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)

Using colony assays in semi-solid media, several investigators have shown that supernatants (SN) of normal and malignant human B-cells can stimulate the growth of granulocyte-macrophage (GM) progenitor cells. So far macrophage colony-stimulating factor (M-CSF) and interleukin-6 (IL-6) have been identified as potential colony-stimulating activity (CSA) present in B-cell SN. However, other CSAs such as GM-CSF, G-CSF, IL-1-beta, IL-3, and IL-4 may also be candidates in this respect. Several human B-cell lines (CL) were screened for the expression of the respective genes at the mRNA and protein level. Constitutive production of GM-CSF was detected in the lymphoblastoid CL Wi-L2-729-HF2 and in the Burkitt line Raji. The signal intensity of specific transcripts and the amount of protein being secreted increased upon exposure to the phorbol ester PMA. The hybridoma line HB-564 also expressed the GM-CSF gene, but required prior stimulation with PMA. 3H-thymidine incorporation of Raji and Wi-L2-729-HF2 cells was unchanged in the presence or absence of a specific neutralizing sheep anti-GM-CSF serum, suggesting that GM-CSF did not serve as an extracellular autocrine growth factor. The expression of the GM-CSF gene was independent of the proliferative state (log phase growth versus plateau phase growth) and of the presence of serum in cultures of the respective CL. The expression of G-CSF, IL-1-beta, IL-3, and IL-4 genes was not detectable in the CL at the mRNA level.
Leukemia 1991 Aug
PMID:Screening for expression of cytokines with hematopoietic growth factor activity by permanent human B-cell lines. 188 24

The drug 3'-azido-3'-deoxythymidine (AZT), a synthetic thymidine analogue, has been used clinically in the management of acquired immune deficiency syndrome (AIDS). The drug is an effective antiviral agent due to its ability to block reverse transcriptase activity. This action of AZT was demonstrated in the Rauscher leukemia virus (RLV)-induced murine erythroleukemia model system. Unfortunately, associated with AZT has been the development of hematopoietic toxicity manifested by anemia, neutropenia, and overall bone marrow suppression. Hematopoietic growth factors (GM-CSF, erythropoietin), cytokines (interleukin-1), and agents known to potentiate hematopoiesis (lithium) have been demonstrated to modulate drug and/or radiation-induced hematopoietic toxicity. We report the results of further studies designed to investigate the ability of GM-CSF, erythropoietin, interleukin-1, and lithium to modulate AZT toxicity on murine hematopoietic granulocyte-macrophage (CFU-GM), megakaryocytic (CFU-Meg), and erythroid (BFU-E) progenitors cultured from bone marrow and spleen cells from mice infected with RLV. Hematopoietic progenitors from either normal or RLV-infected animals when exposed to AZT demonstrated concentration-dependent toxicity and differed for each progenitor with BFU-E being the most sensitive (ID50 concentration, 5 x 10(-9) M) and CFU-GM the least sensitive (ID50 concentration, 5 x 10(-5) M). As has been previously demonstrated using normal murine hematopoietic progenitors, when cultured with RLV-infected marrow or spleen cells, addition of GM-CSF, Meg-CSF or erythropoietin failed to inhibit AZT toxicity in vitro on CFU-GM, CFU-Meg, and BFU-E, respectively. However, in the presence of interleukin-1 (recombinant human IL-1 alpha, 30 ngm) or lithium chloride (ultra-pure, 1.0 mM), AZT toxicity CFU-GM, CFU-Meg, and BFU-E cultured from RLV-infected marrow or spleen cells was reduced. These results further demonstrate interleukin-1 and lithium are effective in modulating the toxic action of AZT on hematopoietic progenitors and that RLV-infected animals serve as a useful viral model system to study the effect of agents capable of modulating hematopoiesis in the presence of the anti-viral drug AZT.
 ...
PMID:Effect of interleukin-1, GM-CSF, erythropoietin, and lithium on the toxicity associated with 3'-azido-3'-deoxythymidine (AZT) in vitro on hematopoietic progenitors (CFU-GM, CFU-MEG, and BFU-E) using murine retrovirus-infected hematopoietic cells. 194 Jun 11

