Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The important advances made in recent years in the therapy of adult ALL have been reviewed. The definition of bad-prognosis patients has been improved and includes those with T-ALL, ABLL, and Ph1+ALL, in addition to those presenting with evidence of extensive disease. In contrast to childhood ALL, induction chemotherapy should include another drug (or drugs) in addition to VCR and prednisolone, and one of the anthracycline drugs (ADR or DNR) has been employed most frequently in this context. Such therapy should result in a CR rate of 70 to 75%. Similar to the experience in childhood ALL, the improvement in haematological response rate has led to an apparent increase in CNS leukaemia, and the need for adequate CNS prophylaxis is stressed. Despite these improvements, the outlook for adults with ALL is not yet as good as it is for childhood ALL. Controlled studies involving large numbers of patients are urgently needed to provide answers to a number of questions. In induction therapy, the use of higher drug dosage, the use of more and other drugs, and the use of an individual patient's risk factors to determine drug dosage, must be assessed. The benefits of consolidation therapy and the optimal duration and intensity of maintenance therapy have yet to be established. Methods of CNS prophylaxis other than cranial irradiation and IT MTX must be carefully studied. These important questions require that adult patients with ALL should be concentrated in centres capable of providing optimal overall care and, at the same time, able to conduct the necessary clinical trials.
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PMID:The management of adult acute lymphoblastic leukaemia. 36 95

A 3-year-old child diagnosed as having acute lymphatic leukemia (ALL), developed meningeal leukemia 36 months after the onset of the disease. He was twice subjected to cranial irradiation plus intrathecal methotrexate (i.t. MTX). Skull radiology showed bilateral gyriform calcification of both cerebral hemispheres. Hematological relapse was first detected 5 years after diagnosis and the child died 5 months later. The most striking findings of a right frontal lobe biopsy and the postmortem examination were wide calcium deposits located in the cortex and in the adjacent white matter. Intense demyelination as well as areas of neuron poverty were apparent in the necropsy but in the biopsy specimen. The possible interrelationship between such deposition and cranial irradiation and/or i.t. MTX suggests a new iatrogenic disorder.
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PMID:Intracerebral calcifications in childhood lymphoblastic leukemia. A new iatrogenic disease? 41 41

This paper describes the case history of a 43 year-old patient with so-called primary reticulum cell sarcoma of the brain. The CSF contained cells suggestive of leukaemia which in view of an assumed myelofibrosis, initially seemed also possible to originate from a haematopoietic focus. The patient complained of intermittent violent headaches, which were controlled by spinal taps to release highly cellularised CSF under high pressure and by intrathecal MTX injection, every 4-6 weeks over a period of 4.5 years. In the terminal stage the patient developed paraplegia which, partly on the basis of neuropathological findings, was ascribed to the large accumulated dose of MTX. The tumour proved to be localised in the fornix; the localisation adjacent to the ventricular system made the intermittent cell eruptions in the CSF possible. On the basis of an erroneous diagnostic assumption, a therapy was instituted which resulted in a survival of 6.5 years, which is exceptionally long for a patient with 'primary reticulum cell sarcoma' of the brain.
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PMID:A patient with so-called primary reticulum cell sarcoma of the brain with 6.5 years' survival, treated as 'meningeal leukaemia'. 80 Sep 69

The killing of the LR subline of the DBA/2J leukemia L1210/MTX by passive antibody was followed in vivo with 131I-iododeoxyuridine-labeled cells and whole-body measurement of retained radioactivity. The in vivo killing of LR cells was proportional to the in vitro 2-mercaptoethanol resistant titer, independent of the complement system, and radioresistant. Although a large percentage of the leukemic cells was killed in passively immunized mice, the protective effect of the passive antiserum was dependent on the active immune response of the host.
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PMID:Antibody-induced killing in vivo of L1210/MTX-R cells quantitated in passively immunized mice with 131I-iododeoxyuridine-labeled cells and whole-body measurement of retained radioactivity. 95 54

