Formulation Optimization and Cytotoxicity Study of GGPFV-modified Daunorubicin/dioscin Liposomes / 中国药房

OBJECTIVE：To prepare GGPFV-modified Daunorubicin/dioscin liposomes ，and to optimize their formulation and to preliminarily evaluate their cytotoxicity to breast cancer cells in vitro . METHODS ：Daunorubicin and diosgenin were wrapped by thin film dispersion method and ammonium sulfate hydration method ；the surface was modified with DSPE-PEG2000-GGPFV to prepare GGPFV-modified Daunorubicin/dioscin liposomes. Taking encapsulation rate as index ，Box-Behnken response surface methodology was used to optimize the film hydration volume ，cholesterol amount and daunorubicin amount in the formulation. The entrapment efficiency of 3 batches of liposomes prepared according to the optimal formulation was determined. The effects of Daunorubicin/dioscin liposomes ，GGPFV-modified Daunorubicin/dioscin liposomes and blank liposomes on the survival rate of human breast cancer MDA-MB- 435S cells were compared. RESULTS ：The optimal formulation was as film hydration volume of 5 mL，cholesterol of 4 mg，yolk lecithin of 22 mg，daunorubicin of 0.55 mg，dioscin of 0.85 mg，DSPE-PEG2000 of 3.5 mg， DSPE-PEG2000-GGPFV of 2 mg. The encapsulation rate of daunorubicin was （96.21±1.54）％ and that of dioscin was （95.39± 2.48）％ in the 3 batches of liposomes prepared. The in vitro cytotoxicity tests showed that the inhibition effect of GGPFV-modified Daunorubicin/dioscin liposome on MDA-MB-435S cells was significantly stronger than that of Daunorubicin/dioscin liposome （P＜ 0.05）. There was no cytotoxicity in the membrane. CONCLUSIONS ：GGPFV-modified Daunorubicin/dioscin liposomes are successfully prepared ，and its inhibitory effect on human breast cancer MDA-MB- 435S cells in vitro was significantly enhanced.

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.

Enhancing effect of chidamide on the sensibility of human chronic myeloid leukemia K562/ADM cells to daunorubicin / 解剖学报

Objective: To investigate whether chidamide (CDM) could influence the sensibility of human chronic myeloid leukemia K562/ADM cells to daunorubicin (DNR) and its possible mechanism. Methods: The K562 and K562/ADM cells were cultured in vitro and treated with CDM and(or) DNR for 48 hous, and then the cell viability was measured by cell counting kit-8(CCK-8) assay. The proliferation, cell cycle and apoptosis were analyzed by flow cytometry. Western blotting was performed to measure the protein levels of histon 2AX (H2AX), γH2AX (Serl39), ataxia telangiectasia mutated gene (ATM), p-ATM (Serl981), breast cancer susceptibility protein 1(BRCAl), and p-BRCAl (Serl524). Results: DNR remarkably inhibited the cell activity of K562/ADM cells in dose-dependent manner with a half maximal inhibitory concentration(IC50) value of 11.76 μmol/L, and the resistant factor was 18.09. Co-treatment with CMD and DNR produced a synergistic effect confidence interval(GI) (CI<1) with a reversal fold of 8.11. DNR remarkably inhibited proliferation (P<0.05), induced G2/M phase arrest and apoptosis (P<0.05), these effects were enhanced under non-toxic concentration of CMD (P<0.05). K562/ADM cells had a significantly higher protein levels of ATM and BRCA1 than K562 cells (P<0.05). DNR significantly up-regulated the protein levels of γH2AX, p-ATM and p-BRCAl (P<0.05), and the protein level of γH2AX appeared higher in the combination group compared to DNR alone (P<0.05); however, the co-treatment with CMD and DNR induced a decreased expression of p-ATM and p-BRCAl than the DNR alone (P< 0.05). Conclusion: CDM may enhance the sensibility of K562/ADM cells to DNR by up-regulating the protein level of γH2AX, and down-regulating the protein levels of p-ATM and p-BRCAl.