The ability to eliminate malignant cells from bone marrow (BM) while retaining sufficient numbers of normal progenitors to ensure engraftment, may well establish the future of autologous BM transplantation (ABMT) for hematologic malignancies. In this study, we describe the effects of methylprednisolone (MP) and etoposide (VP16) alone or in combination on 5 tumor cell lines (HL-60, a promyelocytic cell line; Molt-4, a T cell leukemia; Daudi, a Burkitt's lymphoma and R10/8226 and R40/8226, doxorubicin-resistant myeloma cell lines). The tumor cell kill efficiency of the drugs was assayed using the limiting dilution assay. We determined the toxic effect on progenitor cells by assaying granulocyte-macrophage colony-forming units (CFU). With a combination of MP at 10(-3) M and VP16 at 75 microM, we observed the following log reduction in tumor cell clones: HL-60, 4.695 +/- 0.001; Molt-4, 3.626 +/- 0.036; Daudi, 5.633 +/- 0.001; R10/8226, 3.052 +/- 0.544; R40/8226, 3.126 +/- 0.080. CFU recovery was 24% +/- 5%. Mixing tumor cell lines with a 20-fold excess of normal irradiated BM cells did not eliminate the inhibitory effect of the drug combination. We propose that MP and VP16 used in concert produce effective purging of malignant hematopoietic cells from BM while sparing normal progenitors needed for engraftment.
 ...
PMID:Elimination of clonogenic tumor cells from bone marrow using methylprednisolone (MP) and etoposide VP16: an in vitro pharmacologic study. 195 38

Previous studies have revealed a consistent defect in the cycling behavior of primitive neoplastic progenitor cells in patients with Philadelphia chromosome (Ph1)-positive chronic myeloid leukemia (CML). This is manifested both in vivo and in long-term cultures of CML cells as an increased rate of turnover amongst Ph1-positive progenitor cell types whose counterparts in normal individuals are mainly quiescent. To determine whether this deregulated proliferative activity of primitive Ph1-positive cells might be explained by a perturbation in the production of growth factors that regulate the turnover of primitive normal cells, the possibility of either autocrine or paracrine mechanisms of Ph1-positive cell stimulation was investigated. Northern blot analysis of total cellular RNA extracted from various CML blood cell populations showed no evidence of increased expression of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-3, IL-6, or tumor necrosis factor-alpha (TNF-alpha) compared with analogous normal peripheral blood cell populations in which transcripts for most of these growth factors are not detectable. A similar analysis of RNA extracted from the adherent layer of 4-week-old long-term cultures established from CML marrow (in which the Ph1-positive cells typically disappear) or from CML blood seeded onto normal marrow adherent layers (in which Ph1-positive cells typically persist) also revealed no difference in growth factor production compared with analogous cultures established with exclusively normal cells. For some of the growth factors studied, the assessment of bioactivity detectable in the medium confirmed the RNA data. There was also no evidence of a decreased production of putative inhibitors of primitive hematopoietic cells, i.e. transforming growth factor-beta and macrophage inflammatory protein-1 alpha by CML versus normal cells or cultures. These results do not support the existence of BCR-ABL induced autocrine or paracrine mechanisms in CML and suggest that constitutive activation of events normally dependent on growth factor receptor stimulation is more likely to underlie the lack of proliferation control exhibited by primitive Ph1-positive cells.
Leukemia 1991 Oct
PMID:Lack of evidence for abnormal autocrine or paracrine mechanisms underlying the uncontrolled proliferation of primitive chronic myeloid leukemia progenitor cells. 196 Oct 20

We describe a patient in whom the concomitant diagnosis of refractory anemia with excess of blasts (16% on initial marrow examination) and chronic lymphocytic leukemia was made more than 9 years ago. The myeloid clone showed a complex karyotypic abnormality. Evolution has so far been remarkably stable, without transformation into acute leukemia. Clonogenic assays showed that patient's serum inhibited the patient's own granulocyte-macrophage colony-forming units (CFU-GM). This inhibition was also present for a control subject's CFU-GM and acute myeloid leukemia clonogenic cells. This raises the problem of a down-regulation of the myeloid clone by the malignant lymphoid clone in this patient, and the possible mechanisms for this are discussed.
Leukemia 1991 Nov
PMID:High risk myelodysplastic syndrome coexistent with chronic lymphocytic leukemia for more than 9 years: inhibition of the myeloid clone by the lymphoid clone? 196 Oct 29

