bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of Uptake and Intracellular Induced Structural Changes of Arsenic Trioxide, an Inorganic Compound, and Organic Arsenic Derivative S-Dimethylarsino-Glutathione (SGLU; ZIO-101) in NB4 Acute Promyelocytic Leukemia (APL) Cells.
Authors: Manshouri Taghi , Kala Subbarao V. , Ashoori Faramarz , Zingaro Ralph , Freireich Emil J. , Andreeff Michael , Kantarjian Hagop M. , Verstovsek Srdan 
Published: October 2019

Abstract
Arsenic trioxide (As2O3; ATO) inhibits proliferation and induces apoptosis of APL cells. However, little is known about the intracellular structural changes associated with arsenic exposure. We studied effects of 2 arsenic compounds, ATO and S-dimethylarsino-glutathione (SGLU; ZIO-101) on NB4 APL cells. ZIO-101 is novel water-soluble organic arsenic derivative currently in Phase I clinical studies. Exposure of cancer cells to ZIO-101 results in G2/M cell cycle arrest and apoptosis. NB4 cells were exposed to 10, 50, 100 and 250 μM ZIO-101 or ATO for 1 h and intracellular arsenic content was determined by inductively coupled plasma mass spectrometry (ICP/MS). ZIO-101-treated cells contained 5–8 fold more arsenic then ATO-treated cells. Electron microscopy of NB4 cells exposed to 1 μM ZIO-101 or ATO for 24–72 h revealed different structural changes. ATO treated cells showed time-dependent mitochondrial hypotrophy and apoptosis, including cytoplasmic vacuolization, nuclear condensation and cell blebs. In contrast, ZIO-101 treated cells showed time-dependent mitochondrial atrophy, mitochondrial matrix condensation, and apoptosis. These data suggest that ZIO-101 is more specific mitochondrial toxin than ATO. Studies are in progress to understand the exact mechanism through which ZIO-101 affects mitochondria. Because these arsenic derivatives have different mechanism of action they may have different spectrums of activity against cancers; this should be tested in clinical trials.
A Phase I Open-Label Trial To Determine the Pharmacokinetics of Glucarpidase in Subjects with Normal and Impaired Renal Function.
Authors: Phillips Marc A. , Auton Tim R. , Ward Suzanne B. , Smith William B. , Balan Guhan 
Published: October 2019

Abstract
Methotrexate (MTX) is used in high doses in the treatment of cancers such as NHLs, leukemias and osteosarcoma. In some patients it produces renal damage which delays its elimination from the body. Prolonged exposure to high concentrations of MTX results in serious toxic effects. Glucarpidase (Voraxaze™, formerly carboxypeptidase G2) contains a recombinant enzyme which rapidly and predictably breaks down MTX in the blood within 15 minutes of administration. Multiple studies to date have evaluated glucarpidase as an intervention for patients at risk or experiencing toxicities related to MTX overexposure. Continuing studies seek to evaluate the use of glucarpidase in a planned way to circumvent toxicity and prevent prolonged hospitalization. The current study examined the pharmacokinetics of glucarpidase in subjects who had both normal and severely impaired renal function, similar to that of the intended patient population.
Methods: Twelve male and female subjects participated in this study; 8 with normal renal function (calculated creatinine clearance >80 mL/min) and 4 with severely impaired renal function (calculated creatinine clearance <30 mL/min). Each subject received a single intravenous dose of glucarpidase 50 units/kg (equivalent to 114.5 μg/kg), infused over 5 min. Serum glucarpidase profiles were evaluated for all subjects using 7 mL blood samples collected at the following time points: pre-dose (prior to start of glucarpidase IV dose), end of 5-minute infusion, and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 48, 72, and 96 hours following the start of the infusion. The study protocol was approved by the Crescent City Institutional Review Board IRB (New Orleans, LA) and all subjects gave their written informed consent prior to inclusion in the study.
Results: The mean (SD) Cmax for glucarpidase in renally impaired subjects was 2.9 μg/mL (0.83), the mean half-life was 10.0 (2.1) h and mean AUC0-∞ was 24.5(9.4) μg.h/mL. Similar values were found in subjects with normal renal function (mean Cmax 3.1 μg/mL, mean t1/2 9.0 h and mean AUC0-∞ 23.4 μg.h/mL). No adverse events were recorded in the study.
Conclusions: The results indicated little effect of renal impairment on the serum pharmacokinetics of glucarpidase. Evaluations of adverse events, clinical laboratory assessments, vital signs, ECGs, and physical examinations indicated that a single 50 unit/kg dose of glucarpidase was safe and well-tolerated when administered to subjects with normal renal function and subjects with severe renal impairment. PK parameters found in this study may be relevant to cancer patients treated with 50 units/kg glucarpidase, including those with MTX-induced renal toxicity.
Copper-Complexed Melphalan (MOC*M), a Member of a New Class of Anti-Leukemic and Anti-Tumouric Substances for Treatment of Primary and Relapsed Acute Lymphoblastic Leukemia in Childhood.
Authors: Prokop Aram , Frias Corazon , Henze Guenter , Sadolinnaya Swetlana , Tatarskiy Valeriy 
Published: October 2019

