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For finding better method of acute myeloid leukaemia (AML) induction, we designed a prospective clinical trial to find a more effective regimen with least toxicity for induction therapy of AML. Hence, we examined different accepted doses of daunorubicin and their outcomes. Total of 114 patients were included in the study. Fifty-five patients received 60 mg/m of daunorubicin (arm 1) 1 h IV infusion for 3 days, and the remaining 59 received 80 mg/m (arm 2) 1 h IV infusion for 3 days. Continuous infusion of 100 mg/m /day of cytosine arabinozide IV for 24 h for 7 days was given in both groups. Complete remission rate was 77.78% in group 1 and 76.92% in group 2 (p = 0.92). One-year overall survival was 55.85% [standard error (SE) = 8.05%] in arm 1 and 57.94% (SE = 7.32%) in arm 2. Median follow-up time was 11.1 (SE = 1.43) and 10.28 (SE = 1.29) months, respectively. One-year disease-free survival was 64.41% (SE = 7.39%) in arm 1 and 54.86% (SE = 7.53%) in arm 2. Complete remission, overall survival and disease-free survival were statistically the same in both groups (p = 0.92, 0.697, 0.31). Toxicity and safety profile were similar in two groups but need to transfusion was higher in arm 2. Febrile neutropenia, days of antibiotics consumption and invasive fungal infection prevalence did not show any difference. Mean transfused packed cells and platelets rate were higher in the group that received higher dose of daunorubicin. Considering these results, we found that 60 mg/m of daunorubicin would be more rational and as effective with lower toxicity to 80 mg/m in induction therapy of AML patients at least as scheduled in our trial. Copyright © 2015 John Wiley & Sons, Ltd.
Copyright © 2015 John Wiley & Sons, Ltd.
A whole-genome approach was used to investigate the genetic determinants of cytarabine-induced cytotoxicity. We performed a meta-analysis of genome-wide association studies involving 523 lymphoblastoid cell lines (LCLs) from individuals of European, African, Asian, and African American ancestry. Several of the highest-ranked single-nucleotide polymorphisms (SNPs) were within the mutated in colorectal cancers (MCC) gene. MCC expression was induced by cytarabine treatment from 1.7- to 26.6-fold in LCLs. A total of 33 SNPs ranked at the top of the meta-analysis (P < 10(-5)) were successfully tested in a clinical trial of patients randomized to receive low-dose or high-dose cytarabine plus daunorubicin and etoposide; of these, 18 showed association (P < .05) with either cytarabine 50% inhibitory concentration in leukemia cells or clinical response parameters (minimal residual disease, overall survival (OS), and treatment-related mortality). This count (n = 18) was significantly greater than expected by chance (P = .016). For rs1203633, LCLs with AA genotype were more sensitive to cytarabine-induced cytotoxicity (P = 1.31 × 10(-6)) and AA (vs GA or GG) genotype was associated with poorer OS (P = .015), likely as a result of greater treatment-related mortality (P = .0037) in patients with acute myeloid leukemia (AML). This multicenter AML02 study trial was registered at www.clinicaltrials.gov as #NCT00136084.
The antiapoptotic Bcl-2 family member Mcl-1 is a PEST protein (containing sequences enriched in proline, glutamic acid, serine, and threonine) and is subject to rapid degradation via multiple pathways. Impaired degradation leading to the maintenance of Mcl-1 expression is an important determinant of drug resistance in cancer. Phosphorylation at Thr 163 in the PEST region, stimulated by 12-O-tetradecanoylphorbol acetic acid (TPA)-induced activation of extracellular signal-regulated kinase (ERK), is associated with Mcl-1 stabilization in BL41-3 Burkitt lymphoma cells. This contrasts with the observation that Thr 163 phosphorylation in normal fibroblasts primes glycogen synthase kinase (GSK3)-induced phosphorylation at Ser 159, producing a phosphodegron that targets Mcl-1 for degradation. In the present follow-up studies in BL41-3 cells, Mcl-1 degradation was found to be independent of the GSK3-mediated pathway, providing a parallel to emerging findings showing that Mcl-1 degradation through this pathway is lost in many different types of cancer. Findings in Mcl-1-transfected CHO cells corroborated those in BL41-3 cells in that the GSK3-targeted phosphodegron did not play a major role in Mcl-1 degradation, and a phosphomimetic T163E mutation resulted in marked Mcl-1 stabilization. TPA-treated BL41-3 cells, in addition to exhibiting Thr 163 phosphorylation and Mcl-1 stabilization, exhibited an ∼10-fold increase in resistance to multiple chemotherapeutic agents, including Ara-C, etoposide, vinblastine, or cisplatin. In these cancer cells in which Mcl-1 degradation is not dependent on the GSK3/phosphodegron-targeted pathway, ERK activation and Thr 163 phosphorylation are associated with pronounced Mcl-1 stabilization and drug resistance - effects that can be suppressed by inhibition of ERK activation.
