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.

Enhanced Response of Acute Monocytic Leukemia Cells to Low-dose Cytarabine by 1,25-dihydroxyvitamin D3

Low-dose cytarabine combined with differentiating or DNA hypomethylating agents,such as vitamin D compounds,is a potential regimen to treat acute myeloid leukemia(AML)patients who are unfit for high-intensity chemotherapy.The present study aimed to determine which subset of AML would be most responsive to low-dose cytarabine with the differentiating agent 1,25-dihydroxyvitamin D3(1,25-D3).Here,firstly,c Bio Portal database was used and we found out that vitamin D receptor(VDR)was highly expressed in acute monocytic leukemia(M5)and high VDR expression was associated with a poor survival of AML patients.Then,we confirmed that 1,25-D3 at clinical available concentration could induce more significant differentiation in acute monocytic leukemia cell lines(U937,MOLM-13,THP-1)and blasts from M5 patients than in non-monocytic cell lines(KG1 a and K562)and blasts from M2 patient.Finally,it was shown that the combination of 1,25-D3 and low-dose cytarabine further increased the differentiating rate,growth inhibition and G0/G1 arrest,while mild changes were found in the apoptosis in acute monocytic leukemia cell lines.Our study demonstrates that the enhanced response of acute monocytic leukemia cells to low-dose cytarabine by 1,25-D3 might indicate a novel therapeutic direction for patients with acute monocytic leukemia,especially for elderly and frail ones.

Cytarabine and paclitaxel exhibit different cell-cycle specificities in different cell growing status

Objective： To investigate the cell-cycle specificities of cytarabine and paclitaxel in different growing status of target cell. Methods： Using flow cytometry, we tested the cell-cycle specificities of cytarabine and paclitaxel on acute lymphocyte leukemia cell line Molt-4 in different growing status and on clinical acute lymphocyte leukemia specimens in vitro as well as in leukemia patients in vivo. Results： Cytarabine induced S phase specific cebcyde blockage and apoptosis in exponentially growing Molt-4, but showed G0/G1 phase specificity in high-density cultured Molt-4 and in clinical specimens. Paclitaxel induced G2/M phase specific cell-cycle blockage and apoptosis in exponential Molt-4, but showed G0/G1 phase specificity in high-density cultured Molt-4 and S phase specificity in clinical specimens. In the first day of clinical chemotherapy, cytarabine induced G0/G1 with a little S phase apoptosis in leukemia cells of acute lymphocyte leukemia patient in vivo. Cytarabine plus paclitaxel together had almost the same effect in the second day. Conclusion： The cell-cycle effects of cytarabine and paditaxel were different in different target cell growing status. It should be noted that the in vivo effect of these agents may be different from people usually anticipated during clinical chemotherapy. So the combined chemotherapeutic regimens may need to be redesigned.

Analyses of therapeutic effects using rludarabine and cytarabine on acute myeloid leukemia at different stages during treatment

Objective: To evaluate the therapeutic effect of the fludarabine and cytarabine (FA) regimen on acute myeloid leukemia (AML) at different phases during treatment. Methods: A total of 185 patients with AML were divided into 4 groups based on the outcome of previous treatments. Patients in Group 1 had no remission after the first course of induction chemotherapy (n = 55). Patients in Group 2 had no remission after no less than two courses of induction chemotherapy (n = 41). Patients in Group 3 had early relapse (n = 40). Patients in Group 4 had late relapse (n = 49). Patients in groups 2, 3 and 4 had refractory AML or AML with relapse. We assessed the efficacy and toxicity of FA combination chemotherapy in each of these 4 groups. Results: The complete remission (CR) rates of Groups 1, 2, 3 and 4 were 74.5% (41/55), 45.9% (19/41), 17.5% (7/40) and 38.8% (19/49), respectively. The CR rate was higher in Group 1 than in the other 3 groups (34.6%, 45/130) (P = 0.000). A significant correlation was found between CR rate and the number of chemotherapeutic courses (P = 0.023). The main adverse reactions included bone marrow suppression and secondary infection. Conclusion: FA regimen is a good choice for patients with AML, especially those who have failed to achieve CR after the first course of induction chemotherapy.

