ascorbic-acid and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Vitamin C deficiency in developed countries is typically observed in patients with unique clinical conditions such as cystic fibrosis or anorexia nervosa, or in patients on long-term tube feeds. We report here a clinical observation in six pediatric and adolescent patients (median age 17.5 yr, range 9.8-23.5 yr) with chronic GVHD with mucous membrane involvement found to be vitamin C deficient. These patients' baseline serum vitamin C levels ranged from <0.12 to 0.94 mg/dL (normal value 0.20-1.90 mg/dL), with a mean level 0.56 ± 0.36 mg/dL and a median level 0.6 mg/dL. Among these patients, signs and symptoms of mucositis failed to respond to standard chronic GVHD therapy. After receiving treatment with 2000 mg of ascorbic acid by mouth, daily patients displayed increased serum vitamin C levels. Clinically, this correlated with a remarkable improvement in patients' mucositis and ability to eat.

Topics: Administration, Oral; Adolescent; Adult; Ascorbic Acid; Ascorbic Acid Deficiency; Child; Chronic Disease; Graft vs Host Disease; Humans; Leukemia, Myeloid, Acute; Mucositis; Mucous Membrane; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Scurvy; Stem Cell Transplantation; Young Adult

Vitamin C status and total antioxidant capacity (TAC) in children with acute lymphoblastic leukemia (ALL) was assessed in 28 hospitalized patients and 30 apparently healthy control subjects. It was determined that whereas vitamin C intake in patients with ALL was more than twice as much as in controls, plasma and urinary concentrations of vitamin C were more than 10 times and 2.5 times higher in controls than in the patients with ALL, respectively (P < 0.001). Accordingly, serum TAC levels in the patients with ALL were lower than in healthy subjects (P < 0.001). Vitamin C utilization is increased in children with ALL.

Topics: Adolescent; Antioxidants; Ascorbic Acid; Case-Control Studies; Child; Child, Preschool; Diet; Female; Humans; Iran; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Chemotherapy leads to an increase in reactive oxygen species, which stresses the antioxidant defense system. Children with acute lymphoblastic leukemia rarely are overtly malnourished, which makes this population ideal for an investigation of the relations between dietary antioxidant consumption, plasma antioxidant concentrations, and chemotherapy-induced toxicity.. This study was conducted to investigate the effect of therapy on antioxidant intakes in children with acute lymphoblastic leukemia, the relation between dietary antioxidant intakes and plasma antioxidant concentrations, and the relation between the incidence of side effects due to treatment and antioxidant intake.. We conducted a 6-mo observational study of 103 children with acute lymphoblastic leukemia. Plasma micronutrient concentrations, dietary intakes, and incidence of side effects of chemotherapy were ascertained at diagnosis and after 3 and 6 mo of therapy.. Throughout the 6-mo study period, subjects ingested vitamin E, total carotenoid, beta-carotene, and vitamin A in amounts that were 66%, 30%, 59%, and 29%, respectively, of the US recommended dietary allowance or of the amounts specified in the third National Health and Nutrition Examination Survey. Greater vitamin C intakes at 6 mo were associated with fewer therapy delays, less toxicity, and fewer days spent in the hospital. Greater vitamin E intakes at 3 mo were associated with a lower incidence of infection. Greater beta-carotene intakes at 6 mo were associated with a decreased risk of toxicity.. A large percentage of children undergoing treatment for acute lymphoblastic leukemia have inadequate intakes of antioxidants and vitamin A. Lower intakes of antioxidants are associated with increases in the adverse side effects of chemotherapy.

