Genetic and Metabolic Determinants of Methotrexate Induced Mucositis in Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 939-939
Author(s):  
Marissa den Hoed ◽  
E. Lopez-Lopez ◽  
Mariël L. Te Winkel ◽  
Wim Tissing ◽  
Jasmijn de Rooij ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Plasma Homocysteine ◽  
Nucleotide Polymorphisms ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Plasma Folate ◽  
Pediatric All ◽  
Erythrocyte Folate ◽  
Grade 3

Abstract Introduction: Methotrexate (MTX) is an important and effective chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). However MTX can induce toxicity, which can lead to amendments of treatment and subsequent impaired survival. The aim of this study was to identify metabolic and genetic determinants of MTX toxicity. Patients and Methods: In this prospective study, 134 Dutch pediatric ALL patients were treated with four high dosages MTX (HD-MTX: 5 g/m2) every other week according to the DCOG-ALL10 protocol. Toxicity was prospectively scored and a National Cancer Institute (NCI) grade ≥3 was considered clinically relevant toxicity. Plasma MTX levels were measured at 24 and 48 hours after each HD-MTX infusion. Erythrocyte folate, plasma folate and plasma homocysteine levels were determined at the start of protocol M. Seventeen single nucleotide polymorphisms (SNPs) in 7 candidate genes in the MTX pathway were analyzed. Results: Grade ≥3 mucositis occurred in 20% of the patients, skin toxicity in 7%, diarrhea in 3%, and neurotoxicity in 3%. Mucositis occurred especially after the first course compared to the other courses (p=0.006). Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher baseline levels of erythrocyte folate (median 1.2 μmol/L vs. 1.4 μmol/L, p<0.008). Wildtype rs7317112 in the ABCC4 gene was the only SNP associated with a higher frequency of mucositis (AA (39%) vs. AG/GG (15%), p=0.016). Conclusion: Mucositis is the most frequent occurring toxicity during the HD-MTX phase in pediatric ALL treatment, and occurs especially after the first MTX course. Only a higher baseline erythrocyte folate, which reflects the accumulation of MTX polyglutamates in mucosal cells, and the wild-type variant of rs7317112 SNP in ABCC4 were determinants of mucositis in pediatric ALL during MTX-HD treatment. Disclosures No relevant conflicts of interest to declare.

CNOT1 Microrna Single Nucleotide Polymorphism (SNP) Determines the Occurrence of Methotrexate Related Mucositis in Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1237-1237
Author(s):  
Natanja Oosterom ◽  
Ángela Guttiérez-Camino ◽  
Marissa Den Hoed ◽  
Elixabet López-López ◽  
Saskia MF Pluijm ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Candidate Snps ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All ◽  
Grade 3 ◽  
And Function