Nanoscale chemical imaging of individual chemotherapeutic cytarabineloaded liposomal nanocarriers

Dosage of chemotherapeutic drugs is a tradeoff between efficacy and side-effects.Liposomes are nanocarriers that increase therapy efficacy and minimize side-effects by delivering otherwise difficult to administer therapeutics with improved efficiency and selectivity.Still,variabilities in liposome preparation require assessing drug encapsulation efficiency at the single liposome level,an information that,for non-fluorescent therapeutic cargos,is inaccessible due to the minute drug load per liposome.Photothermal induced resonance (PTIR) provides nanoscale compositional specificity,up to now,by leveraging an atomic force microscope (AFM) tip contacting the sample to transduce the sample's photothermal expansion.However,on soft samples (e.g.,liposomes) PTIR effectiveness is reduced due to the likelihood of tip-induced sample damage and inefficient AFM transduction.Here,individual liposomes loaded with the chemotherapeutic drug cytarabine are deposited intact from suspension via nano-electrospray gas-phase electrophoretic mobility molecular analysis (nES-GEMMA) collection and characterized at the nanoscale with the chemically-sensitive PTIR method.A new tapping-mode PTIR imaging paradigm based on heterodyne detection is shown to be better adapted to measure soft samples,yielding cytarabine distribution in individual liposomes and enabling classification of empty and drug-loaded liposomes.The measurements highlight PTIR capability to detect ~ 103 cytarabine molecules (~ 1.7 zmol) label-free and non-destructively.

Targeted co-delivery of daunorubicin and cytarabine based on the hyaluronic acid prodrug modified liposomes

Breast cancer is the most prevalent cancer in women,and it was hard to prevent or diagnose at an early stage.Thus,it is imperative to develop advanced therapeutics for effective treatment.Herein,a targeted daunorubicin(DNR)and cytarabine(ara-C)co-delivery system was developed by modifying the ara-C loaded liposomes(LIP-ara-C)with the hyaluronic acid-DNR(HA-DNR)prodrugs.The co-assembled hybrid nanoparticles(HA-DNR/LIP-ara-C HNPs)exhibited good serum and storage stability with an average diameter of approximately 100 nm.By specifically binding to the CD44 receptors that overexpressed on cancer cells,these HNPs could be uptake via endocytosis and accumulate intracellularly,in which an optimized DNR and ara-C combination at a molar ratio of 1:5 could generate enhanced synergistic effects with reduced dose-related toxicity on cancer cells.

Cytarabine delivered by CD44 and bone targeting redox-sensitive liposomes for treatment of acute myelogenous leukemia

Acute myelogenous leukemia(AML)remains a serious fatal disease for the patients and effective treatment strategies are urgently needed.Based on the characteristics of the AML,we developed the CD44 and bone targeting liposomes delivery system decorated with the redox-cleavable polymer.First,ALN-HA was obtained by amination between alendronate(ALN)and hyaluronic acid(HA),and cholesterol(Chol)was coupled by a disulfide linker(-SS-)with biological reducibility to obtain the goal polymer,ALN-HA-SS-Chol,decorated the liposomes loaded with the Cytarabine(AraC).ALN-HA-SS-AraC-Lip exhibited a spherical morphology with the diameter of 117.5nm and expanded at the environment of 10mM dithiothreitol.Besides,compared with other groups,ALN-HA-SS-AraC-Lip showed benign hydroxyapatite affinity in vitro and bone targeting in C57/BL6 mice,also,ALN-HA-SS-AraC-Lip exhibited encouraging antitumor which significantly reduced the white blood cell amount in bone marrow and blood smear caused by AML model,besides,the dual targeting liposomes also prolong the survival time of mice.In conclusion,the bone and CD44 dual targeting liposomes with redox sensitivity could target to the leukemia stem cells regions and then uptake by the tumor cells,which would be a valuable target for the treatment of the AML.

Efficacy and safety analysis of the combination of cladribine,cytarabine,granulocyte colony stimulating factor( CLAG ) regime in patients with refractory or relapsed acute myeloid leukemia

Objective To analyze efficacy and safety of CLAG regimen in patients with refractory or relapsed acute myeloid leukemia(AML).Methods Efficacy and adverse events of patients with refractory or relapsed AML who were treated with one course of CLAG from April 1st,2014 through December 9th,2015 in our hospital were retrospectively reviewed.Results Thirty-three

Chemotherapy induced Takotsubo cardiomyopathy

Chemotherapy has been linked with Takotsubo cardiomyopathy. Most of the literature on chemotherapy associated Takotsubo cardiomyopathy is on the drug 5-fluorouracil. In this report, we describe the case of a 55-year-old Asian male who developed Takotsubo cardiomyopathy while receiving dual chemotherapy with cytarabine and daunorubicin for acute myeloid leukemia. To our knowledge, it is the first case of Takotsubo cardiomyopathy associated with daunorubicin and/or cytarabine.