Topics: Adolescent; Adult; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Child; Child, Preschool; Humans; Medical Records; Nutritional Support; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Regression Analysis; Vitamin E

Changes in oxidative stress in children undergoing chemotherapy for acute lymphoblastic leukemia (ALL) have not been well documented. To determine whether the measurement of the DNA oxidized base 8-oxodeoxyguanosine (8-oxo-dG) may be a useful biomarker in this population, the authors conducted an observational study on 103 children with ALL. Blood samples were collected at diagnosis, during interim maintenance (IM), and during delayed intensification (DI). Blood mononuclear cell 8-oxo-dG, measured with an immunohistochemical method, decreased from diagnosis to IM (P = .01) and increased between IM and DI (P < .01). In a pilot study, bone marrow was also collected from 16 patients at diagnosis and after 28 days of treatment, but 8-oxo-dG remained the same. The relationship between plasma and dietary intake of antioxidants and the level of 8-oxo-dG was also explored. There was a direct relationship between the intake of vitamin E at diagnosis and bone marrow 8-oxo-dG (P = .03) and an inverse relationship between beta-carotene intake and blood 8-oxo-dG at IM (P = .03) and vitamin A in-take and blood 8-oxo-dG at DI (P = .003). Plasma vitamin C (P = .02) and total carotenoids (P = .01) were inversely related to blood 8-oxo-dG at IM. In contrast, higher plasma E/total lipid levels were associated with higher 8-oxo-dG at IM and DI (P < .01). At IM, patients with higher 8-oxo-dG had an increased risk of chemotherapy dose reduction (P = .04). In conclusion, the level of 8-oxo-dG in blood mononuclear cells decreases after the start of chemotherapy and increases during aggressive chemotherapy in children with ALL.

Topics: Adolescent; Adult; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Biomarkers; Blood Chemical Analysis; Bone Marrow; Carotenoids; Child; Child, Preschool; Cohort Studies; Deoxyguanosine; Female; Humans; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Probability; Prognosis; Prospective Studies; Risk Assessment; Sensitivity and Specificity; Statistics, Nonparametric; Survival Rate; Treatment Outcome; Vitamin E

To examine the prevalence of supplement use in persons before receiving hematopoietic stem cell transplant (HSCT) and the association of select supplements with outcomes.. This observational cohort study included a questionnaire on supplement use before HSCT. Nonrelapse mortality, recurrence/relapse, and mortality or relapse (the inverse of disease-free survival) were followed to two years. Subjects/Setting Persons receiving HSCT at the Fred Hutchinson Cancer Research Center between September 1994 and December 1997 were eligible (N=1,182). Statistical Analyses Performed Descriptive statistics and univariate and Cox regression analyses were conducted.. Sixty-six percent of patients used supplements (31% vitamin C, 19% vitamin E, and 20% herbs or others preparations). Vitamin C at > or =500 mg/day was inversely associated with recurrence among persons with breast cancer (RR=0.11; 95% CI, 0.02-0.89; P=.03). However, among persons with acute leukemia, vitamin C at > or =500 mg/day was positively associated with nonrelapse mortality (RR=2.25; 95% CI, 1.33-3.83; P=.01) and mortality or relapse (RR=1.63; 95% CI, 1.09-2.44; P=.01), respectively. Vitamin E at > or =400 IU/day was positively associated with mortality or relapse (RR=1.77; 95% CI, 1.06 -2.96; P=.02). Applications/Conclusions Though this work was observational, the results suggest supplemental vitamin C before therapy may be beneficial in persons with breast cancer but both vitamin C and vitamin E may increase risk in persons with acute leukemia receiving HSCT. Practitioners should document supplement use in subjects receiving therapy for cancer.