Abstract BACKGROUND Cure rates of pediatric acute lymphoblastic leukemia (ALL) have reached 90% in the developed countries. However, toxicity due to chemotherapeutic regimens occurs frequently but with great heterogeneity. This suggests that genetic variation is involved. In order to identify determinants of adverse effects, recent studies have investigated pharmacogenetic features in relation to toxicity. Most of these studies examined coding regions of the genome. Recently, it has been described that epi genetic regulators, such as micro-RNA's (miRNA), might also have an important regulatory function in genes involved in drug related toxicity. In a recent study 25 miRNA SNPs were found to be related to toxicity in pediatric ALL treatment (Lopez-Lopez, PLoS ONE, 2014). In pediatric ALL mucositis is one of the most frequent side effects during high dose methotrexate (MTX) treatment. AIM The aim of this study was to detect novel, epigenetic biomarkers that predict MTX related oral mucositis in pediatric acute lymphoblastic leukemia (B- and T cell) by studying single nucleotide polymorphisms (SNP) involved in miRNA levels and function. METHODS DNA was isolated from whole blood of 118 pediatric ALL patients that were treated with high dose MTX (5 gr/m2) according to the Dutch Childhood Oncology Group ALL-10 protocol. The recently published 25 SNPs, involved in miRNA function and located in the DROSHA, CNOT1, CNOT4, EIF2C1, GEMIN3, GEMIN4, MIR604, MIR453, MIR2110, MIR2053, MIR1294, MIR1206, DICER, XPO5 and TNRC6B genes, were selected for genotyping. Toxicity data during the consolidation phase were prospectively collected and documented according to the National Cancer Institute (NCI) v.3.0 score system. Mucositis NCI grade ≥ 3 (grade 3: confluent ulcerations, bleeding with minor trauma), was considered as clinical significant toxicity and was used as endpoint. RESULTS Mucositis was the only recurring toxicity in this prospectively well-documented cohort and therefore used as endpoint of this study. A selection of 20 of the previously identified 25 candidate SNPs was studied based on technical feasibility. In addition, 1 SNP in the XPO 5 gene was not considered for analysis because it was not in Hardy Weinberg equilibrium. Mucositis occurred in 19% of the patients in at least one of the MTX courses. Only the TT genotype of rs11866002 in the CNOT1 (CCR4-NOT complex, subunit 1) gene was associated with a higher risk of developing mucositis (NCI ≥ 3) compared to carries of CC/CT. The other 18 candidate SNPs analyzed did not show statistically significant associations. CONCLUSION The inter-patient variability of mucosal toxicity was not associated with most of our investigated SNPs which are involved in miRNA transcription and function. CNOT1 rs11866002 C>T was the only single nucleotide polymorphism associated with the occurrence of oral mucositis during pediatric acute lymphoblastic leukemia treatment. We acknowledge the Foundation Children Cancerfree (KiKa), Amstelveen, The Netherlands, for funding this research. Disclosures No relevant conflicts of interest to declare.

scholarly journals Transient Elevations in Markers of Hepatic Function during Pediatric Acute Lymphoblastic Leukemia Treatment Are Common but Do Not Influence Outcomes: A Study of 805 Patients from the Learn Consortium

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3814-3814
Author(s):  
Joanna S. Yi ◽  
Tiffany Chambers ◽  
Kelly D Getz ◽  
Tamara P. Miller ◽  
Evanette Burrows ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Intensity ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Chemotherapeutic Agents ◽  
Children's Hospital ◽  
Children’S Hospital ◽  
Pediatric All ◽  
Grade 3 ◽  
All Treatment