The responses to retinoic acid (RA) of acute myeloblastic leukemia (AML) blasts and normal hemopoietic progenitors was examined under defined growth factor conditions. For the leukemic cells marked patient to patient variation was seen; blast colony formation by cells from some patients was stimulated by RA without growth factors or in the presence of recombinant granulocyte colony-simulating factor (rG-CSF), recombinant granulocyte-macrophage-CSF rGM-CSF and recombinant interleukin-3 (rIL-3); for other populations inhibition was observed under the same conditions. Some blast cells were stimulated by RA in the presence of rGM-CSF and rIL-3 and inhibited when cultured with RA and rG-CSF. Supernatants prepared from blasts cultured with RA and growth factors did not show activities that were not readily explained by the carry-over of growth factors; this result did not provide evidence that RA and growth factors interact to produce factors. Titrations of RA showed that activity was first observed at concentrations of 10(-9) M and was maximum at concentrations of 10(-7) M. Different effects of RA in combination with rG-CSF compared with rGM-CSF or IL-3 were not seen when the cells were tested in suspension culture rather than in methylcellulose, a finding that may be interpreted to mean that the interaction between RA and factors affects terminally-dividing blast cells. Three normal bone marrow samples were cultured with RA and growth factors. Colony formation was stimulated by RA in the presence of rGM-CSF or rIL-3 but inhibited by RA with rG-CSF. Thus a differential effect of RA in combination with growth factors occurs in normal hemopoietic cells and persists in some AML populations.
Leukemia 1991 Nov
PMID:Interactions between retinoic acid and colony-stimulating factors affecting the blast cells of acute myeloblastic leukemia. 196 Oct 35

Cytogenetic and bone marrow culture studies were performed sequentially in 13 patients with myelodysplastic syndromes (MDS) who responded to low dose cytosine arabinoside (Ara-C) treatment (complete in nine and partial in four patients). Of nine patients with initial clonal karyotypic abnormalities, six recovered a normal karyotype after attaining a response to treatment, but the other three patients retained partial or total karyotypic abnormalities. A new clonal karyotypic abnormality appeared after treatment in one patient. Eight patients showed normal colony growth of both granulocyte-macrophage colony-forming units and erythroid burst-forming units after treatment, but five were still defective. There was a clear difference in the duration of response to treatment between these two groups. Consolidation treatment was not effective in patients with persistent karyotypic abnormalities or defective colony formation. Although the number of patients studied is small, these results suggest that hemopoiesis in patients with MDS following a response to treatment with low dose Ara-C is heterogeneous. Consolidation chemotherapy is recommended to ensure and prolong the response in patients showing normalization of both cytogenetic and bone marrow culture results.
Leukemia 1991 Nov
PMID:Cytogenetic and clonal culture evaluation after response to low dose Ara-C in myelodysplastic syndromes. 196 Oct 37

We report the retrospective experience of autologous blood stem cell autografts (ABSCT) performed by six teams of the "France Autogreffe" Group in acute leukaemia and in myeloma. Different clinical and biological parameters able to influence the mobilization and the collection of circulating stem cells (CSC) have been reviewed: age seems not to have any significant influence on the peak of peripheral blood granulocyte-macrophage progenitor cells (PB CFU-GM), as opposed to the type of leukaemia, the presence of a chromosome translocation t(4;11) or t(9;22) in acute lymphoblastic leukaemia (ALL), and the intensity of the myeloablative chemotherapy. ABSCT was performed in 52 evaluable patients with acute leukaemia. In acute non lymphoblastic leukaemia, the disease free survival seems not to be inferior to that one of autologous bone marrow transplantation, but with a too short follow-up to be conclusive. In acute lymphoblastic leukaemia, the rate of relapses after ABSCT is very high (about 75%), but all the patients presented initially with high risk leukaemia. In myeloma, ABSCT seems to be a very interesting new therapeutic approach, while may be limited by individual difficulties to obtain a number of CSC sufficient to insure a satisfactory engraftment.
 ...
PMID:Blood stem cell autografts in malignant blood disease: the French experience with a special focus on myeloma. The France Autogreffe Group (FAG). 197 29