Simultaneous Determination of 6 Flavonoids in the Roots of Tetrastigma hemsleyanum by HPLC / 中国药房

OBJECTIVE： To establish a method for simultaneous determination of rutin， isoquercitrin， kaempferol-3-O- rutinoside， daunorubicin， quercetin and kaempferol in the roots of Tetrastigma hemsleyanum.  METHODS： HPLC method was adopted. The determination was performed on Alliance SilGreen C18 column with mobile phase consisted of 0.2％ phosphoric acid solution-acetonitrile solution （gradient elution） at the flow rate of 1.0 mL/min. The detection wavelength was 360 nm and the column temperature was at 35 ℃. The sample size was 15 μL. RESULTS： The linear range of rutin， isoquercitrin， kaempferol-3- O-rutinoside， daunorubicin， quercetin and kaempferol were 21.77-217.77， 12.37-123.75， 13.23-132.31， 4.63-46.30， 5.75-57.50， 3.36-33.66 μg/mL （all r＝0.999 9）， respectively. limit of detection of them were 0.217 8， 0.123 8， 0.066 2， 0.046 3， 0.191 7， 0.112 3 μg/mL， respectively. limit of quantitation of them were 0.435 6， 0.247 5， 0.165 4， 0.154 3， 0.575 0， 0.421 2 μg/mL， respectively. RSDs of precision （n＝6）， stability （24 h， n＝7） and reproducibility tests （n＝6） were lower than 3.20％. The average recoveries of them were 96.23％， 86.88％， 97.51％， 97.67％， 97.50％， 87.46％， RSDs were 1.85％， 1.90％， 1.84％， 1.87％， 1.25％， 2.01％ （n＝9）， respectively. CONCLUSIONS： The method is fast and simple， and could be applied for simultaneous determination of rutin， isoquercitrin， kaempferol-3-O-rutinoside， daunorubicin， quercetin and kaempferol in the roots of T. hemsleyanum.  

Effect of arsenic trioxide maintenance therapy on long - term recurrence rate in patients with acute promyelocytic leukemia / 中国基层医药

Objective To explore the effect of arsenic trioxide maintenance therapy on the long-term recur-rence rate in patients with acute promyelocytic leukemia ( APL ) . Methods From December 2011 to December 2013,60 patients with APL in the First People's Hospital of Huzhou were selected and divided into control group and observation group according to random number table, with 30 cases in each group. All patients received the same induction therapy and consolidation therapy. During the maintenance treatment period, all - trans retinoic acid ( ATRA) was given to the control group,and arsenic trioxide was used in the observation group. The serum levels and incidence of adverse reactions in the two groups were detected and compared after two cycles of the maintenance therapy. Three years of follow - up was conducted after treatment to record and compare the recurrence rate and survival rate in the two groups. Results The levels of TC and TG after 1 and 2 cycles of treatment were higher than those before treatment in both two groups(all P<0. 05),but the levels of lipid indicators in the observation group were lower than those in the control group,and the differences were statistically significant (t=2. 044,2. 175,all P<0. 05). The incidence rates of retinoic acid syndrome,elevated intracranial pressure and other adverse reactions in the observation group during the treatment were lower than those in the control group(6. 67％ vs. 26. 67％,6. 67％ vs. 30. 00％,6. 67％ vs. 26. 67％),and the differences were statistically significant(χ2 =0. 043,0. 023,0. 043,all P<0. 05). The survival rates after 2 and 3 years of treatment in the observation group were higher than those in the control group(90. 00％ vs. 66. 67％,83. 33％ vs. 60. 00％),and the differences were statistically significant(χ2 =4. 812,4. 812,all P<0. 05). The recurrence rate after 3 years of treatment in the observation group was lower than that in the control group(10. 00％ vs. 33. 33％),and the difference was statistically significant(χ2 =4. 812,P <0. 05). Conclusion For patients with APL, the application of arsenic trioxide in the maintenance therapy can produce no significant effect on their lipid metabolism, and at a certain extent, can help reduce the incidence of adverse reactions and recurrence rate,and improve the survival rate.