Introduction: Hepatotoxicity is a frequent and challenging adverse event in children with acute lymphoblastic leukemia (ALL), but patient factors that are predictive of hepatotoxicity are not well understood. We leveraged a data repository jointly developed by two pediatric oncology centers within the Leukemia Electronic Abstraction of Records [LEARN] Consortium to assess the landscape and determinants of liver dysfunction throughout ALL therapy in patients who were risk-stratified to receive either standard- or high-intensity treatment blocks. Methods: The subjects were children ages 1-21 years who were treated for ALL between 2006-2014 at either Children's Hospital of Philadelphia or Texas Children's Hospital. Demographics, disease-related data, and every laboratory value collected during treatment were obtained by targeted manual abstraction and extensive semi-automated extraction of patient electronic medical record (EMR) data. To reduce cohort heterogeneity, we excluded patients who received non-standard ALL therapies. Patients were categorized as receiving either standard-intensity or high-intensity treatment for their first three blocks of therapy (Induction, Consolidation, Interim Maintenance 1 [IM1]) based on chemotherapeutic agents delivered in those blocks. Differences in laboratory value-determined hepatoxicity were then analyzed based on this categorization for all remaining phases of therapy. Hepatic lab values (AST [SGOT], ALT [SGPT], total bilirubin [t. bili], and conjugated bilirubin [c. bili]) were first normalized to the age-based upper limit of normal (ULN), and the median value was then determined. A multivariate mixed-effects linear regression model with random effects was used to identify differences in the treatment group medians and the following covariates: age, race/ethnicity, sex, BMI, and ALL immunophenotype. Laboratory values were classified by the CTCAE v5.0 grading system, with grade ≥ 3 considered 'elevated.' Results: 805 pediatric ALL patients were included in the analysis, representing 114,095 hepatic lab values (Table 1). Less than 10% of patients had elevated lab values at diagnosis. Throughout treatment, the majority of lab values fell within 1-2x ULN for age for both standard- and high-intensity treatment groups (Fig. 1a-d). The median hepatic lab values for the high-intensity group were slightly higher than the standard risk group across all treatment phases, and this difference was most consistently significant in Consolidation and Delayed Intensification. Among the four hepatic labs that were assessed, ALT had the most significant deviation above normal (up to 30x ULN, Fig 1a). Patients were more likely to have elevated transaminases during maintenance than prior to maintenance (Fig. 1e). Similarly, but to a lesser degree, patients were more likely to have elevated t. or c. bili during maintenance than prior to maintenance. Age, race, and BMI were correlated with elevated hepatic labs, with Hispanic and/or overweight patients more likely to have elevations in 3 or more phases of therapy (Table 2). However, no hepatic lab abnormalities were correlated with either overall or relapse-free survival. Conclusions: This is the first comprehensive study of measures of hepatotoxicity in a large and uniformly-treated cohort of pediatric ALL. While significantly elevated hepatic labs are rare at diagnosis, they are common during ALL treatment and are seen more commonly in maintenance than in prior phases. Patients who are overweight and/or Hispanic are more likely to experience grade 3 or higher hepatoxicity. We observed no relationship between hepatotoxicity and relapse or survival. Further studies are ongoing to delineate the temporal correlation of liver function and chemotherapy dosing and administration. Disclosures No relevant conflicts of interest to declare.

Role of Matrix Metalloproteinase MMP-2, MMP-9 and Tissue Inhibitor of Metalloproteinase (TIMP-1) in Clinical Progression of Pediatric Acute Lymphoblastic Leukemia

2021 ◽  
Author(s):  
Maha Saleh ◽  
Mohamed Khalil ◽  
Mona S. Abdellateif ◽  
Emad Ebeid ◽  
Eman Z. Kandeel
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Count ◽  
Cancer Progression ◽  
Lymphoblastic Leukemia ◽  
Multivariate Logistic Regression Analysis ◽  
Blast Cell ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All

Abstract Background: Matrix metalloproteinases (MMPs) play a crucial role in cancer progression and metastasis, however their role in pediatric Acute lymphoblastic leukemia (ALL) is still unrevealed.Methods: The diagnostic, prognostic and predictive value of tissue inhibitor of metalloproteinase (TIMP-1), MMP-2, MMP-9 and CD34+CD38- CSCs were assessed in bone marrow (BM) samples of 76 ALL children using Flow Cytometry analysis. Results: There was a significant increase in TIMP-1 [1.52 (0.41-10) versus 0.91(0.6-1.12); respectively, P<0.001], and CSCs CD84+CD38- [1 (0.03-18.6) versus 0.3 (0.01-1.1), P<0.001] expression in ALL patients compared to controls. While there were no significant differences regarding MMP-2 and MMP-9 expression between the two groups. The sensitivity, specificity, AUC of MMP-2 were (80.3%, 53.3% and 0.568, P=0.404), and that of MMP-9 were (53.9%, 40% and 0.660, P=0.053). While that of TIMP-1 were (78.9%, 100% and 0.892, P<0.001), and that of CSCs CD34+ CD38- were (78.9%, 73.3% and 0.855, P<0.001). There was a significant association between MMP-2 overexpression and MRD at day-15, increased BM blast cell count at diagnosis and at day-15, (P=0.020, P=0.047 and P=0.001). Increased TIMP-1 expression associated with the high-risk disease (P<0.001), increased BM blast cell count at diagnosis and at day-15 (P=0.033 and P=0.001), as well as MRD at day 15 and day 42 (P<0.001 for both). CD34+CD38- CSCs associated with MRD at day-15, increased BM blast cell count at diagnosis and at day-15 (P=0.015, P=0.005 and P=0.003). TIMP-1 overexpression associated with shorter DFS and OS rates (P=0.009 and P=0.048). Multivariate logistic regression analysis showed that both TIMP-1 [OR: 4.224, P=0.046], and CD34+CD38- CSCs [OR: 6.873, P=0.005] are independent diagnostic factors for pediatric ALL.Conclusion: TIMP-1 and CD34+CD38- CSCs could be useful independent diagnostic markers for pediatric ALL. Also, TIMP-1 is a promising prognostic marker for poor outcome of the patients.

