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

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease of the elderly which can present in one of three stages; benign, intermediate or advanced. The molecular events governing the progression of CLL are poorly understood. In order to develop model systems for predicting the aggressiveness of leukemic clones in CLL, in vivo transplantation of SCID mice with CLL cells, and the in vitro growth of CLL cells on mouse and human stromal layers, were investigated. Bone marrow or peripheral blood cells from 40 patients at different stages of CLL were transplanted into 172 immune-deficient SCID mice. Thirty-five percent of SCID mice injected with CLL cells were positive for the presence of human DNA by Southern blot or PCR analysis. The most frequently involved sites were the spleen, lung, kidney and bone marrow, at levels corresponding from 0.1 to 10 percent human DNA. Thrice-weekly intraperitoneal injections of IL-2, alone or in combination with IL-7, did not increase the level of human cell engraftment. SCID mice developed endogenous thymic lymphomas at an incidence of 10-33 percent, a rate that was not increased by CLL cell transplantation. In vitro, CLL cells were able to proliferate for 9 weeks on human stromal layers supplemented with CM (conditioned media from a culture of the human bladder carcinoma cell line 5637), but failed to thrive on the murine stromal cell line MTE cultured either in CM or autologous serum. FACS analysis revealed that 81 percent of proliferating cells on human stromal layers carried the CD5 cell surface marker, identifying them as CLL cells. Previously EBV-negative CLL cells became EBV-positive after 9 to 12 weeks in culture. The results of this study provide a firm foundation for the development of in vivo and in vitro model systems for the study of human CLL.
Leukemia 1996 Aug
PMID:Engraftment of human chronic lymphocytic leukemia cells in SCID mice: in vivo and in vitro studies. 870 47

The investigational biotherapeutic agent, B43(anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin, has shown substantial anti-leukemic activity in SCID mouse models of human B-lineage leukemia and lymphoma. In this report, we describe the results of a comprehensive preclinical toxicity study which determined the toxicity profile of B43-PAP in BALB/c mice. Administration of unconjugated B43 monoclonal antibody was not associated with any toxicity, whereas B43-PAP caused dose-limiting and cardiac and renal toxicities which were fatal. In addition, B43-PAP also caused multifocal skeletal myofiber necrosis, which was associated with abnormal gait and lethargy. Notably, parenteral administrations of methylprednisolone, pentoxyphylline, or dopamine were able to markedly reduce B43-PAP related toxicity. This study provides a basis for further evaluation of the toxicity of B43-PAP in monkeys and humans.
 ...
PMID:Toxicity profile of the investigational new biotherapeutic agent, B43 (anti-CD19)-pokeweed antiviral protein immunotoxin. 872 29

We grafted childhood B-precursor acute lymphoblastic leukemia (ALL) bone marrow (BM) cells into mice with severe combined immunodeficiency (SCID), in order to study the clonal evolution of immunoglobulin heavy chain (IgH) rearrangements in the absence of selective pressure by chemotherapy. BM cells from nine patients (six diagnosis samples and three relapse samples) were intravenously injected into SCID mice (three mice for each patient). All mice injected with cells from four patients developed a leukemia-like illness 12-40 weeks after injection. By PCR, new subclones that were the result of ongoing IgH rearrangement according to the mechanism operative in the injected cell populations (VH-replacement or VH to D-JH joining) were detected in the engrafted cell populations for all four patients. Subclones were mouse-specific, suggesting that subclone formation is a continuous process. Southern analysis after engraftment was unaltered as compared to the injected cells for one patient and revealed changes indicative of altered clonal composition for three patients. For two patients the observed changes possibly reflect the initial engraftment of a limited number of cells and occurred without changes in other parameters of the engrafted cell population, such as time needed for the development of leukemia, macroscopic organ involvement, immunophenotype and S-phase fraction. In one patient, we demonstrated the selective outgrowth of only a single cell type present at diagnosis, as characterized by IgH rearrangements. Our data show that evolution of clonal IgH rearrangements in B-precursor ALL may occur without the selective pressure of chemotherapy. Additionally, in some patients subclones present at diagnosis, as defined by IgH rearrangements, also possess different biological properties.
Leukemia 1996 Sep
PMID:Clonal evolution of immunoglobulin heavy chain rearrangements in childhood B-precursor acute lymphoblastic leukemia after engraftment in SCID mice. 875 65