Study on the Preparation and Antileukemic Activity of New Lipophilic 1-β-D-arabinofuranosylcytosine Derivatives

Cytarabine(1-β-D-arabinofuranosylcytosine, Ara-C), isolated from a Caribbean sponge species Tethyacrypta, is the first antitumor drug from a marine resource. In 1980, the US Food and Drug Administration approved this drug for the treatment of different types of leukemia. This drug has a short plasma half-life, low stability, limited bioavailability, and severe side effects. To improve stability and bioavailability, we synthesized nine novel derivatives by blocking the cytarabine metabolic sites and improving lipophilicity. The c Log P values of the newly synthesized compounds were calculated. All the synthesized compounds were more lipophilic than cytarabine, resulting in membrane permeability and bioavailability improvement. The antitumor activities against leukemia cell line HL-60 were evaluated by using the MTT assay. The bioassay results revealed that the IC_(50) values of compounds 5, 8 and 9 were 0.080, 0.090 and 0.057 μmol L^(-1), respectively, which was similar with that of cytarabine(0.056 μmol L^(-1),). In comparison, compound 4 with a phosphate group at O5' was inactive. Because phosphoester bonds are easily hydrolyzed by alkaline phosphatase and are commonly used in producing prodrug strategies, compound 4 might also be metabolized in vivo and generate compound 3 or even cytarabine through a multi-step reaction. Thus, compound 4 might be a promising compound to be developed as a prodrug.

Is Takotsubo syndrome in patients receiving chemotherapy drug-specific?

In commenting on a case report of a 55-year-old man who suffered Takotsubo syndrome(TTS), in the setting of receiving chemotherapy with cytarabine and daunorubicin for acute myeloid leukemia, the author expresses his views that TTS in the setting of chemotherapy for malignancies may not be chemotherapeutic drug-specific(like in the chemotherapeutic drug induced-cardiomyopathy), but may be due to the emotional and physical stresses resulting from the realization of having diagnosed with a malignancy, and the diagnostic testing, and therapeutic management which follows.

急性髓细胞白血病缓解后用大剂量阿糖胞苷治疗对无病生存的影响

提 要 本文对37例急性髓细胞白血病(AML)患者在CR后用大剂量阿糖胞苷(HD-Ara -c)进行强化治疗,并与28例同期未用HD-Ara-c强化治疗的患者做对照,试图探讨对无病生存的影响,结果治疗组的中位CR期为16个月,18例复发(48.6%)。对照组的中位CR期为10.7个月,21例复发(75%)。Kaplan-Meier生存曲线示治疗组的3年和5年预期DFS分别为50.2%和43.0%,对照组分别为31.0%和16.7%,两组有显著性差异(P<0.05).

Entrapment of DNA topoisomerase-DNA complexes by nucleotide/nucleoside analogs

Topoisomerases are well-validated targets for cancer chemotherapy and DNA topoisomerase 1(Top1)is the sole target of the camptothecin(CPT)class of anticancer drugs.Over the last 20 years,multiple studies have shown Top1 activity is modulated by non-native DNA structures and this can lead to trapping of Top1 cleavage complexes(Top1cc)and conversion to DNA double strand breaks.Among the perturbations to DNA structure that generate Top1cc are nucleoside analogs that are incorporated into genomic DNA during replication including cytarabine,gemcitabine,and 5-fluoro-2’-deoxyuridine(FdU).We review the literature summarizing the role of Top1cc in mediating the DNA damaging and cytotoxic activities of nucleoside analogs.We also summarize studies demonstrating distinct differences between Top1cc induced by nucleoside analogs and CPTs,particularly with regard to DNA repair.Collectively,these studies demonstrate that,while Top1 is a common target for both Top1 poisons such as CPT and nucleoside analogs such as FdU,these agents are not redundant.In recent years,studies have shown that Top1 poisons and nucleoside analogs together with other anti-cancer drugs such as cisplatin cause replication stress and the DNA repair pathways that modulate the cytotoxic activities of these compounds are being elucidated.We present an overview of this evolving literature,which has implications for how targeting of Top1 with nucleoside analogs can be used more effectively for cancer treatment.