Experience with CNS prophylaxis in 35 children with acute lymphatic leukaemia is reported. Before prophylactic irradiation of the skull was given the average survival time in 36 children was 2,8 (2,7) years. Menigeal leukaemia preceeded bone marrow relapse in 9 cases and followed relapse in a further 5 cases (39%). Between 1971 and 1973 Pinkel's treatment scheme VII was given to 35 children. This included prophylactic skull irradiation and intraspinal MTX injections. 29 children are still in their first remissions which range from 10 - 35 months in length. Meningeal leukaemia has not so far been observed, in this latter group.
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PMID:Prevention of meningeal leukaemia and relapses by cranial irradiation and intrathecal MTX in acute lymphatic leukaemia. 105 42

During maintenance therapy with intraventricular methotrexate, progressive dementia developed in a child with meningeal leukemia. Cerebrospinal fluid levels of MTX were in the nontoxic range and neurologic evaluation failed to demonstrate anatomic obstruction, infection, or folate depletion. The patient's symptoms gradually resolved when the methotrexate was discontinued, suggesting that methotrexate neurotoxicity may occur in the absence of an elevated CSF concentration of MTX.
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PMID:Reversible dementia temporally associated with intraventricular therapy with methotrexate in a child with acute myelogenous leukemia. 106 Jul 45

A protocol for the prophylaxis of CNS leukemia was devised involving intermittent low-dosage radiation of the craniospinal axis combined with single intrathecal injections of MTX. The retionale for this protocol was the timing of first CNS relapses in patients not receiving prophylaxis which suggests that leukemic colonization of the CNS is not restricted to the initial stage of the disease and that periodic measures might be advantageous. The low dosage of radiation was chosen because it is well tolerated and has been found temporaily effective in overt CNS relapse. The two series of patients were comparable as to various parameters. Results after three years of observation were comparable to those obtained by other with a single initial course of high-dose radiation, with an expected 50% uninterrupted complete 5-year remission. On the basis of 30 months follow up in 26 patients, the therapy is well tolerated. An increase in morbidity due to infections in remission was not associated with a higher mortality.
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PMID:IMFRA (intermittent intrathecal methotrexate and fractional radiation) plus chemotherapy in childhood leukemia. 106 74

A variant line (CEM-7A) "overproducing" the reduced folate/MTX carrier system was isolated from human CCRF-CEM leukemia cells grown under selective conditions in medium containing 0.25 nM 5-formyl-THF as the sole folate source. This line exhibits a 95-fold increased Vmax for [3H]-MTX influx as compared to parental cells. The values for [3H]-MTX influx Km, efflux t1/2 and structural specificity for other (anti)folate compounds were unchanged. The amount of carrier protein, estimated by NHS-[3H]-MTX affinity labeling, was approximately 30-fold higher in CEM-7A cells than in parental cells. Influx of [3H]-MTX in CEM-7A cells was found to be down-regulated 6-7-fold after preincubation of cells with adenosine, 5-formyl-THF or 5-methyl-THF, but could be prevented exclusively by inhibitors of dihydrofolate reductase. The underlying mechanism(s) of these effects have not as yet been elucidated. A radioiodinated photoaffinity analog of MTX was used to prove the molecular events in carrier-mediated MTX uptake in parental CCRF-CEM cells, CEM-7A cells, and a line exhibiting a MTX-transport defect (CEM-MTX). Specific labeling of an 80-85 kDa membrane protein was observed in parental cells, but not in CEM/MTX cells. Uptake of photoprobe and levels of the 80-85 kDa membrane protein were significantly increased in CEM-7A cells. Due to extensive glycosylation the MW of the carrier protein in human cells seems to be substantially higher than that of its counterpart in murine L1210 leukemia cells (46-48 kDa). Pulse-labeling experiments at 37 degrees C demonstrated that in CEM-7A cells photoprobe uptake proceeds via a specific pathway. The 80-85 kDa membrane protein is involved in the initial binding and translocation of photoprobe, after which a 38 kDa cytosolic protein is responsible for further intracellular distribution. At this time, the combination of photoaffinity labeling techniques and the availability of variant cell lines overexpressing the reduced folate/MTX carrier protein has provided new insights into the MTX transport process in human leukemia cell lines. In the near future this approach should also allow a further elucidation of the regulatory aspects of carrier function.
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PMID:Molecular events in the membrane transport of methotrexate in human CCRF-CEM leukemia cell lines. 132 3