Topics: Adolescent; Adult; Antioxidants; Ascorbic Acid; Breast Neoplasms; Cohort Studies; Dietary Supplements; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proportional Hazards Models; Vitamin E

Vincristine (VCR), a microtubule interfering anti-cancer agent, plays a key role in the treatment of childhood acute lymphoblastic leukaemia (ALL). The route of VCR induced apoptosis in ALL cells is not well defined. In this study we demonstrated caspase-9 and -3 activation in vivo in bone marrow leukaemic cells of a child with newly diagnosed ALL, after treatment with a single dose of VCR. We hypothesized that VCR induced apoptosis in ALL cells proceeds by a mitochondrial controlled pathway. We further studied the route of VCR induced apoptosis in Jurkat acute lymphoblastic leukaemia cells. First we showed that VCR induces activation of caspase-9 and -3 in Jurkat cells. With the caspase-9 inhibitor Z-LEHD-FMK we proved that caspase-9 was activated prior to caspase-3. Loss of mitochondrial transmembrane potential was independent of caspase-9 activation. To confirm the mitochondrial role in VCR induced apoptosis, the effect of blocking the mitochondrial route upstream of caspase-9 activation was investigated at two different levels: reactive oxygen species (ROS) scavenging and Bcl-2 overexpression. Generation of ROS was detected early in Jurkat cells during VCR exposure. Ascorbic acid, a ROS scavenger, inhibited ROS generation as well as caspase-9 and -3 activation and cell death induced by VCR. Furthermore, in Bcl-2 overexpressing Jurkat cells mitochondrial membrane potential changes, caspase-9 and -3 activation and cell death upon VCR exposure were decreased, in comparison to parental Jurkat cells. However, generation of ROS was not decreased in Jurkat cells with Bcl-2 overexpression. We concluded that ROS play a regulatory role in the initial phase of a mitochondrial controlled pathway of VCR induced apoptosis in Jurkat cells.

Topics: Amino Acid Chloromethyl Ketones; Antineoplastic Agents, Phytogenic; Apoptosis; Ascorbic Acid; Blotting, Western; Bone Marrow Cells; Caspase 3; Caspase 9; Caspase Inhibitors; Caspases; Enzyme Activation; Enzyme Inhibitors; Humans; Jurkat Cells; Membrane Potentials; Mitochondria; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Vincristine

Ascorbyl radical (ASR) in human cerebrospinal fluid (CSF) of various patients using electron paramagnetic resonance (EPR) at ambient temperature was investigated. Also, effect of chemotherapy on ASR as well as ascorbate (ASA) in CSF and serum of acute lymphoblastic leukemia (ALL) was studied. EPR spectra of various CSF samples showed a characteristic doublet, which was attributed to ASR. ASR in CSF and serum was directly measured without any chemical modification. ASA and ASR concentration in CSF were approximately two times higher than those in serum. ASA and ASR concentrations in CSF and serum were statistically analyzed. The analyses showed that ASR and ASA in CSF and serum had good correlation for patients undergoing chemotherapy but not for patients after the therapy. The correlation for ASR and ASA suggests that ascorbate may play an important role during chemotherapy. In addition, dynamic aspects of ASA and ASR in CSF and serum are discussed.

Topics: Adolescent; Adult; Antineoplastic Agents; Ascorbic Acid; Child; Child, Preschool; Dehydroascorbic Acid; Electron Spin Resonance Spectroscopy; Female; Humans; Male; Middle Aged; Models, Chemical; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Temperature

Human tumors may contain high concentrations of ascorbic acid, but little is known about how they acquire the vitamin. Certain specialized cells can transport ascorbic acid directly through a sodium ascorbate cotransporter, but in most cells, vitamin C enters through the facilitative glucose transporters (GLUTs) in the form of dehydroascorbic acid, which is then reduced intracellularly and retained as ascorbic acid. Mice with established hematopoietic and epithelial cell xenografts were studied for the accumulation of injected ascorbic acid and dehydroascorbic acid. Most hematopoietic and epithelial tumor cell lines can only transport vitamin C in the oxidized form (dehydroascorbic acid) in vitro; however, when grown as xenografts in mice, they rapidly accumulated vitamin C after administration of radiolabeled ascorbic acid. The involvement of the GLUTs in vitamin C uptake by the xenografted tumors was demonstrated by competitive inhibition with D-glucose but not L-glucose. Because the malignant cells were not capable of directly transporting ascorbic acid, we reasoned that the ascorbic acid was oxidized to dehydroascorbic acid in the tumor microenvironment. Tumor accumulation of vitamin C in animals injected with ascorbic acid was inhibited by coadministration of superoxide dismutase, implying a role for superoxide anion in the oxidation of ascorbic acid. Whereas the epithelial cancer cell lines could not generate superoxide anion in culture, the minced xenograft tumors did. Our studies show the transport of dehydroascorbic acid by GLUTs is a means by which tumors acquire vitamin C and indicate the oxidation of ascorbic acid by superoxide anion produced by cells in the tumor stroma as a mechanism for generating the transportable form of the vitamin.