Improving pneumococcal vaccination rates in pediatric acute lymphoblastic leukemia/lymphoblastic lymphoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18666-e18666
Author(s):  
Simone Chang ◽  
Alexandra Cheerva ◽  
Michael Angelo Huang ◽  
Kerry McGowan ◽  
Esther E Knapp ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Pneumococcal Vaccination ◽  
Vaccination Rate ◽  
Lymphoblastic Lymphoma ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Vaccination Rates ◽  
Targeted Interventions ◽  
Pediatric All

e18666 Background: Pediatric Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma (ALL/LLy) is the most common pediatric cancer. Invasive pneumococcal disease (IPD) is prevalent in this population and the Centers for Disease Control and Prevention recommends pneumococcal vaccination to decrease morbidity and mortality. Despite these recommendations, vaccination rates remain low and the incidence of IPD among children with hematologic malignancy is significantly higher compared to the average pediatric population. An interventional study was designed to improve the vaccination rate and reduce the incidence of IPD in our institution. Methods: A plan-do-study-act (PDSA) model of quality improvement (QI) was used. Chart review at our institute was done for the 6-month period of January 2020 - June 2020 and baseline rates for pneumococcal polysaccharide (PPSV23) vaccination were calculated. Patients were included if they were ≥ 2 years old, diagnosed with ALL/LLy, and undergoing maintenance. A multidisciplinary team performed the root cause analysis. Immunization records were obtained and reviewed and targeted interventions were implemented. The interventions used are outlined in Table. The percentage of pediatric ALL/LLy patients per month in maintenance who received age-appropriate pneumococcal vaccinations was monitored before and after the interventions. Results: Analysis of the 6-month retrospective cohort (n=36) showed a baseline vaccination rate of 5.5%. During the subsequent 6-month phase with interventions, 40 patients were prospectively enrolled. Demographics showed a mean age of 10.2 years (range, 2-21) and a predominantly male (66.7%) cohort. B-cell ALL/LLy comprised the majority (78.9%); the rest included T-cell ALL/LLy and mixed phenotype acute leukemia. As seen in Table, the percentage receiving at least 1 pneumococcal vaccine increased from 5.5% to 84.8% over the first 3 months, this plateaued around 81%. Completion of the series mirrored this and increased to 74.2%. Pre-visit planning and cues proved to be the most helpful interventions. Conclusions: Use of a PDSA model successfully improved pneumococcal vaccination rates in the pediatric ALL/LLy population. We suggest these results can be achieved with planning and implementation of the outlined interventions. [Table: see text]

scholarly journals Methionine synthase A2756G polymorphism influences pediatric acute lymphoblastic leukemia risk: a meta-analysis

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Li-Min Ma ◽  
Hai-Ping Yang ◽  
Xue-Wen Yang ◽  
Lin-Hai Ruan
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Large Scale ◽  
Lymphoblastic Leukemia ◽  
Meta Analysis ◽  
Population Based ◽  
Methionine Synthase ◽  
China National Knowledge Infrastructure ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All ◽  
And Control