Abstract
Acute lymphoblastic leukemia (ALL) is the most frequent malignant disease of childhood. Despite a relatively good prognosis (survival 80 %), approximately ¼ of the patients suffer from relapses with a much poorer prognosis (survival 40 %). If a complete remission through chemotherapy is not achieved, the patients will not survive. Thus, the search for new cytostatic substances which can break the resistance against conventional cytostatic drugs is of great interest.
We developed a new class of copper-containing cytostatic agents with apoptosis-inducing properties. The present study deals with 20 children, who suffer from de novo ALL or relapsed ALL. In vitro measurement of DNA-fragmentation in primary lymphoblasts of the children showed, that the copper-complexed cytostatic drugs are considerably more effective, compared to conventional analogues and other cytostatic drugs (cytarabine p<0.002, vincristine p< 0.006) used against childhood ALL. Furthermore, the new copper-containing analogues overcome drug resistance against doxorubicin (p<0.001) in vitro. In addition, the prototype of copper-complexed drug analogues, MOC*M, a melphalan-copper-acetoacetonate-complex, has synergistic effects in apoptosis induction combined with melphalan or conventional drugs in therapy of ALL in childhood like vincristin, doxorubicin and cytarabine.
Experiments revealed that MOC*M specifically induces apoptosis, as evidenced by DNA fragmentation and dissipation of the mitochondrial membrane potential. MOC*M induces cell death, which was functionally characterized by the use of different cellular model systems being devoid of defined molecular parts of the apoptosis machinery. MOC*M triggers apoptosis in a Bcl-2-independent manner in the multi-resistant melanoma cell line MelHO with a 30-fold over-expression of Bcl-2. In vitro and in vivo experiments on mice with tumors sarcom S-180, melanoma B-16 and adenocarcenom in the large intestine proved a high anti-tumor activity of MOC*M with anti-metastasis and immunizing properties without any side effects in kidney or liver. Thus, MOC*M is able to prolong the life of animals with leucosis L-1210 and P-388.
We could show that the accumulation of the tritium-labelled MOC*M compounds took place mainly in the tumor cells in vivo. Moreover, MOC*M is also inhibiting glycolysis in the tumor cells.
The result of pre-clinical tests with MOC*M preparations, tested on a limited quota of oncological patients with different tumors, was a very large spectrum of anti-tumor and anti-leukemic activities. Further MOC*M has an immense tolerability in vivo. All in all, copper-containing cytostatic drugs comprise an innovative, highly promising class of cytostatic agents for cancer and leukemia therapy, especially for the therapy of relapsed ALL in childhood.
Synergistic Effects of Bortezomib with Low Dose Melphalan Against Human AML Cells.
Authors: Gautier Marc , Bubis Jeffrey A. , Wu Jia-Yan , Meehan Kenneth R. 
Published: October 2019