Pharmacologic and immunologic methods of ex-vivo bone marrow (BM) purging for acute nonlymphocytic leukemia (ANLL) were combined to augment the effect of either method alone. Etoposide (VP16; 20 to 30 micrograms/mL) with or without cytosine arabinoside (Ara C; 10 mg/mL) was used in tandem with the anti-CD33 monoclonal antibody (MoAb), MY9, chosen because CD33 is found on the stem cell pool in the majority of patients with ANLL. The agents were tested singly or sequentially, with a 1-hour incubation of the drugs preceding complement-mediated lysis using MY9. VP16 combined with Ara C killed up to 3.9 +/- 0.3 and 5.11 +/- 0.4 logs of the human ANLL cell lines HL60 and K562 at drug concentrations that killed only 1.2 +/- 0.1 logs of normal committed granulocyte/macrophage stem cells (CFU-GM). Adding a single exposure of the MY9 and complement (C') to the drug-treated cells, greater than 5.4 logs of HL60 were killed. Similar to other pharmacologic agents, no differential kill for clonagenic leukemic cells (colony-forming unit-leukemia; CFU-L) from patients with ANLL was seen for drug only treated blasts versus normal CFU-granulocyte-macrophage (CFU-GM), with less than 1 log CFU-L kill at drug concentrations that spared 1 log of CFU-GM. Similarly, only 1.1 +/- 0.3 logs of ANLL CFU-L were eliminated using MY9 and C'. However, with the sequential VP16/Ara C----MY9 + C' treatment, synergy was demonstrated and 2.6 +/- 0.3 logs of CFU-L were eliminated. Because CD33 is also found on the normal CFU-GM pool, two-stage long-term BM cultures were performed to determine pluripotent stem cell elimination by the drug/MoAb purging combination. No difference of CFU-GM or BFU-E production at 4 to 6 weeks of culture for VP16/Ara C, MY9 + C', or VP16/AraC----My9 + C' treated cells was seen compared with untreated controls indicating sparing of early progenitor cells. Sequential ex vivo treatment of human ANLL CFU-L with VP16/Ara C followed by complement-mediated lysis using MY9 synergistically kills CFU-L while sparing early normal hematopoietic progenitor cells, and thus may be a more effective way to purge BM than either alone.
 ...
PMID:Anti-CD33 monoclonal antibody and etoposide/cytosine arabinoside combinations for the ex vivo purification of bone marrow in acute nonlymphocytic leukemia. 198

In newly diagnosed patients with acute lymphoblastic leukemia (ALL), bone marrow (BM) morphology always shows "replacement" by blasts with decreased or absent normal hematopoietic elements. To answer the question of whether ALL blasts inhibit replication and maturation of normal marrow progenitors, we studied the interaction of normal marrow with BM specimens from 16 new cases of ALL. Irradiated ALL blasts, supernatant derived from ALL blasts in suspension cultures, and conditioned medium prepared from ALL blasts augmented the colony-forming ability of normal marrow erythroid burst-forming unit (BFU-E), granulocyte-macrophage colony-forming unit (CFU-GM), megakaryocyte colony-forming unit (CFU-MK), and multilineage colony-forming unit (CFU-GEMM) progenitors. In sharp contrast to published data on the suppressive effects of acute myeloblastic leukemia cells on normal hematopoiesis in vitro, our results indicate that the growth advantage of ALL cells over normal marrow elements is not mediated through an inhibitory mechanism derived from leukemia cells.
 ...
PMID:Acute lymphoblastic leukemia blast cells do not inhibit bone marrow hematopoietic progenitor colony formation. 199 13


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