Preparation and Anti-Leukemia Efficacy of Daunorubicin-Loaded Microparticles / 中国药学杂志

OBJECTIVE: To construct a novel daunorubicin-loaded microparticles (DNR-MPs) drug delivery system, and study its proliferation inhibiton effect on leukemia cells. METHODS: Both DNR-MPs-IDL(DNR microparticles with intracellular drug loading method) and DNR-MPs-EDL (DNR microparticles with extracellular drug loading method) were prepared from HL-60 cells, and the average particle size, Zeta potential and drug loading efficiency of DNR-MPs were measured. The uptake of DNR-MPs by HL-60 cells was analyzed by confocal laser scanning microscopy (CLSM) and flow cytometry (FCM). The inhibition effect of DNR-MPs on the proliferation of HL-60 cells was evaluated by MTT assay. RESULTS: There was no significant difference in the average particle size and Zeta potential of the two DNR-MPs. The drug loading efficiency of DNR-MPs-EDL was higher compared with DNR-MPs-IDL. The uptake results showed that the two DNR-MPs significantly increased the drug uptake compared with free DNR (P < 0.05). DNR-MPs- IDL showed a higher drug uptake by the cells than DNR-MPs-EDL did (P < 0.05). They also exhibited an enhanced inhibition effect on the proliferation of HL-60 cells compared with DNR (P < 0.05). CONCLUSION: The different ways of preparation of drug-loaded microparticles can cause varying anti-tumor effect. Microparticles can significantly augment the anti-leukemia efficacy of DNR, indicating a promising drug carrier for the therapy of leukemia.

Changes of microparticle levels before and after daunorubicin-based chemotherapy in patients with acute leukemia / 白血病·淋巴瘤

Objective To observe the serum levels of endothelial microparticles (EMP) and tissue factor-bearing microparticles (TF+MP) in patients with acute leukemia before and after daunorubicin-based chemotherapy. Methods From July 2012 to February 2013, 15 patients with newly diagnosed acute leukemia in Peking Union Medical College Hospital received DA (daunorubicin + cytarabine) regimen or VDCLP (vincristine + daunorubicin + cyclophosphamide + L-asparaginase + prednisone) regimen chemotherapy. There were 8 males and 7 females, and the median age of patients was 44 years old. Eleven patients were acute myeloid leukemia (M01 case, M11 case, M29 cases), and 4 were acute lymphocytic leukemia. The peripheral blood samples were taken before induction chemotherapy and after 3 days of daunorubicin. Levels of EMP and TF+MP were assessed using flow cytometry. Results The serum EMP and TF+MP levels were significantly higher after 3-day daunorubicin infusions than those before induction chemotherapy (28.94/μl vs. 10.74/μl, P= 0.001; 64.24/μl vs. 43.80/μl, P= 0.02). Conclusion Daunorubicin-based chemotherapy may cause increased numbers of EMP and TF+MP in patients with acute leukemia.

Resistance to daunorubicin in acute myeloid leukemia is associated with mutations in the TET2 gene / 安徽医科大学学报

Objective To investigate the effect of leukemia-related genes on drug resistance in patients with acute myeloid leukemia (AML). Methods 74 patients with newly diagnosed AML were selected and 54 leukemia-associated genes of all patients were sequenced by second-generation gene sequencing. The gene with the highest mutation rate was further analyzed in association with resistance to several common chemotherapy medicines in in vitro drug sensitivity assays. In addition, in vitro drug resistance data were compared with the clinical data of patients. Results The TET2 gene was the most frequent mutation among 74 patients with newly diagnosed AML, with 11 positive patients. Among these 11 TET2 positive patients, 9 (81. 82％ ) were resistant to daunorubicin, while only 4 (6. 35％ ) out of 63 TET2 negative patients were resistant to daunorubicin. Besides, there was no significant difference between in vitro resistance rate to daunorubicin and the clinical data of patients. Conclusion TET2 gene mutation is associated with resistance to daunorubicin in AML patients, which may become an important indicator of the therapeutic efficacy of DA regimen.

