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)

Biological modification in cancer therapy involves many different strategies and substances. Bacterial products with established usefulness include BCG, C. parvum and L-Asparaginase. Immunotherapy with such agents has not, however, found general application, although revived interest in 'Coley's mixed toxins' (used earlier this century) paralleled the development of their presumed effector molecules, tumour necrosis factor and lymphotoxin. Many other Cytokines, both natural or recombinant, are now produced on a vast scale following the recent biotechnology revolution. Of these, Alpha Interferons have already proved useful in hairy cell leukaemia, carcinoid tumours, renal cell cancer, Kaposi's sarcoma, chronic granulocytic leukaemia and certain lymphomas, whilst their use as adjuvants or in combination is currently being investigated. More recently, Interleukin-2, which stimulates the clonal expansion of activated T-cells, has shown promise both as a single agent, and when used with lymphokine activated killer (LAK) cells or tumour infiltrating lymphocytes (TILS). A different approach involves the Colony Stimulating Factors such as G-CSF and GM-CSF which reduce the degree and duration of treatment-related myelosuppression, thereby allowing more intensive cytotoxic or radiation therapy, as well as facilitating early recovery following bone marrow transplantation. Monoclonal antibodies have not proved as specific for malignant cells as was originally hoped, but certain tumours, such as lymphoma, are now realistic targets for therapy. Increasingly sophisticated effector mechanisms (e.g. conjugated pro-drugs) and genetically engineered "humanised" monoclonal antibody hybrids present the brightest hopes for the future. Biotherapy, the "fourth modality of cancer treatment" has already assumed its place alongside surgery, radiotherapy and cytotoxic chemotherapy, and will grow in importance as our understanding of the molecular biology of cancer increases in the coming decades.
 ...
PMID:Biological modifiers and their role in cancer therapy. 218 42

Human acute myelocytic leukemia (AML) marrow cells respond to stimulation with increased proliferation and enhanced intracellular metabolism of the cytotoxic antimetabolite 1-B-D arabinofuranosylcytosine (ara-C). Our previous studies have focused on the drug-induced humoral stimulatory activity (HSA) present in serum following initial cytoreduction which augments in vitro growth and biochemical pharmacology. The activity of HSA likely relates to the presence of multiple stimulators. The effect of 18-hr culture in purified recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) (1 ng/ml) on in vitro AML marrow cell [3H]dThd incorporation into DNA, intracellular ara-C activation to the triphosphate form (ara-CTP), and subsequent ara-CTP retention were determined in leukemic cells of 11 patients and compared with cells similarly cultured in HSA-containing sera. The stimulatory effects of rhGM-CSF and HSA on both growth and pharmacologic parameters were comparable for each AML population, with maximal response to both regulators detected for FAB M2. These data demonstrate that GM-CSF acts similarly to HSA as an active stimulator of leukemic cell proliferation and net intracellular ara-C metabolism in vitro, and support clinical trials designed to examine the role of rhGM-CSF in enhancing ara-C cytotoxicity by increasing the growth fraction of drug-responsive target cells in vivo.
Leukemia 1990 Aug
PMID:Effects of rhGM-CSF on intracellular ara-C pharmacology in vitro in acute myelocytic leukemia: comparability with drug-induced humoral stimulatory activity. 220 33

We showed that these two cell lines obviously expressed megakaryocytic phenotypes, such as multilobular, hyperploid nuclei, expression of GPIIb/IIIa complex, GPIb and PPO, although they have been originated from patients with leukemia. Furthermore, these cells had following characteristics. First, they responded to various kinds of hemopoietic factors. Especially, UT-7 cells were solely dependent on GM-CSF, IL-3 or Ep. Therefore UT-7 cells are useful to the assay of these factors as megakaryocytic cells. These facts provide us with new questions: why they are dependent on plural number of factors? How are the expressions of their receptors controlled. Is there an "autocrine" mechanism controlling their growth? Among these questions, we have just started with the Ep receptors, and most of the problems remain to be clarified. Second, PMA treatment suppressed their growth, but enhanced their differentiation and maturation. Among the megakaryocytic phenotypes, increase in GPIIb/IIIa complex, determined by a biochemical method, PPO by ultrastructural study, and the increase in cellular ploidy were clearly observed by PMA treatment. The phorbol ester PMA is well known to induce the differentiation of various kinds of leukemic cells (Rovera et al., 1979). Detailed molecular basis to clarify why the same PMA treatment causes differentiation into different cell lineages, dependent on cellular origin of the target cells, should be further studies. Third, the cells produced hemopoietic growth factors by PMA treatment, the majority of which was GM-CSF. Humoral control of megakaryopoiesis still remains unsettled. Our study may shed a light on its "multistep" regulatory mechanisms. Availability of a large amount of homogeneous megakaryocytic populations, which are responsive to hemopoietic factors and phorbol ester, will provide us with a great deal of informations concerning the molecular insight of megakaryocytopoiesis and thrombocytopoiesis.
 ...
PMID:Growth and differentiation of two human megakaryoblastic cell lines; CMK and UT-7. 221 43

