatment Outcome

PURPOSE: The aim of this retrospective study was to identify the reliable long term prognostic factors in patients with stage II/III breast cancer who were treated with an adjuvant extension of neoadjuvant chemotherapy (NC). METHODS: Women under the age of 70-years, with previously untreated clinical stage II and III breast cancer, were treated with NC, which was comprised of three cycles of FEC (5-FU, epirubicin, and cyclophosphamide every 3 weeks) or MMM (methotrexate, mitoxantrone, and mitomycin-C every 3 weeks) with an adjuvant extension of three cycles of the same regimen. RESULTS: Cumulative 10-years disease-free survival (DFS) was 87.3% for patients with a good response and 55.5% for patients with no response (p=0.032); 92.9% for node negative patients, 75.0% for 1-3 positive nodes, 50.0% for 4-9 positive nodes and no survival for 10 or more positive nodes (p<0.001). Cumulative 10-years overall survival (OS) was 89.1% for patients with good response and 55.5% for patients with no response (p=0.024); 95.2% for node negative patients, 80.0% for 1-3 positive nodes, 50.0% for 4-9 positive nodes and no survival for 10 or more positive nodes (p<0.001). No significant difference was observed in DFS and OS between the FEC and MMM treated groups. CONCLUSION: Based on a review of data with a long follow-up, only the clinical response to NC and the absolute number of metastatic axillary lymph node identified at surgical staging were independent predictors of both DFS and OS in patients with stage II/III breast cancer patients treated with adjuvant extension of NC.
Breast ; Breast Neoplasms ; Cohort Studies ; Cyclophosphamide ; Disease-Free Survival ; Epirubicin ; Female ; Follow-Up Studies ; Humans ; Lymph Nodes ; Mitomycin ; Mitoxantrone ; Neoadjuvant Therapy ; Prognosis ; Retrospective Studies