Inducing therapy of cytarabine combined with daunorubicin or idarubicin for the newly diagnosed acute myeloid leukemia：comparison of clinical efficacy / 白血病·淋巴瘤

Objective To explore the clinical effect and toxicity of daunorubicin combined with cytarabine (DA regimen) and idarubicin combined with cytarabine (IA regimen) for the treatment of patients with acute myeloid leukemia (AML) as induction chemotherapy. Methods The clinical data of 84 newly diagnosed AML patients (except M3) treated with DA or IA regimen were analyzed retrospectively. DA regimen group included 32 patients (17 males and 15 females with median age of 46 years), while IA regimen group included 52 patients (29 males and 23 females with media age of 49 years). Efficacy index was complete remission (CR), total efficiency and adverse reactions after one course of chemotherapy rate. Results In DA regimen group,the CR rate was 65.6 %(21/32), and the total efficiency rate was 75.0 %(24/32), while in IA regimen group, the CR rate was 71.2 %(31/52), and the total efficiency rate was 80.8 %(42/52), respectively, but, the differences of media survival and 5-year survival rate were not statistically significant (16.8 months vs. 24.9 months, 26 % vs. 44 %, both P>0.05). The main side effect in the two groups included hematologic (bone marrow suppression) and non-hematologic adverse reactions, with no significant difference between the two groups (all P>0.05). Conclusion For newly diagnosed AML patients, remission rate and total efficiency of DA regimen are same as IA regimen after one course treatment, and adverse events between the two regimens do not differ significantly.

Curcumin enhancing sensitivity of acute myeloid leukemia stem cells to daunorubicin by down-regulating expression of CyclinD1 and Bcl-2 / 重庆医学

Objective To explore the potential mechanism of curcumin(CUR) enhancing the sensitivity of acute myeloid leu-kemistem cells(LSCs) CD34+CD38-KG1cellto daunorubicin (DNR) .MethodThe expression of surface moleculeCD34 , CD38 in KG1cellwadetected by the flow cytometry .The half maximal inhibitory concentration (IC50 ) of curcumin to CD34+CD38-Kglcellwacalculated by the Mtmethod .MT,methylcellulose colony formation assay and flow cytometry were ap-plied to examine the effectof Dnon the proliferation ,clone forming ability and apoptosiin the two kindof cell(CD34+CD38-KG1celland CUR/CD34+CD38-KG1cells) respectively .The mRNA-expression of Bcl-2 ,Bax and XIAP in the two cellwere analyzed by RT-PC.Meanwhile ,the protein-expression of CyclinD1 ,Bcl-2 ,Bax and XIAP were detected by Western Blo.ResultThe percentage of CD34+CD38-KG1in KG1cell line wa(98 .2 ± 3 .2)% .The IC50 of curcumin treating CD34+CD38-KG1fo24 h wa100 μmol/L .The inhibition effecof high and middle concentration(0 .8 ,2 .0 μg/mL) of Dnon the proliferation of CUR/CD34+CD38-KG1cellwastrongethan thaof CD34+CD38-KG1cell(P＜0 .05) .The inhibitory role of Dnto the colony formation on CUR/CD34+CD38-KG1cellwamore effective than thaof CD34+ CD38-KG1cells(P＜0 .05) .The ap-optotirate of CUR/CD34+ CD38- KG1cellin each concentration group of Dnwahighethan thaof CD 34+ CD38- KG1cells(P＜0 .05) .The mRNA-expression of Bcl-2 and the protein-expression of Bcl-2 and CyclinD1 were down-regulated .Howeve, no significanchange waobserved aboth mRNA-expression and protein-expression of Bax and XIAP .Conclusion Cucan en-hance the sensitivity of CD34+CD38-KG1cellto DN,which mighbe associated with down-regulating the expression of Cy-clinD1and Bcl-2 .