Neural stem cells (NSCs) persist in the subventricular zone (SVZ) of the adult brain. Location within this germinal region determines the type of neuronal progeny NSCs generate, but the mechanism of adult NSC positional specification remains unknown. We show that sonic hedgehog (Shh) signaling, resulting in high gli1 levels, occurs in the ventral SVZ and is associated with the genesis of specific neuronal progeny. Shh is selectively produced by a small group of ventral forebrain neurons. Ablation of Shh decreases production of ventrally derived neuron types, while ectopic activation of this pathway in dorsal NSCs respecifies their progeny to deep granule interneurons and calbindin-positive periglomerular cells. These results show that Shh is necessary and sufficient for the specification of adult ventral NSCs.
Copyright © 2011 Elsevier Inc. All rights reserved.
BACKGROUND - Research on the physical and psychological late effects of treatment of childhood cancer has led to the identification of significant long-term neurocognitive deficits experienced by some survivors, particularly in the areas of memory and executive functioning. Despite indications of deficits based on cognitive assessment, the identification of specific mechanisms of neurocognitive deficits using neuroimaging techniques has yet to be adequately considered.
PROCEDURE - This study used functional neuroimaging techniques to examine working memory and executive functioning deficits of survivors of childhood acute lymphocytic leukemia (ALL), as compared to age- and gender-matched healthy controls.
RESULTS - There was a trend for ALL survivors to perform more poorly on a working memory task in terms of overall accuracy. Additionally, survivors displayed significantly greater activation in areas underlying working memory (dorsolateral and ventrolateral prefrontal cortex) and error monitoring (dorsal and ventral anterior cingulate cortex).
CONCLUSIONS - These results support the theory of compensatory activation in necessary brain regions in order to complete tasks in pediatric ALL survivors, similar to that observed in multiple sclerosis patients. Concurrent examination of testing and brain imaging enables the connection of behavioral observations with underlying neurological characteristics of deficits in survivors and may help provide insight into mechanisms through which deficits appear.
Myeloblasts from Down syndrome (DS) children with acute myeloid leukemia (AML) are significantly more sensitive in vitro to 1-beta-D-arabinofuranosylcytosine (ara-C) and generate higher 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) than non-DS AML myeloblasts. Semiquantitative reverse transcription-PCR analyses demonstrated that transcripts for cytidine deaminase (CDA) were 2.7-fold lower in DS than for non-DS myeloblasts. In contrast, transcripts of cystathionine-beta-synthase and deoxycytidine kinase were a median 12.5- and 2.6-fold higher in DS compared with non-DS myeloblasts. The ratio of deoxycytidine kinase/CDA transcripts significantly correlated with ara-C sensitivities and ara-CTP generation. In clinically relevant AML cell line models, high cystathionine-beta-synthase transcripts in DS CMK cells were accompanied by 10-fold greater ara-C sensitivity and 2.4-fold higher levels of ara-CTP compared with non-DS CMS cells. Overexpression of CDA in non-DS THP-1 cells was associated with a 100-fold decreased ara-C sensitivity and 40-fold decreased ara-CTP generation. THP-1 cells secreted CDA into the incubation media and converted extracellular ara-C completely to 1-beta-D-arabinofuranosyluracil within 30 min. Rapid amplification of 5'-cDNA ends (5'-RACE) and reverse transcription-PCR assays identified short- (sf) and long-form (lf) CDA transcripts in THP-1 cells with different 5' untranslated regions and translational start sites; however, only the latter resulted in the active CDA. Although 5' flanking sequences for both CDA transcripts exhibited promoter activity in reporter gene assays, activity for the CDAlf was low. The presence of several GATA1 binding sites in the CDAsf promoter and the uniform detection of GATA1 mutations in DS megakaryocytic leukemia suggested the potential role of GATA1 in regulating CDA transcription and the CDAsf promoter acting as an enhancer. Transfection of GATA1 into Drosophila Mel-2 cells stimulated the CDAlf promoter in a dose-dependent fashion. Additional identification of the mechanisms of differential expression of genes encoding enzymes involved in ara-C metabolism between DS and non-DS myeloblasts may lead to improvements in AML therapy.