Abstract
The treatment of AML in the elderly population is difficult given the inherent resistant disease, the toxic effects of therapy and the presence of co-morbid conditions. We proposed preclinical studies to investigate the potential synergy of bortezomib with melphalan against AML cells, with the anticipation of developing a clinical trial. To test the killing potential of bortezomib or melphalan, limiting dilution experiments were performed with subsequent analysis using the MTT assay. Two human AML cell lines, GDM-1 and Kasumi-1, were used as targets. Tumor cells (7.5 x 103 cells/well) were plated on 96-well tissue culture plates and incubated overnight at 37 °C with 5% CO2. At 24 hrs, varying concentrations of melphalan (doses: 100 uM to 1 uM) or bortezomib (doses: 100 nM to 1 nM) were added to each well. After 48 hrs of culture, the MTT assay was performed. Each test was run in triplicate. When using the GDM-1 cell line, the addition of melphalan alone (1 uM) resulted in 80% viability (+/− 1.7%), while bortezomib alone (1 nM) yielded 86% viability (+/− 3.6%). An increased dose of each medication decreased the viability of the GDM-1 cells. An increased dose of Melphalan (3 uM) reduced the viability to 23% (+/− 4.2 %). The viability dropped to 62% (+/− 4.9 %) with an increased dose of Bortezomib (3 nM). After combining the medications, the inhibitory activity against the GDM-1 cells required lower doses then either drug alone. For example, melphalan (1uM) with bortezomib (1 nM) reduced the viability of GDM-1 cells to 20% (+/− 2.8%); While melphalan (3 uM) and bortezomib (3 nM) further suppressed the viability to 3.7 % (+/−2.5 %). Similar results were found using the Kasumi-1 AML cell line. These results demonstrate the potential synergy of the combination of bortezomib with melphalan against AML cells. These preclinical results are currently being tested in a clinical trial using low dose melphalan with bortuzimab in elderly AML and MDS patients.
Guggulsterones Induce Apoptosis and Differentiation in AML: Identification of Isomer-Specific Antileukemic Activities of the Pregnanedienedione Structure.
Authors: Samudio Ismael , Konopleva Marina , Safe Stephen , Andreeff Michael 
Published: October 2019

Abstract
The gum resin from the guggul tree, commiphora mukul, has been used in Ayurvedic medicine for centuries to treat inflammatory and lipid disorders, and an ethylacetate extract of the resin, termed guggulipid, has been reported to have an anti-obesity and antilipidemic effect in clinical trials with no significant toxicity. In this study, we investigate the antileukemic effects of the active components in guggulipid, namely cis- and trans-guggulsterone (cGS and tGS, respectively), and compare their effects to those of the unrelated structural isomer 16-dehyroprogesterone (P). Our results demonstrate that all three compounds inhibited the proliferation of HL60 and U937 cells with IC50 values ranging from 3.6 - 10.9 μM after treatment for 6 days. These growth inhibitory effects correlated with externalization of phosphatidyl serine (PS) and loss of mitochondrial membrane potential (ΔψM) suggesting that these isomeric steroids induce apoptosis in leukemia cells. Z-VAD-fmk prevented PS externalization, but not ΔψM loss indicating that mitochondrial dysfunction occurred in the absence of caspase activation. Interestingly, while all three compounds increased the generation of reactive oxygen species and decreased phosphorylation of ERK, only cGS induced a rapid depletion of reduced glutathione levels and oxidation of the mitochondrial phospholipid cardiolipin. Curiously, the potent antioxidant n-acetylcysteine (NAC) only reversed the cytotoxicity of P suggesting that this structural isomer induces a different cytotoxic response from that of cGS and tGS. P and tGS induced differentiation of HL60 and NB4 cells as evidenced by increased surface expression of CD11b and/or CD14, and all three steroids rapidly induced mitochondrial dysfunction and PS externalization of CD34-positive blasts from primary leukemic samples. This study is the first to demonstrate that guggulsterones and 16-dehydroprogesterone exert antileukemic effects via the induction of apoptosis and differentiation, and more importantly, identifies the pregnadienedione structure as a potential chemotherapeutic scaffold for the development of novel antileukemic agents.
Cytotoxic Activity of the Proteasome Inhibitor MLN-273 but Not of Bortezomib Is Inhibited by MDR1.
Authors: Rumpold Holger , Wolf Anna M. , Untergasser Gerold , Gastl Guenther , Gunsilius Eberhard , Wolf Dominik 
Published: October 2019