Prepraration of PLGA-PLL-PEG Nanoparticles Simultaneously Loaded with Daunorubicin and Tetrandrine / 中国药学杂志

OBJECTIVE: To prepare PLGA-PLL-PEG nanoparticles simultaneously loaded with daunorubicin (DNR) and tetrandrine (Tet).

Protective Effects of (-)-Epigallocatechin Gallate on Daunorubicin-induced Cardiotoxicity in Mice / 医药导报

Objective To investigate the protective effects of (-)-epigallocatechin gallate ( EGCG ) on daunorubicin ( DNR)-induced cardiotoxicity in mice. Methods The qualified mice were randomly divided into four groups:normal control group, myocardial injured model control group,high dose group (80 mg·kg-1 ) and low dose group (40 mg·kg-1 ) of EGCG. EGCG was administered intragastrically once daily for 7 days,followed by a single intraperitoneal injection of DNR (15 mg·kg-1 ) except in the normal control group. The electrocardiogram,myocardial enzymes and TNT-Hs in serum,cardiac ultrastructure of mice were detected after 48 h. Results In DNR model control group,the incidence of arrhythmia was 64. 7%. The activity of serum cardic enzymes including CK,CK-MB,LDH,α-HBDH and ALT,AST, level of TNT-Hs were significantly higher than those in the normal control group(P<0. 01),and myocardial ultrastructure was injured remarkably. The incidence of arrhythmia was 44. 4% in mice treated with high dose of EGCG and 31. 6% in mice with low dose of EGCG. Compared to the model control group, the activity of CK,CK-MB,LDH,α-HBDH and ALT,AST, level of TNT-Hs in serum decreased remarkably in EGCG groups( P<0. 05 or P<0. 01). Low can EGCG alleviated the injury to the ultrastructure of myocardium compared to the model control group. Conclusion EGCG can prevent the cardiac toxicity induced by DNR in mice.

Effect of decitabine combined with daunorubicin on apoptosis of HL-60 cell line / 肿瘤研究与临床

Objective To observe the cell proliferation inhibition of DNA methyltransferase (DNMT) inhibitors decitabine (DAC) combined with daunorubicin (DNR) in human leukemia cell line HL-60.Methods The effects of DNR and DAC were examined in HL-60 cells by cell viability using MTT method,and cell death using flow cytometric (FCM).Results DAC,DNR single drug application showed their effects on cell proliferation was dependent of dose and time,the inhibition effect of combined treatment group was much clearer [inhibition ratio of 72 hours was (80.23±1.71) ％,P ＜ 0.001].The highest apoptosis rate was at 5.0 μmol/L DAC combined with 1.0 μmol/L DNR for 72 hours,which was statistic significant (F =30.199,P ＜ 0.001).Combinations of different concentrations of DAC and DNR increased expression of PTEN mRNA in concentration-dependent manner,which was significantly higher than the control group and DNR single drug group (F =578.218,P ＜ 0.001).Conclusions DAC can significantly inhibit the proliferation of HL-60 cells and induce apoptosis,synergistic effect can be observed when DAC combined with DNR.The underlying mechanism can be due to DAC demethylation effect to increase PTEN mRNA expression.

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.

Resistance and mechanisms underlying the anticancer activity of daunorubicin in CD34+ acute myeloid leukemia cells / 安徽医科大学学报