Between 1991 and 1999, 67 patients with acute non-lymphocytic leukemia (ANLL) in complete remission received high dose cytarabine (HiDAC) 3 gm/m2 q12h x 12 doses followed by daunorubicin 45 mg/m2/day x 3 days as consolidation therapy. Five year actuarial event free survival (EFS) was 34% +/- 6%. Age was significantly associated with EFS. EFS was 60% +/- 15% in patients age 20 to 29, 48% +/- 16% in patients age 30 to 39, 23% +/- 10% in patients age 40 to 49, 31% +/- 11% in patients age 50 to 59, and 0% in patients age > or = 60. Contrary to other reports which have used different HiDAC regimens, we found no relationship between cytogenetics and EFS. Cytogenetics were defined as favorable risk: t(8;21), inv (16), and del (16); neutral risk: normal or t(15;17); and unfavorable risk: any abnormality not included in favorable risk or neutral risk. EFS was 29% +/- 17% in patients with favorable cytogenetics, 37% +/- 14% in patients with neutral cytogenetics, and 31% +/- 12% in patients with unfavorable cytogenetics. These differences were not statistically significant. Because of the successful use of allogeneic transplantation at relapse in patients with matched related donors, five year actuarial survival (S) in this series was 40% +/- 6%. Five year actuarial survival was 57% +/- 9% for patients age < or = 44 and 25% +/- 8% for patients age > or = 45. This difference is statistically significant, p < .025. Clinicians should be cautious about making clinical decisions regarding consolidation therapy of ANLL on the basis of the presence or absence of cytogenetic abnormalities as the importance of cytogenetics may depend on the specific therapy which is employed.
Cytosine arabinoside (araC) is an important drug used for the treatment of human leukemias. In order to exert its cytotoxic effects, araC must be incorporated into chromosomal DNA. Although specific DNA lesions that involve base loss or modification stimulate nucleic acid cleavage mediated by type II topoisomerases, the effects of deoxyribose sugar ring modification on enzyme activity have not been examined. Therefore, the effects of incorporated araC residues on the DNA cleavage/religation equilibrium of human topoisomerase IIalpha and beta were characterized. AraC lesions were position-specific topoisomerase II poisons and stimulated DNA scission mediated by both human type II enzymes. However, the positional specificity of araC residues differed from that previously reported for other cleavage-enhancing DNA lesions. Finally, additive or synergistic increases in DNA cleavage were observed in the presence of araC lesions and etoposide. These findings broaden the range of DNA lesions known to alter topoisomerase II function and raise the possibility that this enzyme may mediate some of the cellular effects of araC.
The purpose of this study was to examine the feasibility of administering all chemotherapy pre-operatively to patients with resectable adenocarcinoma of the oesophagus or gastrooesophageal junction. 32 patients with potentially resectable adenocarcinoma of the oesophagus or gastrooesophageal junction were studied in a stepwise fashion in which combination chemotherapy with cisplatin, high-dose arabinoside and 5-fluorouracil was administered. In the first part, 15 patients were to receive three chemotherapy courses pre-operatively and two chemotherapy courses postoperatively. In the second part, the next 15 patients were to receive all five chemotherapy courses pre-operatively, provided there was an objective response after three courses. Endoscopic ultrasonography was also performed, when feasible, prior to chemotherapy and surgery, and in some patients sequentially between chemotherapy courses. All of the 14 assessable patients in the first group tolerated all three courses of pre-operative chemotherapy, and 86% of patients in this group completed all protocol chemotherapy. In the second group, 9 of 18 (50%) assessable patients tolerated all five courses of preoperative chemotherapy, and 100% of patients in this group received all protocol chemotherapy. The median number of chemotherapy courses for the entire group (32 patients) was five (range one to five). Forty-one per cent (13/32) of patients had a major response to chemotherapy. Sixty-nine per cent (or 76% of 29 patients taken to surgery) had a curative resection. One patient had a pathological complete response. The median survival time of 32 patients was 17 months (range 2-36+ months). 14 patients (37%) remain alive at a median follow-up time of 26+ months. There was a correlation between endoscopic ultrasonographic tumour and nodal stage and pathological tumour and nodal stages in 16 patients. The tumour stage correlation was higher (75%) than the nodal stage correlation (62%). Our data suggest that it is feasible to administer five courses of cisplatin-based chemotherapy to patients with potentially resectable adenocarcinoma of the oesophagus or gastrooesophageal junction. More effective chemotherapy regimens that might result in higher pathological complete response rates and acceptable toxic effects are needed.