Abstract Plenty of studies have investigated the effect of methionine synthase (MTR) A2756G polymorphism on risk of developing pediatric acute lymphoblastic leukemia (ALL), but the available results were inconsistent. Therefore, a meta-analysis was conducted to derive a more precise estimation of the association between MTR A2756G polymorphism and genetic susceptibility to pediatric ALL. The PubMed, Embase, Google Scholar, Web of Science, ScienceDirect, Wanfang Databases and China National Knowledge Infrastructure were systematically searched to identify all the previous published studies exploring the relationship between MTR A2756G polymorphism and pediatric ALL risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the strength of association. Sensitivity analysis and publication bias were also systematically assessed. This meta-analysis finally included ten available studies with 3224 ALL cases and 4077 matched controls. The results showed that there was significant association between MTR A2756G polymorphism and risk of pediatric ALL in overall population (AG vs. AA: OR = 1.13, 95%CI = 1.02–1.26, P = 0.02; AG+GG vs. AA: OR = 1.13, 95%CI = 1.02–1.25, P = 0.01; G allele vs. A allele: OR = 1.10, 95%CI = 1.01–1.20, P = 0.03). In the stratification analyses by ethnicity, quality score and control source, significant association was found in Caucasians, population-based designed studies and studies assigned as high quality. In conclusion, this meta-analysis suggests that MTR A2756G polymorphism may influence the development risk of pediatric ALL in Caucasians. Future large scale and well-designed studies are required to validate our findings.

scholarly journals Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 468
Author(s):  
Nikola Kotur ◽  
Jelena Lazic ◽  
Bojan Ristivojevic ◽  
Biljana Stankovic ◽  
Vladimir Gasic ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Allele Frequency ◽  
Methylenetetrahydrofolate Reductase ◽  
Lymphoblastic Leukemia ◽  
Statistical Modelling ◽  
Joint Effect ◽  
Allele Frequency Distribution ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Consolidation Phase ◽  
Pediatric All

Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.

scholarly journals Opposing regulation of BIM and BCL2 controls glucocorticoid-induced apoptosis of pediatric acute lymphoblastic leukemia cells

Blood ◽  
2015 ◽  
Vol 125 (2) ◽  
pp. 273-283 ◽  
Author(s):  
Duohui Jing ◽  
Vivek A. Bhadri ◽  
Dominik Beck ◽  
Julie A. I. Thoms ◽  
Nurul A. Yakob ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Glucocorticoid Receptor ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Intronic Region ◽  
Key Points ◽  
Pediatric All ◽  
Induced Apoptosis

Key Points The glucocorticoid receptor coordinately regulates the antiapoptotic BCL2 and proapoptotic BIM genes in pediatric ALL cells in vivo. GR binding at a novel intronic region is associated with BIM transcription and dexamethasone sensitivity in pediatric ALL cells in vivo.

In-Vitro Efficacy of the Deoxyguanoside Analogs Forodesine (BCX-1777) and ARA-G in Pediatric Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2038-2038
Author(s):  
Irene Homminga ◽  
Michel C. Zwaan ◽  
Amel Seghouani ◽  
Chantal Y. Manz ◽  
Shanta Bantia ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Nucleoside Transporter ◽  
Nucleotide Synthesis ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Expression Levels ◽  
Lc50 Value ◽  
Pediatric All