We studied the effect of preincubation with recombinant GM-CSF on the activity of cytarabine and doxorubicin against clonogenic acute myeloid leukemia cells (CFU-AML). Leukemia cells from seven persons with AML, three myeloid cell lines (HL60, KG1, K562) and two control cell lines (U937, MOLT3) were tested. Preincubation with GM-CSF (0.01-0.1 microgram/ml) increased DNA synthesis as measured by tritiated thymidine incorporation and intranuclear Ki67 expression in cells from six persons with AML and in HL60 cells. Leukemia cells preincubated with GM-CSF for 6-48 h were exposed to cytarabine (2-200 micrograms/ml) or doxorubicin (0.01-0.1 microgram/ml) for 3 h and CFU-AML assayed. This approach further reduced CFU-AML in samples from six persons with AML and in HL60 and KG1 cells compared to cells not preincubated with GM-CSF prior to drug treatment. In most instances, reduced CFU-AML correlated with GM-CSF induced DNA synthesis. These data suggest a possible strategy of GM-CSF pretreatment to increase anti-leukemia efficacy of chemotherapy in AML.
 ...
PMID:GM-CSF incubation prior to treatment with cytarabine or doxorubicin enhances drug activity against AML cells in vitro: a model for leukemia chemotherapy. 223 47

In patients with acute myeloblastic leukemia incomplete response to induction chemotherapy and short disease-free survival may be related to cell kinetic quiescence of leukemic cells. In this in vitro study, we tested the hypothesis that treatment with cytokines and subsequent chemotherapy (ARA-C, daunorubicin) can increase proliferation and enhance leukemic cell kill. We evaluated the effects of recombinant human interleukin-3 (rh-IL-3), granulocyte-macrophage colony stimulating factor (rhGM-CSF) and granulocyte colony stimulating factor (rhG-CSF) alone and in combination on AML (N = 11) and blastic phase CML (N = 3) samples. Cellular DNA and RNA, incorporation of bromodeoxyuridine (BrdU), cell growth fraction, cell viability, and differentiation markers were evaluated in vitro. A decrease of the quiescent cell population (p = 0.003) and an increase in S-phase cells (p = 0.001) was observed in 8/11 AML samples treated with cytokine combinations. Pronounced heterogeneity or proliferative response was seen between individual cases and different cytokines, but in the majority of the samples IL-3 was most effective. Significantly increased Ki67 expression (p = 0.009) and BrdU incorporation (p = 0.01) were also found after exposure to cytokines indicating an increase in growth fraction. DNA synthesis time was unaffected. Eight samples of AML were treated for 24 hr with ara-C following 2 days of in vitro cytokine incubation. Evaluation of leukemic cell kill showed increased cytotoxicity in three of those five samples which had significant depletions of G0 cells and increases in S-phase. None of the leukemic samples without recruitment from G0 had an increase in ARA-C cytotoxicity. This study provides detailed cell kinetic analysis of cytokine effects on AML blasts and provides a rationale for a novel approach to the treatment of AML.
Leukemia 1990 Dec
PMID:Kinetic rationale for cytokine-induced recruitment of myeloblastic leukemia followed by cycle-specific chemotherapy in vitro. 224 6

Using (a) somatic cell hybrids retaining partial chromosome 5 and (b) clinical samples from patients with acquired deletions of the long arm of chromosome 5, combined with chromosome 5-linked DNA probes, some of which exhibited RFLPs, we have determined the order of a series of genes on chromosome 5. The order established is 5pter----MLVI-2----cen----HEXB----DHFR----Pi227- --- cp12.6----(IL5,IL4)----IL3----GMCSF---- FGFA---- (CSF1R,PDGFR)----(treC,ADRBR)----(ARH-H9,CSF1 )----qter. The suggested order and orientation for the closely linked IL3/GMCSF gene pair is cen----5' IL3 3'----5' GMCSF 3'----qter, on the basis of analysis of the GMCSF rearrangement in HL60 DNA. The map position of the GRL locus, which was consistent with both somatic cell hybrid and 5q- analyses, was telomeric to GMCSF and centromeric to CSF1R/PDGFR, near FGFA. Long-range restriction-enzyme analysis of 5q- DNAs did not detect rearrangements of 5q-linked probes except in HL60 DNA, but it did reveal putative long-range RFLPs of several loci. RFLPs for GRL, Pi227, cp12.6, IL3, and CSF1R can detect deletions in bone marrow and in leukemia cells from patients with acquired 5q deletions.
 ...
PMID:Order of genes on human chromosome 5q with respect to 5q interstitial deletions. 229 53