Objective To explore the resistance and molecular mechanisms underlying the anticancer activity of daunorubicin in CD34 +acute myeloid leukemia(AML) cells. Methods CD34 +AML cell lines(KG1a and Kasu-mi-1)were used as objectives, and CD34 -AML cell line U937 was used as positive control. Western blot analysis was used to examine the protein expression of Bcl-2 and Bax in CD34 +AML and CD34 -AML cell lines incubated with/without daunorubicin to compare the sensitivity of CD34 +AML and CD34 -AML cells to daunorubicin. SiRNA against Bcl-2 was used in KG1a and Kasumi-1 cells and examined the effect on cell viability by MTT assay. Results Western blot analysis showed that Bcl-2 protein levels in CD34 +AML cells appeared to be significantly higher than in CD34 -AML cells. Western blot analysis showed that treatment with 0.4 μg/ml daunorubicin for 48 h caused down-regulation of Bcl-2 only in CD34 -AML cells,but not in CD34 +AML cells. Suppression of Bcl-2 with siRNA increased the susceptibility of KG1a and Kasumi-1 to daunorubicin. Conclusion CD34 +AML cell lines ex-press higher levels of Bcl-2 protein. Daunorubicin fails to down-regulate the high Bcl-2 protein levels in CD34 +AML cells. Suppression of Bcl-2 with siRNA increases the susceptibility of KG1a and Kasumi-1 to daunorubicin. The high Bcl-2 protein levels in CD34 +AML cells may be involved in the insensitivity to daunorubicin.

The clinical observation of reduced dose idarubicin combined with cytarabine, semustine regimen in the treatment of patients with acute myeloid leukemia / 中国综合临床

ObjectiveTo evaluate the clinical efficacy and toxicity of reduced dose idarubicin and cytarabine,semustine(IAS) regimen as induction therapy in patients with acute myeloid leukemia.MethodsA total of fifty-eight newly acute myeloid leukemia(AML) patients were randomly divided into 2 groups,including 30 cases with IAS regimen,28 cases with DA regimen The IAS regimen was treated with reduced dose idarubicin (8 ～ 10 mg/m2,days 1 to 3) and cytarabine( 100 ～ 150 mg/m2,days 1 to 7),semustine(200mg,d0).The DA regimen was treated with daunorubicin(40 ～60 mg/m2,days 1 to 3) and cytarabine ( 100 ～ 150 mg/m2,days 1 to 7).The responses ( CR and overall response rate ) were compared between the 2 groups.Results Complete remission(CR) rate in IAS and DA groups were 24 of 30( 80.0％ ) and 16 of 28 (57.1％ ) respectively,while the overall response rate were 26 of 30 ( 86.7％ ) and 18 of 28 ( 64.3％ ) respectively.There was significant difference in CR rate and overall response rate between IAS group and DA group( P ＜ 0.05 ).Myelosuppression and infections due to neutropenia were the most frequent adverse effects,severe nonhematologic toxicity was not observed.The incidence rates of toxicities in the 2 groups were not significantly different ( P ＞ 0.05 ).Conclusion The effect of reduced dose idarubicin and cytarabine,semustine regimen in the treatment for acute myeloid leukemia is superior to that of DA regimen,and the toxicities are tolerable.IAS regimen can be as the optional induction therapy in newly patients with acute myeloid leukemia.

Telmisartan inhibits the progression of cardiomyopathy in daunorubicin treated rats: the role of advanced glycation end products.

Background: Anthracyclines have been reported to induce cardiotoxicity through mechanisms involving formation of advanced glycation end-products (AGEs), including pentosidine and Nє-(carboxymethyl) lysine (CML). We investigated the potential utility of telmisartan (TML), an angiotensin II receptor antagonists (ARB) on anthracycline-induced cardiotoxicity. Methods: Three groups of Sprague-Dawley rats were treated as follows: The first group received daunorubicin (DNR) 3 mg/kgBW every alternating day to reach a cumulative dose of 9 mg/kg DNR . The second group received DNR plus TLM at a dose10 mg/kgBW, by oral gavage for 6 weeks, and the third group served as control group (CTL) which only received vehicle of DNR. Mean blood pressure (MBP) peak left ventricular pressure (LVP), LV end-diastolic pressure (LVEDP), and intra-ventricular contractility (±dP/dt) were recorded by using Powerlab instrumentation. Ejection fraction (EF), and fractional shortening (FS) were measured by echocardiography. Expression of receptor of AGE (RAGE), pentosidine and CML were measured by immunohistochemistry and Western blot in LV tissue. Results: DNR treatment was associated with significant weakening of some hemodynamic parameters which could be reversed by TML (LVP: 124.3 ± 6.0; 111 ± 7; and 115.1 ± 5.4 mmHg, respectively in CTL, DNR and DNR-TLM groups; LVEDP: 7.5 ± 0.9; 10.7 ± 0.3; 8.7 ± 0.4 mmHg, respectively; +dP/dt: 6813 ± 541; 4800 ± 345; 5950 ± 398 mmHg/s, respectively). The same phenomenons were also observed on echocardiographic parameters (EF: 78.9 ± 1.8; 59.6 ± 1.4; 76.2 ± 2.75 %, resepectively; FS: 42.8 ± 1.7; 29.1 ± 1.3; 41 ± 2.7 %) respectively. Expression of RAGE as well as pentosidine and CML were increased in DNR-rats. TML treatment ameliorated these changes. Conclusion: These results suggested the role of AGE formation in DNR-induced cardiotoxicity and telmisartan could inhibit the progression of cardiac toxicity at least in part by reduction RAGE expressiom.