Abstract Abstract 2038 Poster Board II-15 Purine nucleoside phosphorylase (PNP) deficiency in humans is associated with elevated deoxyguanosine (dGuo) plasma levels. DGuo is converted into dGTP inducing apoptosis in T-cells and this provides the rationale for the development of deoxyguanosine analogues as a potential treatment option for T-cell malignancies. Forodesine (BCX-1777; BioCryst-Mundipharma) is an efficient blocker of PNP activity, thereby boosting the conversion of dGuo into dGTP and raising intracellular dGTP levels. AraG (9-b-D-arabinofuranosyl-guanine) is a compound that is resistant to PNP-mediated degradation that is efficiently converted into AraGTP. AraGTP becomes incorporated in the DNA, blocking DNA synthesis and promoting apoptosis. In a phase II clinical trial, the AraG prodrug Nelarabine enforced a complete remission rate of 55% for pediatric T-ALL patients at 1st relapse. (Berg, JCO 2005). Clinical data of Forodesine treatment in pediatric ALL patients are not yet available. As tested on primary pediatric acute lymphoblastic leukemia (ALL) patient samples (4 T-ALL, 2 BCP-ALL), 1μM of Forodesine is sufficient to completely block PNP and abolish rapid dGuo degradation resulting in a median 7.9 (range 0.5-378) fold raise of intracellular dGTP levels. Accumulation of dGTP is comparable for T-ALL (n=31) and BCP-ALL (n=11) patient samples. This reflects equal intrinsic ability of salvage nucleotide synthesis for both T-ALL and BCP-ALL cells. Cytotoxic effect of Forodesine was tested on primary leukemia cells from newly diagnosed pediatric ALL patients in-vitro by incubating cells with Forodesine (1μM) in the presence of increasing concentrations of dGuo (0.001-50μM). In accordance with selective T-cell toxicity, T-ALL cells were more sensitive to Forodesine/dGuo treatment (median T-ALL LC50 value: 1.1μM dGuo/1μM Forodesine, n=27, p=0.001) compared to BCP-ALL cells, which had a median LC50 value of 8.8μM dGuo/1μM Forodesine (n=30). All patients that responded demonstrated dGTP accumulation (1.5-222.1 fold), although the raise of dGTP levels did not correlate with Forodesine/dGuo toxicity (r2= 0.10, p=0.22). Studying in-vitro responsiveness to AraG, T-ALL cells were more sensitive compared to BCP-ALL cells (p=0.0002) with a median AraG LC50 value of 20.5μM for T-ALL samples (n=24) versus 48.3μM for BCP-ALL samples (n=20). Remarkably, TELAML1 positive BCP-ALL cases were insensitive to AraG treatment (median LC50 value >50μM, n=9). No correlation was identified between in-vitro Forodesine/dGuo and AraG cytotoxicities (r2=0.05, p=0.29). Most patient samples that displayed AraG resistance still responded to Forodesine/dGuo treatment. This may be explained by the fact that the uptake of both drugs may be facilitated by different transporters. Using RQ-PCR we could demonstrate that AraG toxicity, in contrast to Forodesine, was significantly associated with ENT1 (equilibrative nucleoside transporter 1) expression levels (p=0.008), which was previously identified as strong predictor for AraC cytotoxicity in pediatric ALL (Stam RW. et al., Blood 2003). AraG cytotoxicity strongly correlated with AraC cytotoxicity (r2=0.71, p<0.0001). We found no significant correlation between Forodesine sensitivity and the expression levels of other nucleoside transporters (CNT1, CNT2, CNT3, ENT2), kinases (dCK, dGK), nucleotidases (NT5C1A, NT5C2, PNI) or other enzymes that are involved in dGuo metabolism (PNP, RRM1, RRM2). In conclusion, T-ALL cells are more sensitive to Forodesine/dGuo treatment in-vitro than BCP-ALL cells that have nearly 8 fold higher dGuo LC50 values. Resistance to AraG treatment does not preclude responsiveness to Forodesine treatment and vice versa, indicating that Forodesine and AraG rely on different cellular mechanisms for cytotoxicity, possibly involving differences in dependence on the nucleoside transporter ENT1. Disclosures: No relevant conflicts of interest to declare.

Triptolide Induces Apoptosis In Acute Lymphoblastic Leukemia Cells by Inhibition of the Oncoprotein MDM2

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4934-4934
Author(s):  
Mei Huang ◽  
Lubing Gu ◽  
Muxiang Zhou
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Biological Action ◽  
Leukemic Cells ◽  
Transcriptional Level ◽  
Antitumor Effects ◽  
Mdm2 Expression ◽  
Pediatric All ◽  
Chinese Plant

