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)

A highly aggressive subclone of the human CALLA+C mu+ pre-B acute lymphoblastic leukemia (ALL) cell line NALM-6 (designated NALM-6-UM1) caused disseminated and fatal leukemia in CB.17 mice with severe combined immunodeficiency (SCID). An intravenous challenge with 1 x 10(6) (NALM-6-UM1 cells caused 15 of 27 (56%) SCID mice to become paraplegic at 31 +/- 2 days (median = 33 days) and 27 of 27 (100%) mice to die of disseminated leukemia at 38 +/- 1 days (median = 39 days). We used this SCID mouse model of aggressive human pre-B ALL to evaluate the in vivo antileukemic efficacy of B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin. A 3-day treatment with nontoxic doses of B43-PAP markedly reduced the incidence of paraplegia and improved event-free survival (EFS) in SCID mice challenged with 1 x 10(6) NALM-6-UM1 pre-B ALL cells, as reflected by significantly higher cumulative proportions of mice free of paraplegia or alive at 1 to 7 months, as compared with phosphate-buffered saline (PBS) treated control mice. The Kaplan-Meier estimates and standard errors of the probability of developing paraplegia after inoculation of 1 x 10(6) NALM-6-UM1 cells was 64% +/- 10% for PBS-treated mice (median time to paraplegia = 37 days) (N = 27), 18% +/- 8% for mice treated with 15 micrograms B43-PAP (5 micrograms/mouse/d x 3 days) (N = 23) and 5% +/- 5% for mice treated with 30 micrograms B43-PAP (10 micrograms/mouse/d x 3 days) (N = 21). While 27 of 27 PBS-treated control SCID mice died of leukemia at 38 +/- 1 days (range = 24 to 54 days), only 16 of 44 B43-PAP-treated mice developed leukemia at 74 +/- 12 days (range = 30 to 182 days), consistent with greater than or equal to 6 logs kill of clonogenic NALM-6-UM1 cells in 64% of SCID mice. The Kaplan-Meier estimates and standard errors of the probability of long-term EFS after inoculation of 1 x 10(6) NALM-6-UM1 cells were 65% +/- 10% for mice treated with 15 micrograms B43-PAP and 60% +/- 11% for mice treated with 30 micrograms B43-PAP with a median survival time of greater than 7 months for both groups. In contrast, neither unconjugated B43 monoclonal antibody nor the anti-T-cell immunotoxin G17.2 (anti-CD4)-PAP decreased the incidence of paraplegia or improved EFS.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In vivo efficacy of B43 (anti-CD19)-pokeweed antiviral protein immunotoxin against human pre-B cell acute lymphoblastic leukemia in mice with severe combined immunodeficiency. 137 67

The use of ex vivo purging agents has shown to be beneficial for both allogeneic and autologous bone marrow transplantations. We have shown previously that spermine dialdehyde (SDA), an oxidized product of spermine, when used in phosphate-buffered saline (PBS) preferentially inhibits T-cell proliferation while sparing myeloid cells. Lethally irradiated mice were rescued by reconstitution with SDA-treated allogeneic marrow and showed no sign of graft-vs-host disease (GVHD). In this paper, we show by HPLC analysis that SDA degraded rapidly in PBS but remained intact in saline. Administered in saline, SDA was more inhibitory on leukemic cell lines than normal myeloid or T-cells. Lethally irradiated mice receiving a syngeneic bone marrow leukemic cell mixture treated ex vivo with SDA in saline did not manifest leukemia. Thus, the preferential inhibitory effect of SDA and its degraded products in different buffers suggest that SDA could act as a novel purging agent for both allogeneic and autologous bone marrow transplantations.
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PMID:Spermine dialdehyde, a novel ex vivo purging agent for both allogenic and autologous bone marrow transplantations. 142 63