The therapeutic potential of the IgM complement-fixing murine monoclonal antibody (mAb) PM-81 (anti-CD15) against acute myeloid leukemia (AML) was assessed in a SCID/hu leukemia model. Intraperitoneal (i.p.) injection of NB4 leukemia cells resulted in aggressive growth of leukemia cells in the peritoneal cavity of irradiated SCID/CB-17 mice. Flow cytometric analysis of human CD15, 33 and 45 expression, as well as cytologic examination, revealed that leukemia cells disseminated into the peripheral blood and multiple tissues of the mice. The approximately linear relationship between the injected leukemia cells and the subsequent leukemia cell proliferation provided a reliable model for monitoring the therapeutic effects of immunotherapy. Intraperitoneal injection of the mAb PM-81 markedly suppressed leukemia cell growth in this SCID/leukemia model. Most of the untreated mice died within 35-50 days of leukemia cell inoculation. Four weeks after inoculation of NB4 cells, five of nine mAb PM-81 treated mice had no solid tumor growth and six of nine had no detectable peritoneal exudate leukemia cells as determined by flow cytometry. In contrast, 100% of the mice in the untreated or control mAb groups were found to have both solid and peritoneal leukemia growth. In further experiments designed to evaluate the effects of therapy on survival, 50% (4/8) of PM-81 treated mice survived to 150 days, and had no detectable solid or suspension leukemia cells detectable at necropsy. In contrast, the median survival of untreated or negative control antibody-treated mice was 40 days (comparison to PM-81 treated; p = 0.006 and p = 0.03, respectively). The mechanism of leukemia cell suppression is not likely due to complement fixation since we could not demonstrate in vitro any cytotoxicity mediated by SCID mouse plasma. Further study is required to understand the mechanism of the antileukemia effect of PM-81 in this model.
 ...
PMID:Evaluation of monoclonal antibody-mediated anti-acute myeloid leukemia immunotherapy in a SCID/hu model. 879 92

We show that the adenylate cyclase activating diterpine, forskolin, the phosphodiesterase inhibitor, aminophylline, and the permeant cAMP analog dibutyryl cAMP inhibit the in vitro clonogenic growth of leukemic B-cell precursors. We also used a SCID mouse xenograft model of refractory human B-cell precursor leukemia to evaluate the anti-leukemic effect of aminophylline in vivo. Treatment with aminophylline (6 mg/kg bolus followed by 0.1-0.5 mg/kg/hour x 7 days) significantly prolonged the event-free survival of SCID mice (median survival of control mice, 39 days, N = 79; median survival of aminophylline-treated mice, 60 days, N = 10; P < 0.0001 by log-rank test) and it was more effective than treatment with vincristine (median survival = 51 days, N = 5) or L asparaginase (median survival = 44 days, N = 5). However, aminophylline was not as effective as methylprednisolone (median survival: 103 days, N = 5). These results indicate that cAMP modulating agents may be useful in treatment of refractory human B-cell precursor leukemia.
 ...
PMID:In vitro and in vivo anti-leukemic efficacy of cyclic AMP modulating agents against human leukemic B-cell precursors. 881 74

A subset of leukemic cells is assumed to maintain long-term growth of acute myeloid leukemia (AML) in vivo. Characterization of these AML progenitor cells may further define growth properties of human leukemia. In vitro incubations with 5-fluorouracil (5-FU) have been used for enrichment of normal primitive hematopoietic stem cells. By analogy to normal hematopoiesis, it was hypothesized that primitive leukemic stem cells might be kinetically more inactive than colony-forming cells (colony-forming units-AML [CFU-AML]). To examine this hypothesis, conditions were established for incubation with 5-FU that eliminated all CFU-AML. These conditions selected a 5-FU-resistant AML fraction that was evaluated for its capacity for long-term growth by transplantation into mice with severe combined immunodeficiency (SCID) and long-term culture in the quantitative cobblestone area-forming cell (CAFC) assay. Transplantation of the 5-FU-resistant fraction of four cases of AML into SCID mice resulted in growth of AML. Whereas no CFU-AML survived, 31% to 82% of primitive (week-6) CAFC were recovered from the 5-FU-treated cells. Hematopoietic cells proliferating in the CAFC assay were shown to be leukemic by cytologic, cytogenetic, or molecular analysis. The reduction of AML growth as determined by outgrowth of AML in SCID mice was in the same order of magnitude as the primitive (week-6) CAFC reduction. This indicates that both assays measure closely related cell populations and that the CAFC assay can be used to study long-term growth of AML. These results show a hierarchy of AML cells that includes 5-FU-resistant progenitors. These cells are characterized as primitive (week-6) CAFC and as leukemia-initiating cells in SCID mice.
 ...
PMID:Fluorouracil selectively spares acute myeloid leukemia cells with long-term growth abilities in immunodeficient mice and in culture. 882 11