Tratamiento de la leucemia linfoide aguda del adulto: Experiencia de un hospital en la Ciudad de México / Results of treatment of acute lymphoblastic leukemia in two cohorts of Mexican patients

Background: GIMEMA ALL 0288 trial was designed to evaluate the impact of a 7-day prednisone (PDN) pretreatment on complete remission of acute lymphoblastic leukemia. We adopted this trial in 2007. Aim: To evaluate the results of treatment in two cohorts of patients with acute lymphoblastic leukemia, treated from 2007 to January 2009 and from February to December 2009. Material and Methods: We studied 99 patients treated in the first period (58 males) and 54 patients treated in the second period (33 males) The age of patients ranged from 16 to 60 years and 70 percent of patients were of high risk. BCR/ABL fusion transcript was present in 12 percent of patients. Results: Remission rates were 61 and 51 percent for patients of the first and second group of treatment, respectively. The main cause of death were infections during the induction period. There were 49 relapses, mainly detected in the blood marrow. Global and event free 34 months survival were 32 and 30 percent respectively. Multivariate analysis disclosed risk stratification and central nervous system infiltration as risk factors for mortality. Conclusions: The main obstacles for the treatment of acute lymphoblastic leukemia in these cohorts of patients were the high incidence of infections and the lack of use of growth stimulating factors.

Comparison of domestic idataubicin and imported daunorubicin on the treatment of acute leukemia / 白血病·淋巴瘤

Objective To compare the effect and toxicity of domestic idarubicin (IDA) and imported daunorubicin (DNR) in the treatment of acute leukemia (AL).Methods According to the random number table method,68 patients were randomly divided in IDA group with 35 patients and DNR group with 33 patients.In IDA group,the patients with acute myelocytic leukemia were treated following IA scheme (domestic idataubicin plus cytosine arabinoside) and the patients with acute lymphoblastic leukemia were treated following VICLP scheme (vincristine,domestic idataubicin,cyclophosphamide,lasparaginase and prednisone).In DNR group,the patients with acute myelocytic leukemia were treated following DA scheme (imported daunorubicin plus cytosine arabinoside) and the patients with acute lymphoblastic leukemia were treated following VDCLP scheme (vincristine,imported daunorubicin,cyclophosphamide,lasparaginase and prednisone).Results In IDA group,21 patients achieved a complete remission(CR),5 patients achieved a partial remission(PR),with a 74.2 ％ (26/35) remission rate (RR).In DNR group,the remission rate was 62.3 ％ (20/33).No differences of the remission rate was found between the two groups (t =0.89,P =0.50).17 patients were found remission over one year in IDA group,and 6 patients were in DNR group.The difference was statistically significant between the two groups (x2 =5.56,P =0.02).Conclusion IDA is more effective than DNR in AL treatment.The higher RR and longer remission time are found in IDA group than DNR group.IDA is effective and safe in the treatment of AL.