Biotin derivatives of methotrexate (biotin-SS-MTX) and folate (biotin-SS-folate), in which the functional components are joined by a dissociable disulfide-containing spacer, have been synthesized, purified by DEAE-Trisacryl chromatography, and characterized by HPLC, elemental analysis and mass spectrometry. These compounds provide a convenient means for the single-step purification of the folate transporters from L1210 cells. Parental L1210 murine leukemia cells, which contain only the microM transporter (the reduced folate/MTX transport protein) were treated with the N-hydroxysulfosuccinimide ester of biotin-SS-MTX, and a detergent extract of the plasma membranes was exposed to streptavidin-agarose beads to adsorb the labeled protein. Dithiothreitol cleavage of the disulfide linkage released the transporter, which migrated as a well-defined component (43 kDa) on SDS-PAGE gels; no other proteins were present. An L1210 subline (JF), obtained by adapting cells to grow on nanomolar concentrations of folate, contains both the microM transporter and the nM transporter (high-affinity folate binding protein). When these cells were treated with the N-hydroxysulfosuccimide ester of biotin-SS-folate and processed as described above, analysis on SDS-PAGE gels revealed the presence of two proteins, the microM transporter (43 kDa) and the nM transporter (39 kDa). Both transporters were characterized with respect to amino acid content; blocked N-termini precluded Edman sequencing. Treatment of the nM transporter with peptide:N-glycosidase F produced a smaller component (32 kDa); the microM transporter, conversely, was unchanged by this procedure. When the microM transporter in parental L1210 cells was labeled with fluorescein-MTX and then treated with phosphoinositol-specific phospholipase C (PI-PLC), no change in fluorescence was detected. Alternatively, when the nM transporter in the JF subline was labeled with fluorescein-folate and then treated with PI-PLC, complete loss of fluorescence was observed. These results indicate that the L1210 microM transporter is a non-glycosylated, integral membrane protein, while its nM counterpart is heavily glycosylated and anchored exofacially to the membrane by a glycosylphosphatidylinositol component.
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PMID:Multiple folate transport systems in L1210 cells. 132 5

An episode of transient encephalopathy after the first course of intravenous high-dose methotrexate (HD-MTX; 1000 mg/m2) was observed in a 4-year-old girl with acute lymphoblastic leukemia. The neurological abnormalities took place 5 days after HD-MTX therapy. She experienced complex partial seizure and left hemiparesis, which resolved spontaneously in 5 days. Cranial computed tomographic scan and magnetic resonance imaging showed multiple low-density lesions in bilateral hemispheres. It is well appreciated that neurotoxicity from MTX follows prolonged exposures, often accompanying or following radiation therapy. To our knowledge, however, there have been no reports that such neurological complications developed following a single exposure of HD-MTX in patients with ALL. Follow-up electroencephalograms showed that she had periodic lateralized epileptiform discharges (PLEDS), suggesting functional deafferentation of cortical neurons following HD-MTX. Moreover, the serum and CSF MTX levels following a second low-dose course and her clinical course suggested that she had presumably central nervous system leukemia at the time of HD-MTX therapy, which might have been related to neurological complications. The pathogenesis of MTX-induced neurotoxicity is discussed.
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PMID:Transient encephalopathy following a single exposure of high-dose methotrexate in a child with acute lymphoblastic leukemia. 138 40


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