The effects of anti-asialo GM-1 antibody (AAGM) treatment on the engraftment of human T-cell leukemia virus type I (HTLV-I)-infected human T cells in severe combined immunodeficiency (SCID) mice were studied. The frequency of tumor formation in an HTLV-I-transformed human T-cell line, MT-2 cells, at the site of inoculation was significantly higher in AAGM-treated than untreated mice (P<0.05): 16/18 (89%) and 16/26 (62%), respectively. The promotive effect of AAGM treatment on tumor development was marked in the early stage (less than 3 weeks), suggesting that the immediate reaction of natural killers to the inoculated cells may be important for the prevention of tumor development. The surface phenotypes and clonality of the tumor cells were the same as the MT-2 cells inoculated. Inoculation of peripheral blood mononuclear cells (PBMC) from one of the 4 adult T-cell leukemia/lymphoma (ATL) patients resulted in the development of tumors in AAGM-treated SCID mice. However, the surface phenotypes of the cells from these tumors were a mixture of B cells and T cells, suggesting that these tumors consisted of Epstein-Barr virus-transformed B cells and HTLV-I-transformed T cells. In addition, HTLV-I was detected by polymerase chain reaction in various organs of the mice inoculated with PBMC from the ATL patient and the asymptomatic carrier examined. These results suggest that elimination of natural killer function by AAGM treatment is important, although such treatment is not always necessary for the engraftment of HTLV-I-infected cells in SCID mice.
 ...
PMID:Enhanced engraftment of HTLV-I-infected human T cells in severe combined immunodeficiency mice by anti-asialo GM-1 antibody treatment. 887 27

A variant of severe combined immunodeficiency syndrome (SCID) with a selective inability to produce CD8 single positive T cells and a signal transduction defect in peripheral CD4+ cells has recently been shown to be the result of mutations in the ZAP-70 gene. T cell receptor (TCR) signaling requires the association of the ZAP-70 protein tyrosine kinase with the TCR complex. Human T cell leukemia virus type I-transformed CD4+ T cell lines were established from ZAP-70-deficient patients and normal controls. ZAP-70 was expressed and appropriately phosphorylated in normal T cell lines after TCR engagement, but was not detected in T cell lines from ZAP-70-deficient patients. To determine whether signaling could be reconstituted, wild-type ZAP-70 was introduced into deficient cells with a ZAP-70 retroviral vector. High titer producer clones expressing ZAP-70 were generated in the Gibbon ape leukemia virus packaging line PG13. After transduction, ZAP-70 was detected at levels equivalent to those observed in normal cells, and was appropriately phosphorylated on tyrosine after receptor engagement. The kinase activity of ZAP-70 in the reconstituted cells was also appropriately upregulated by receptor aggregation. Moreover, normal and transduced cells, but not ZAP-70-deficient cells, were able to mobilize calcium after receptor ligation, indicating that proximal TCR signaling was reconstituted. These results indicate that this form of SCID may be corrected by gene therapy.
 ...
PMID:Reconstitution of T cell receptor signaling in ZAP-70-deficient cells by retroviral transduction of the ZAP-70 gene. 892 Aug 91

To investigate whether the lymphocyte homing receptors, adhesion molecules regulating normal lymphocyte traffic, influence the dissemination of lymphoma cells, 24 lymphoma/leukemia cell lines were inoculated into SCID mice subcutaneously, and the correlation between the expression of the adhesion molecules and the metastatic potential of the cell lines was examined. Among the six adhesion molecules examined (LFA-1, ICAM-1, CLA, VLA-4, L-selectin and CD44), L-selectin increased the incidence of lymph node metastasis, and CD44 expression was related to both lymph node and organ (hematogenous) metastasis. A monoclonal antibody to the standard form of CD44 (CD44s), Hermes-3, inhibited the local growth and remote metastasis of CD44+ cell lines. Thus, it is concluded that at least CD44s expression is important in both lymphatic and hematogenous metastasis.
 ...
PMID:Metastatic potential of lymphoma/leukemia cell lines in SCID mice is closely related to expression of CD44. 895 66

Gene therapy is a novel approach under investigation for the treatment of genetic diseases, cancer and AIDS. Hematopoietic stem cells would be the target cell for correction of hemoglobinopathies, immune deficiencies and lysosomal storage diseases. Retroviral vectors derived from murine leukemia viruses have been used most extensively for gene delivery, but are limited in their capacity to transduce pluripotent human hematopoietic stem cells. In a trial of gene transfer for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID), three neonates were treated with infusion of autologous umbilical cord blood CC34+ cells. Up to 3 years later, a low number of leukocytes are still being produced containing the inserted ADA gene, with evidence of selective accumulation of transduced T lymphocytes. Further successful applications of gene therapy will require development of more efficient methods of gene transfer into stem cells.
 ...
PMID:Gene therapy for hematopoietic and immune disorders. 897 10


<< Previous 1 2 3 4 5 6 7 8 9 10