Fludarabine phosphate (F-ara-AMP, Fludara) is rapidly converted in the circulation to fludarabine (F-ara-A) and is among the most effective single agents in the treatment of chronic lymphocytic leukemia. Although current treatment protocols are well tolerated, severe neurotoxicity was a consequence of high-dose F-ara-AMP regimens used in early phase I trials against adult acute leukemia. The present study showed that in mice implanted with leukemia L1210, fatal neurotoxicity, which initially manifested as hind-limb paralysis, was a consequence of high-dose F-ara-AMP treatment. However, the incidence of neurotoxicity was reduced by the coadministration of NBMPR-P, the 5'-phosphate of nitrobenzylthioinosine, a potent inhibitor of the es equilibrative nucleoside transport (NT) system. NBTGR-P, the 5'-phosphate of nitrobenzylthioguanosine (also a potent NT inhibitor) similarly prevented F-ara-AMP neurotoxicity in this experimental system. Treatment with F-ara-AMP/NBMPR-P combinations was more effective with respect to the fractional yield of "cured" mice than were the same treatment regimens without NBMPR-P.
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PMID:Protection against fludarabine neurotoxicity in leukemic mice by the nucleoside transport inhibitor nitrobenzylthioinosine. 145 62

Chimeric DNA expression vectors containing regulatory sequences proximal to the 5' end of coding sequences for mammalian genes provide valuable tools to study gene expression. Genes coding for easily measured products (reporter genes) can be used to study promoter strength and regulation of gene expression after transient expression of promoter-reporter constructs in mammalian cells. To determine the strength of a variety of mammalian and viral promoter-enhancer sequences in primary cultures of human mammary epithelial cells (HMEC), these sequences were fused to the bacterial chloramphenicol acetyltransferase (CAT) gene and transfected into HMEC using strontium phosphate. The long terminal repeat (LTR) of the endogenous murine leukemia virus AKR-623 was the most potent promoter of transient CAT expression in HMEC. A number of commonly available promoter sequences displayed a wide range of activities in these cells. The glucocorticoid responsive LTR promoter from the murine mammary tumor virus modulated expression of CAT and was sensitive to the concentration of dexamethasone in the growth media. In a similar fashion, the regulatory sequences from the murine metallothionein-1 gene retained responsiveness to zinc concentration in the growth media.
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PMID:Relative promoter activity in human mammary epithelial cells assayed by transient expression. 148 64

The cyclopropylpyrroloindole analogues are DNA minor-groove binders containing a cyclopropyl group, which mediates N3-adenine covalent adduct formation in a sequence-selective fashion. Carzelesin (U-80244) is a cyclopropylpyrroloindole prodrug containing a relatively nonreactive chloromethyl precursor to the cyclopropyl function. Activation of carzelesin requires two steps, (a) hydrolysis of a phenylurethane substituent to form U-76073, followed by (b) ring closure to form the cyclopropyl-containing DNA-reactive U-76074. The formation of the DNA-reactive U-76074, via U-76073, from carzelesin was shown to proceed very slowly in phosphate-buffered saline (t1/2 greater than 24 h) but to occur rapidly in plasma from mouse, rat, dog, and human (initial t1/2 values ranging from 18 min for mouse to 52 min for rat) and in cell culture medium (t1/2 approximately 40 min). Although carzelesin was less potent in terms of in vitro cytotoxicity and in vivo optimal dosage and showed low affinity for binding to DNA, it was therapeutically more efficacious against mouse L1210 leukemia than was U-76074 or adozelesin (U-73975), another cyclopropylpyrroloindole analogue which is currently in phase I clinical trials. Carzelesin also proved to be more efficacious than U-76074 or adozelesin against mouse pancreatic ductal 02 adenocarcinoma, a system reported to be resistant to every agent tested. Carzelesin was highly effective against this tumor and produced 97% tumor growth inhibition. In addition, i.v. administered carzelesin showed significant activity (National Cancer Institute criteria) against i.v. or s.c. implanted Lewis lung carcinoma, i.p. or s.c. implanted B16 melanoma, s.c. implanted colon 38 carcinoma, and five s.c. implanted human tumor xenografts, including clear cell Caki-1 carcinoma, colon CX-1 adenocarcinoma, lung LX-1 tumor, ovarian 2780 carcinoma, and prostatic DU-145 carcinoma. Carzelesin treatment produced 100% complete remissions (no palpable tumor mass at the termination of the experiment) in mice bearing early-stage human ovarian 2780. Pharmacologically, carzelesin proved to be relatively schedule and route independent and was highly active against i.p. implanted L1210 leukemia, regardless of whether the analogue was given i.v., i.p., s.c., or p.o. These results, collectively, suggest that carzelesin is absorbed and distributed well. Both carzelesin and adozelesin caused marked tumor shrinkage in mice bearing human lung LX-1 or advanced-stage human ovarian 2780 carcinoma; however, tumor regrowth occurred shortly after the treatment with adozelesin was stopped. Little or no apparent tumor regrowth occurred after treatment with carzelesin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cytotoxicity and antitumor activity of carzelesin, a prodrug cyclopropylpyrroloindole analogue. 151 47