Topics: Animals; Ascorbic Acid; Biological Transport; Breast Neoplasms; Female; Glucose; Glucose Transporter Type 1; HL-60 Cells; Humans; Male; Mice; Mice, Nude; Models, Biological; Monosaccharide Transport Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prostatic Neoplasms; Stromal Cells; Transplantation, Heterologous

We have detected and analyzed a free radical in human cerebrospinal fluid (CSF) of acute lymphoblastic leukemia (ALL) for the first time using electron paramagnetic resonance (EPR) at ambient temperature. We have also introduced an alternative capillary method to measure the radical. EPR spectra of the radical show a characteristic doublet with hyperfine coupling value of 1.8 G and g = 2.005. Based on EPR measurements, computer simulation, and literature values, we have determined that the species is ascorbyl radical (AsR). The radical has been investigated in CSF samples from ALL patients having no therapy, undergoing chemotherapy, and following therapy. Determination of the ascorbyl radical concentrations in CSF and serum was attempted using known concentrations of a nitroxyl radical. In addition, comparison in CSF and serum for ALL has been made along with statistical analyses of the data obtained. We found that AsR in CSF and serum has a strong correlation in patients undergoing chemotherapy (n = 57, r = 0.57, P < 0.0001). Ascorbate in CSF and serum show good correlation in patients having therapy but not for patients after therapy.

Topics: Antineoplastic Agents; Ascorbic Acid; Colorimetry; Cyclic N-Oxides; Electron Spin Resonance Spectroscopy; Female; Free Radicals; Humans; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Regression Analysis; Spin Labels

Topics: Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Child; Electron Spin Resonance Spectroscopy; Free Radicals; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction

Plasma levels and cumulative urine excretion of 6-mercaptopurine (6-MP) were measured using a specific and sensitive high-performance liquid chromatographic assay in seven children with acute lymphoblastic leukemia (ALL) as well as in one healthy volunteer. The dose of 6-MP varied in the range of 25-75 mg/m2 of body surface area and was administered with a standard breakfast. A 4- to 11-fold variation between individuals was found in the pharmacokinetic parameters: peak concentration, time to reach peak, area under the plasma concentration-time curve (AUC), and fraction of dose excreted in the urine. Three repeated determinations in one individual revealed that AUC also varied more than sixfold following an overnight fast. In three individuals, the reducing agents glutathione (10 mg/kg) and ascorbic acid (15 mg/kg) were coadministered with 6-MP to evaluate their possible role in the protection of 6-MP from oxidation and degradation in the intestinal lumen. No consistent effect was observed, however, on the AUCs of either of these agents. A clear relationship was found between AUCs and the 24-h urinary excretion of unchanged drug (r = 0.9381), indicating that determinations of 6-MP in the urine may replace the painful procedure of repeated blood sampling. Further studies are necessary to determine the factors contributing to the unpredictable plasma levels following oral doses of 6-MP and to determine the value of pharmacokinetic monitoring in ALL patients.

Topics: Administration, Oral; Adolescent; Adult; Ascorbic Acid; Biological Availability; Child; Chromatography, High Pressure Liquid; Female; Glutathione; Humans; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Time Factors