Abstract Abstract 4934 Triptolide, a nature product derived from the Chinese plant Tripterygium wilfordii, is reported to exhibit antitumor effects in a broad range of cancers. Recent studies indicate that the antitumor activity of triptolide is associated with its biological action to inhibit expression of many oncoproteins and anti-apoptotic or survival factors that were expressed in the cancer cells. Herein, we demonstrate that triptolide induces apoptosis in a subgroup of acute lymphoblastic leukemia (ALL) cells that overexpress MDM2 oncoprotein by inhibiting the MDM2 expression. In pediatric ALL, overexpression of MDM2 by leukemic cells is typically associated with a wild-type (wt) p53 phenotype and resistance to conventional chemotherapeutic drugs such as doxorubicin. In the present study, we evaluated the role of triptolide in regulating MDM2 and in inducing apoptosis, as compared to doxorubicin, using ALL lines and primary ALL samples. In contrast to doxorubicin, which induced p53 activation and a subsequent upregulation of MDM2, triptolide strongly induced persistent inhibition of MDM2 followed by a steady-state activation of p53, which resulted in potent apoptosis of the MDM2-overexpressing ALL cells tested, even if they were doxorubicin-resistant. We discovered that triptolide's inhibition of MDM2 in ALL cells occurred at the post-transcriptional level through inhibition of mRNA synthesis. Because p53 function is inhibited by MDM2 in chemoresistant/MDM2-overexpressing ALL cells, potent killing of these cells by triptolide suggests that this naturally-derived agent may be a novel therapeutic for refractory ALL. Disclosures: No relevant conflicts of interest to declare.

Targeting Survivin with YM155 As a Potential Therapy in Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2490-2490
Author(s):  
Abdusebur Jemal ◽  
Jeffrey W Tyner ◽  
Mathew Thayer ◽  
Markus Muschen ◽  
Brian J. Druker ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Ectopic Expression ◽  
Survivin Expression ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All

Abstract Abstract 2490 Background: Pediatric Acute Lymphoblastic Leukemia (ALL) remains the most common pediatric malignancy. Despite advances in treatment and outcomes, there continue to be subsets of patients that are refractory to standard intensive chemotherapy and hematopoietic stem cell transplant. Therefore, novel gene targets for therapy are needed to further advance treatment for this disease. Survivin, a member of the chromosome passenger complex and inhibitor of apoptosis has been shown to be over-expressed in malignant cells and in relapsed ALL. Therefore, survivin may be a potential target for therapy in pediatric ALL. The selective survivin suppressant, YM155 (Astellas) has been shown to inhibit survivin expression and activate cell death in multiple cell lines. Early phase I studies show promise in both tolerability and possible efficacy in B-cell malignancies. Therefore, this drug may have the potential of improving treatment for pediatric B-cell precursor ALL. Design/methods: Pediatric lymphoblastic cell lines, fresh primary lymphoblast cells from newly diagnosed patients with ALL and xenografted patient samples were used in this study. Cells were incubated in the presence of YM155 at doses ranging from 1nM to 10μM. Viability was measured using a standard methane-thiosulfonate viability assay. Activation of apoptosis was identified using the Guava nexin Annexin V binding assay for cell lines. Results: Treatment of ALL cell lines, primary patient samples and xenograft samples show a dose-dependent sensitivity to YM155 by both activation of apoptosis and by cell viability. IC50 doses for the majority of the samples are in the low nanomolar range (Table). Interestingly, there is some variability amongst patient samples suggesting possible variable responses in vivo. Ectopic expression of survivin in cell lines treated with YM155 rescues the effect of the drug. Further, t(9;22) positive ALL samples, including primary patient, xenograft, and dasatinib resistant samples remain significantly sensitive to YM155. For dasatinib sensitive Ph+ALL samples, combination therapy suggest an additive effect by isobologram analysis. Conclusion: Pediatric ALL samples remain sensitive to treatment with YM155 in cell lines, primary patient and xenografted samples. The results of these experiments will be used as a foundation to develop a comprehensive understanding of the mechanisms of survivin dependence in pediatric ALL. Future studies will also be designed to develop YM155 as an additional therapy for pediatric acute lymphoblastic leukemia. Disclosures: Druker: Cylene:; MolecularMD:; Novartis:; Bristol-Myers-Squibb:.

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