The human gene GLVR1 has been shown to render mouse cells sensitive to infection by gibbon ape leukemia virus. This indication that the GLVR1 protein acts as a virus receptor does not reveal the protein's normal physiological role. We now report that GLVR1 is homologous to pho-4+, a phosphate permease of Neurospora crassa, at a level sufficiently high to predict that GLVR1 is also a transport protein, although the substrate transported remains unknown. To characterize the gene further, we have cloned cDNA for the mouse homolog of the gene, Glvr-1. The sequence of the murine protein differs from that of the human protein in 10% of residues, and it may be presumed that some of these differences are responsible for the inability of gibbon ape leukemia virus to infect mouse fibroblasts. Glvr-1 RNA is most abundant in mouse brain and thymus, although it is present in all tissues examined. The pattern of RNA expression found in mouse tissues was also found in rat tissues, in which the RNA was expressed at high levels in all compartments of the brain except the caudate nucleus and was expressed most abundantly early in embryogenesis. Thus, high-level expression of Glvr-1 appears to be restricted to specific tissues and may have developmental consequences.
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PMID:GLVR1, a receptor for gibbon ape leukemia virus, is homologous to a phosphate permease of Neurospora crassa and is expressed at high levels in the brain and thymus. 153 69

Tartrate-resistant acid phosphatase (TRAcP) is a reliable cytochemical marker for the diagnosis of hairy cell leukemia (HCL). The enzyme has been the subject of much biochemical investigation yet its function in the hairy cells (HC) is still unknown. Two TRAcPs have been purified from HCL spleen tissues by a series of chromatographic separations. The two enzymes, provisionally called peak 1 and peak 2, had specific activities of greater than 600 U/mg and 800 U/mg respectively when p-nitrophenyl phosphate (p-NPP) was used as substrate and had Km values in the range of 1 to 5 mM p-NPP. The two TRAcPs had the same substrate specificities and inhibitor sensitivities, therefore could be isoforms of the same enzyme. Their pH optima were between 5 and 6 for all substrates tested including the phosphotyrosine-containing peptide, Raytide, which was still hydrolyzed efficiently at neutral pH. Neither phosphoserine nor phosphoserine-containing casein were hydrolyzed by either enzyme. The TRAcPs of HC may thus be capable of functioning as protein-tyrosine phosphatases (PTP). High activity of a PTP could regulate the activities of protein-tyrosine kinases and thereby influence the growth and differentiation of the hairy cells.
Leukemia 1992 Mar
PMID:Protein-tyrosine phosphatase activity of hairy cell tartrate-resistant acid phosphatase. 156 56