Abstract
Proteasome inhibitors as bortezomib have been included in standard treatment regimens in several hematological malignancies, especially multiple myeloma. As resistance mechanisms depending on MDR1 expression have not been evaluated in detail for proteasome-inhibitors it was the aim of our study to investigate resistance of cells to Bortezomib and MLN-273 conferred by MDR1.
To address that question K562Dox cells have been long-term cultured in low concentrated doxorubicin to obtain MDR1 overexpression. These cells were stably transfected with a Sleeping-Beauty vector system carrying an siRNA targeting the mRNA of PgP. With that approach, PgP was reduced to 10% compared to the wild-type cell line. PgP-positive and PgP-negative cells were exposed to bortezomib and MLN-273 and proliferation measured was in a 3H-Thymidine incorporation assay. This showed a dose-dependent reduction of DNA-synthesis in cells exposed to Bortezomib, regardless of PgP-expression. In contrast, MLN-273 showed a PgP-dependency by inhibiting cells expressing PgP (K562Dox: EC 50 of 5,6 ng/ml and vector control cells K562Dox-Co: EC 50 of 29 ng/ml) less than MDR1-knock-down cells (K562Dox-siMDR1: EC50 of 0.3 ng/ml). In MDR1 positive cells this growth inhibition was reveresed by addition of verapamil, a MDR1 blocking substance (K562Dox: EC50 of 2.4 ng/ml and K562Dox-Co: EC50 of 2.8 ng/ml). This growth inhibitory effect was due to apoptosis induction, which has been shown by staining for Annexin V and propidium iodide. The direct effect of MDR1 on proteasome activity was measured by western blotting IkBα, a substrate of the proteasome, which was still present in MLN-273 treated MDR1-negative cells but not in MDR1-positive cells incubated with MLN-273.
These results show that MLN-273 highly likely is a substrate for MDR1, which may gain clinical significance in treating hematological malignancies in the future.
A Novel Multiparameter Flow Cytometric Cytotoxicity Assay Detects p53 Deletion as the Major Cause of In Vitro Resistance to Fludarabine in B-Cell Chronic Lymphocytic Leukemia.
Authors: Huang James Z. , Bakke Antony C. , Fan Guang , Braziel Rita , Gatter Ken M. , Maziarz Richard T. , Leis Jose F. , Zhong Yanping 
Published: October 2019

Abstract
Individual patients with B-CLL demonstrate variable responses to standard induction and salvage therapeutic regimens. It would be highly desirable to develop a predictable and reproducible laboratory diagnostic strategy that guides the selection of appropriate drugs and/or regimens based on the drug sensitivity and resistance profiles of leukemic cells for individual patients. As a first step towards this goal, a study was designed to investigate the differences of in vitro drug sensitivity profiles of leukemic cells with different cytogenetic abnormalities from CLL patients. CLL cells from 43 patients were incubated in vitro with four commonly used chemotherapeutic agents (fludarabine, chlorambucil, cladribine or prednisolone) individually or in combination. Multiparameter flow cytometry was utilized to determine the decrease in leukemic cell viability after drug exposure. Both fresh and cryopreserved samples were assessed and were found to be equivalent for assay, regardless of the percentage of B-CLL cells or the degree of spontaneous apoptosis. The highest in vitro resistance to fludarabine, was seen in all seven cases of B-CLL cells with deletions of p53, a cytogenetic abnormality associated with poor clinical outcome. Interestingly, in vitro response to chlorambucil and prednisolone was seen some CLL cases with p53 deletion and correlated with clinical response to these drugs. In CLL cases without p53 deletion, a marked variability in vitro drug sensitivity CLL cells was observed but no significant difference was detected among cases with normal cytogenetics (n=13), ATM deletion (n=4), trisomy 12 (n=3), or 13q deletion (n=7). Our findings provide direct evidence of cellular resistance to fludarabine in CLL associated with p53 deletion, confirming prior clinical observations. In vitro drug sensitivity assay may prove useful in guiding choices for therapy for CLL patients based on the drug sensitivity profile of leukemic cells in individuals.
High Incidence of Bcl-2/IgH Rearrangement in Mexican Patients With Follicular Lymphoma and Its Relevance as a Marker for Minimal Residual Disease.
Authors: Arana Rosa M. , Sobrevilla-Calvo Pedro , Rivas-Vera Silvia , Baez Enrique , Baltazar Severiano , Duque Jorge , Gregorio Ignacio , Tripp Francisco , Garces Oscar , Aguilar Luis , Flores Luis 
Published: October 2019