Examples are presented in which normal as well as abnormal chromosome distributions could be obtained from the same individual by means of bivariate flow karyotyping. Selective stimulation of T-lymphocytes obtained by E-rosetting from the blood of a patient with acute myelocytic leukemia resulted in a normal flow karyogram. The specific stimulation of myelocytic leukemia cells with granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 3 (IL-3) yielded flow karyograms displaying the leukemia-associated chromosome abnormalities. The resulting flow karyograms could be used to discriminate between homolog differences, which appear normally in virtually every individual, and leukemia-associated chromosomal aberrations. In the case of a female chronic myelocytic leukemia patient who received bone marrow form an HLA-identical male donor, specific stimulation of various subsets of cells enabled to discriminate between leukemic host cells and non-leukemic donor cells. Both the leukemia-specific translocations and sex chromosomes were used as markers to analyse the flow karyograms obtained from the same sample.
 ...
PMID:Clinical applications of flow karyotyping in myelocytic leukemia by stimulation of different subpopulations of cells in blood or bone marrow samples. 230 58

Conditioned media (CM) from a human lung adenocarcinoma cell line expressing interleukins 1 and 6 (IL-1, IL-6), granulocyte (G), macrophage (M), and GM colony-stimulating factors (G, M, GM-CSF) and transforming growth factor beta (TGF beta) were used to stimulate growth of bone marrow (BM) cells from 18 persons with leukemia, myelodysplastic syndrome, or lymphoma. The objective was to increase numbers of analyzable metaphases and to enhance the likelihood of detecting cytogenetic abnormalities. Although more mitotic cells were observed with CM, the detection rate of cytogenetic abnormalities decreased in 12 of 18 cases. These data indicate that use of CM for cytogenetic analyses may favor growth of normal versus leukemia cells and mask cytogenetic abnormalities.
 ...
PMID:Use of conditioned media in cell culture can mask cytogenetic abnormalities in acute leukemia. 233 74

In vitro clonal culture of leukemic cells from patients with acute myeloid leukemia (AML) showed that cells from all subtypes tested could be stimulated to proliferate clonally either by purified recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) or by human cross-reactive, purified murine granulocyte CSF (G-CSF). The responsiveness of AML populations to CSF stimulation was quantitatively variable but was within the heterogeneous range exhibited by normal granulocyte-monocyte progenitor cells. A general concordance was noted between the proliferative effects of GM-CSF and G-CSF on the individual leukemic populations. All AML populations tested specifically bound 125I-labeled murine G-CSF; the level of labeling varied widely and correlated with AML subtype. Labeling levels on individual labeled leukemic cells were within the heterogeneous range exhibited by normal cells, but significant numbers of blast cells in M2, M4, and M5 AMLs appeared to lack membrane receptors for G-CSF. The level of labeling with G-CSF did not correlate with the frequency of clonogenic cells able to be stimulated by G-CSF. The data emphasized that GM-CSF and G-CSF are equivalent proliferative stimuli for human myeloid leukemia cells. Further, despite the potential ability of G-CSF to suppress murine leukemic cells, many AML blast cells lack significant numbers of G-CSF receptors. These considerations warrant caution in future attempts to use G-CSF in the therapy of acute myeloid leukemia.
Leukemia 1987 Jan
PMID:Primary human myeloid leukemia cells: comparative responsiveness to proliferative stimulation by GM-CSF or G-CSF and membrane expression of CSF receptors. 244 28

To further define the growth factors required for the in vitro proliferation of acute myeloblastic leukemic (AML) cells, we have compared the ability of recombinant interleukin-3 (IL-3), granulocyte-macrophage colony stimulating factor (GM-CSF), and granulocyte colony stimulating factor (G-CSF) to support growth of AML colony forming cells (AML-CFU). IL-3, GM-CSF, and G-CSF are active as single growth factors in short-term colony cultures and have additive effects when used in combination in some cases. The effects of these CSFs on the proliferation of AML cells in long-term-cell-suspension cultures were also investigated. These cultures provide an estimate of the "self-renewal" capacity and long-term proliferation potential of AML cells. There was considerably heterogeneity with regard to the effects of individual growth factors, but in general, IL-3, GM-CSF, and G-CSF promoted self-renewal of AML cells, and combinations tended to be more effective in supporting long-term survival of AML-CFU. There was evidence of gradual differentiation, but this was evident in control cells and did not appear to be accelerated by CSF treatment. These results of short-term and long-term cultures indicate that each of the CSFs tested can be used by AML cells to support proliferation. The lack of evidence that the CSFs enhance in vitro differentiation does not suggest they will be valuable as therapeutic differentiation agents.
Leukemia 1987 Aug
PMID:Effects of recombinant IL-3, GM-CSF, and G-CSF on proliferation of leukemic clonogenic cells in short-term and long-term cultures. 244 35


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