Associação do quimioterápico daunorrubicina a uma nanoemulsão rica em colesterol: estudos de regressão tumoral e farmacocinética / Association of the chemotherapeutic agent daunorubicin a cholesterol-rich nanoemulsion: regression studies pharmacokinetics and tumor

A nanoemulsão lipídica (LDE) se concentra nas células neoplásicas e pode ser utilizada como transportador de derivado lipofílico da daunorrubicina, como o Noleil- daunorrubicina (oDNR). Neste estudo, a LDE-oDNR foi preparada por homogeneização em alta pressão e sua toxicidade e atividade anti-tumoral testadas. A associação LDE-oDNR teve rendimento elevado e permaneceu estável por longo período. Em camundongosC57BL/6J, a dose máxima tolerada (DMT) foi 65 vezes maior e a DL50 48 vezes maior no tratamento LDE-oDNR comparado ao tratamento DNR comercial, resultando em alta redução da toxicidade. Em camundongos implantados com células de melanoma B16, a preparação LDE-oDNR (7,5 mol/kg) levou a redução de 59 ± 2% do crescimento do tumor comparado a redução de 23 ± 2% para o tratamento DNR comercial na mesma dose (p<0,001). A probabilidade de sobrevida teve aumento pronunciado nos animais tratados com LDE-oDNR comparado à DNR comercial (p <0,01). Além disso, apenas 30% dos animais portadores de melanoma submetidos ao tratamento com LDE-oDNR apresentaram metástases, comparado a 82% quando tratados com DNR comercial. Uma forte redução de toxicidade também foi observada pela redução da anemia e leucopenia nos animais tratados com LDE-oDNR, em comparação com DNR comercial. A preparacao LDE-oDNR foi eficaz também no quadro de trombocitose induzida por tumor. Os testes com fragmentos extraídos de tumores dos animais tratados mostraram que a LDE-oDNR foi mais eficaz na destruição das células neoplásicas comparado ao tratamento DNR comercial (9% de células viáveis com tratamento LDE-oDNR, 27% sob tratamento DNR). O estudo mostrou que o tratamento proposto com o derivado ODNR associado à nanoemulsão (LDE-oDNR) é efetivo no combate às células tumorais, seletivo, menos tóxico e melhor tolerado. Os estudos de farmacocinética e biodistribuição somam a este protocolo informações importantes relacionadas às propriedades de absorção, distribuição, metabolismo e excreção...

A lipidic nanoemulsion (LDE) that concentrates in neoplastic cells can be used as vehicle to daunorubicin lipophylic derivatives, such as N-oleyl-daunorubicin (oDNR). Here, LDE-oDNR was prepared by high pressure homogenization to test toxicity and anti-tumor activity. LDE-oDNR association yield was high and stable for long period. In mice, maximum tolerated dose was 65 and LD50 was 48-fold greater in LDE-oDNR than in commercial DNR treatment, showing very strong toxicity reduction. In melanoma B16-tumor bearing mice, LDE-oDNR (7.5 mol/Kg) reduced tumorgrowth by of 59±2%, and DNR by only 23±2% at same dose level (p<0.001). Survival was pronouncedly increased in LDE-oDNR compared to DNR treatment (p<0.01). Furthermore, the number of melanoma-bearing mice with metastasis was 30% under LDE-oDNR, compared to 82% under DNR treatment. Strong reduction of toxicity was also observed by reduction of anemia and leucopenia under LDE-oDNR, compared to commercial DNR tumor-induced thrombocytosis was more effective with LDE-oDNR than with DNR. Tests with fragments extracted from tumors of treated animals showed that LDE-oDNR was more effective in killing neoplastic cells than DNR (9% of viable cells under LDE-oDNR; 27% under DNR). The pharmacokinetics and biodistribution studies add important information to this protocol related to the properties of absorption, distribution, metabolism and excretion of the formulation under study compared to free DNR. The remarkable toxicity reduction and increase in pharmacological action supports novel LDE-oDNR as a promising weapon in cancer treatment.