Abstract
Follicular lymphoma is frequently associated with the chromosomal rearrangement t(14;18)(q32;q21), which joints one of the JH segments of the heavy chains of immunoglobulins (IgH) gene in 14q32 with the Bcl-2 gene in 18q2, originating a chimeric protein. The frequency of this marker is unknown in the Mexican population.
OBJECTIVE: To determine the incidence of the Bcl2-IgH rearrangement in Mexican patients with follicular lymphoma and its frequency as a marker of minimal residual disease after therapy.
PATIENTS AND METHODS: 200 patients (102 male and 98 female) were evaluated; the analysis was made in peripheral blood samples (PB) in 64 cases (32%) or bone marrow (BM) in 136 (68%). Genomic DNA was obtained and the Bcl-2/IgH rearrangement was amplified by both PCR and nested PCR using primers for JH and exon-intron 3 region of Bcl-2 (MBR and MCR regions). The Bcl-2/IgH rearrangement was used as a marker to determine minimal residual disease (MDR) in 90 out of 200 patients in clinical remission, with a follow up ranging from 12 to 60 months; The incidence and tissue type analysis were compared using chi-square statistics.
RESULTS AND DISCUSSION: We found a positive Bcl-2/IgH rearrangement in 80% of the Follicular NHL cases, with a breakage in the MBR region in 160 cases and in MCR in 10 cases, in the remaining 30 patients the Bcl-2/IgH was negative. We detected the Bcl-2/IgH rearrangement more frequently in the BM samples (86%) than in the PB (42%) (p<0.0001). Fifty of 90 initially Bcl-2/IgH positive patients converted to negative PCR, after treatment. It is also of interest that in this population the molecular response rates in BM were lower (18/50=36%) than in the PB (32/50=64%) (p<0.0001). In conclusion we found a high frequency of Bcl-2/IgH rearrangement in cases of follicular lymphoma in Mexican patients, highlighting the relevance of the molecular analysis at diagnosis and its use as a marker for molecular minimal residual disease.
Expression of Leukemia-Associated Antigens (LAA) in Patients with Acute Myelogenous Leukemia (AML).
Authors: Schoettker Bjoern , Reimer Peter , Kunzmann Volker , Einsele Hermann , Weissinger Florian 
Published: October 2019

Abstract
Introduction: Immunotherapeutic approaches may be effective additional options to conventional chemotherapy and stem cell transplantation regimens in the treatment of patients with acute myelogenous leukaemia (AML). Without eliciting significant side effects they may help to prolong disease-free survival or at least may delay the time to progression. Immuniotherapeutic strategies comprise vaccination with professional antigen-presenting dendritic cells or transfusion of T-cells with specific anti-leukemic activity. Leukemia-associated antigens are useful targets as they are expressed predominantly in the malignant cells and constitutively not detectable in normal tissue, or as they are at least significantly overexpressed in the leukemic blasts. To determine potential targets for specific immunotherapy in our patients with AML, we started to analyze the antigen profiles of these patients’ leukemia cells using the previously characterized leukemia-associated antigens survivin, WT1, and proteinase-3 (with the HLA-A2-specific nonameric peptide PR-1), and c-Ski, an antigen recently found to be predominantly but not exclusively overexpressed in AML with deletion or monosomy of chromosome 7, indicating a poor prognosis.
Methods: The mRNA expression of the above mentioned antigens was examined by conventional RT-PCR. Blasts from patients with AML were collected at diagnosis or at first relapse from peripheral blood and analyzed.
Results: The antigen expression pattern in comparison to the AML cell lines HL-60 and K-562 is shown in Table 1.
Conclusions: Although treatment of AML patients became more effective during the last decades, high relapse rates contribute to the poor prognosis of the disease. Additional therapeutic strategies are needed to help and prevent disease relapse. Immunotherapy directed to LAA might elicit specific CTL responses effectively eliminating minimal residual disease. Using the LAA profile shown above, we should be able to determine at least one antigen in each patient with AML to serve as a target for individual specific immunotherapy with antigen-loaded autologous dendritic cells or /and specific autologous T-cells.
Table 1: Expression pattern of the LAA survivin, WT1, proteinase-3 und c-Ski in AML cell lines HL-60 and K-562, and in seven patients with AML. +/++/+++ positive, - negative, n.d. not determined yet -actinβ survivin WT-1 PRO3 c-ski HL-60 +++ +++ ++ + +++ K-562 +++ ++ ++ − − B.R. +++ +++ ++ +++ +++ B.G. +++ − ++ + − B.C. +++ − n.d. n.d. n.d. E.B. +++ − − n.d. n.d. E.E. +++ +++ +++ ++ + S.T. +++ +++ +++ ++ + V.B. +++ +++ n.d. n.d. n.d.