31P NMR was used to study the systemic effects of a tumor on a host organism by monitoring the phosphate metabolite content in freshly excised mouse liver at 0-4 degrees C and in ethanolic liver extracts of animals suffering from La, L1210 and P388 leukemias and Ehrlich ascites tumor (EAT). The progression of murine leukemia is characterized by increases in the intensities of the resonances of Pi and phosphomonoesters (PME), in particular, phosphorylethanolamine, in liver; phosphodiester (PDE) signals increase two- to four-fold during the period of rapid tumor growth and decline to undetectable levels in the terminal stage. There were no reliable alterations detected in the ATP content and intracellular pH throughout the course of the leukemia. The kinetics of intracellular phosphates are similar in various kinds of leukemia but quite different in EAT. The reduction of inoculum causes the appearance of maxima in the Pi and PME profiles in the latent period of La leukemia, but the profiles of liver PDE considered from the end of the latent period are independent of inoculum. Possible mechanisms for the changes in PDE concentrations and their biochemical role are discussed. NMR spectroscopy of liver may be used to indirectly monitor the progression of tumors unavailable for direct NMR assay.
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PMID:General features of systemic effects of murine leukemias on phosphate metabolism in liver studied by 31P NMR. 164 67

A reversed phase high performance liquid chromatographic method for the simultaneous determination of pseudouridine (PU) and creatinine (Cr) in urine is described. The mobile phase was 0.01 mol phosphate buffer (pH 6.1) containing 2.5 mmol octanesulphonic acid as the ion pairing agent. UV detection was set at 250 nm. Variation in pH value affected the retention time of PU and Cr significantly; Their separation from interfering peaks was also affected. The recoveries of PU and Cr were 89.93% and 90.35%, respectively. The standard deviation of the method for PU was 48.69 +/- 0.063 (nmol/mumol Cr, mean +/- SD, n = 5). The urine samples from 233 normal children of different ages and 119 patients with leukaemia were analysed by this method. The normal reference value was appraised by comparison with the percentage of immature cells in the bone marrow. The results showed that the sensitivity of the method was 94.12%, the specificity was 95.86%, the accuracy was 95.50%, the positive predictive value was 82.05% and the negative predictive value was 98.78%. The method can be used to evaluate the state of the leukaemia, and to monitor the effect of treatment.
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PMID:Simultaneous determination of pseudouridine and creatinine in urine of normal children and patients with leukaemia by high performance liquid chromatography. 164 87

The suppressive effect of glucocorticoids (GC) upon antigen-induced phosphatidylinositol phospholipase C (PI-PLC) activity and inositol phosphate formation by rat basophilic leukemia cells (RBL-2H3) has been characterized. Addition of antigen for a period of 1-30 min enhanced production of [3H]inositol monophosphate (IP1), inositol 1,4-bisphosphate (IP2) and inositol 1,4,5-trisphosphate (IP3) by about 5-10-fold. Pretreatment with hydrocortisone (HC) reduced formation of the various inositol phosphates (IPs) and degradation of phosphatidylinositol 4,5-bisphosphate (PIP2) by an average of 50%. Maximal inhibition of hydrolysis of PIP2 and reduction in stimulation of IP3 formation was reached after 4 h of preincubation with 2.10(-6) M of HC. Cycloheximide and RU486, a GC receptor antagonist, completely prevented the inhibitory effect of HC on IP formation. Other GC, dexamethasone (DEX) and triamcinolone (each at 2.10(-7) M) markedly suppressed antigen induced IP3 production, while aldosterone and sex steroids such as estradiol and progesterone (each at 2.10(-6) M) were virtually inactive. Antigen-stimulated phosphorylation of a 18 kDa and other proteins was inhibited by about 60% following pretreatment with the GC. This inhibition was in turn prevented by cycloheximide. DEX also doubled the activity of cellular acid phosphatase activity. The results suggest that the inhibitory effect of GC is specific, receptor-mediated, dependent on protein synthesis and possibly mediated by protein phosphatase activity.
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PMID:Characterization of glucocorticoid inhibition of antigen-induced inositolphosphate formation by rat basophilic leukemia cells: possible involvement of phosphatases. 166 Nov 66


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