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 potential of various photoradiation therapy for the in vitro purging of residual tumor cells from autologous bone marrow (BM) transplants is discussed in this paper. The results with fluorescent dyes, Dihematoporphyrin Ether (DHE) and Merocyanine-540 (MC-540) are detailed. Following photoradiation of cells with white light, both DHE and MC-540 showed high cytocidal activity towards lymphoid and myeloid neoplastic cells, but had significantly less effect on normal granulocyte-macrophage (CFU-GM), erythroid (BFU-E) and mixed colony-forming (CFU-GEMM) progenitor cells. Acute promyelocytic leukemia (HL-60), non-B, non-T, cALLa positive acute lymphoblastic leukemia (Reh), and diffuse histiocytic B-cell lymphoma (SK-DHL-2) cell lines were exposed to different drug concentrations in combination with white light at a constant illumination rate of 50,000 lux. With DHE doses varying from 2.0 to 2.5 ug/ml and MC-540 concentrations of 15 to 20 ug/ml, clonogenic tumor cells could be reduced by more than 4 logs, when treated alone or in mixtures with normal irradiated human marrow cells. However, preferential cytotoxicity towards neoplastic cells was highly dependent on the mode of light activation. MC-540 had no substantial effect on malignant lymphoid (SK-DHL-2) and myeloid (HL-60) cells, and on normal marrow myeloid (CFU-GM) precursors, when the drug incubation was performed in the dark and followed by light exposure of washed cells. Equal doses of MC-540 (15-20 ug/ml) could preferentially eliminate tumor cells under conditions of simultaneous light and drug treatment (30 minutes at 37 degrees C). Using DHE (2.5 ug/ml), 29.3%, 46.8%, and 27.5% of normal marrow CFU-GM, BFU-E, and CFU-GEMM, respectively, were spared, following sequential drug and light exposure of cells, while simultaneous treatment reduced both normal (CFU-GM) and neoplastic cells below the limits of detection. The data from various centers is briefly discussed with special emphasis on clinical trials. Our results provide a useful model for leukemia and lymphoma cells and suggest that these phototherapy experiments can be implemented into clinical trials.
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PMID:Photoradiation methods for purging autologous bone marrow grafts. 213 34

Human and mouse bone marrow cells were cultured for 1 h in the presence of either the antileukaemia drug amsacrine or its 4-methyl,5-[N-methyl]carboxamide disubstituted analogue CI-921, before being plated in methylcellulose medium to determine the survival of granulocyte-macrophage colony forming units (CFU-GM). The drug concentration required for 50% reduction in survival was approx. 0.4 microM for both drugs and was similar for both human and mouse cells. A comparison of the two drugs was then made, at an added drug concentration of 0.5 microM, using cultured mouse L1210 and P388 leukaemia, Lewis lung carcinoma cell lines LLAK and LLTC, human Jurkat leukaemia, human histiocytic lymphoma U937 and human colon carcinoma SW620. The sensitivity of the mouse lines for amsacrine was in the order L1210 greater than P388 greater than LLAK greater than LLTC, similar to the in vivo sensitivity. The selectivity of CI-921 for L1210 versus bone marrow, and for LLAK versus L1210 or P388, was greater than that of amsacrine, again in keeping with its in vivo properties. The sensitivity of the human Jurkat and U937 lines for amsacrine was intermediate between that of L1210 and P388, while SW620 was resistant. The selectivity of CI-921 for Jurkat and U937 versus bone marrow was greater than that of amsacrine, suggesting that CI-921 could have additional advantages over amsacrine in the treatment of some tumours.
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PMID:Comparison of the cytotoxicity of amsacrine and its analogue CI-921 against cultured human and mouse bone marrow tumour cells. 213 78

Prognostic factors affecting the leukemic transformation were studied in 43 patients with myelodysplastic syndrome (MDS). Acute leukemia developed in 17 cases and it was nonlymphocytic leukemia in every case. No remission was achieved following antileukemic therapy and most of the cases proved to be true drug-resistant leukemia. Initial granulopenia, thrombopenia or anemia alone did not influence the occurrence of leukemic transformation but pancytopenia indicates bad prognosis. According to FAB classification especially refractory anemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-T) were often followed by leukemic transformation. The granulocyte-macrophage progenitor cell (GM-CFC) content of bone marrow were also studied. The GM-CFC content was decreased in each patient. There was no correlation between GM-CFC number and leukemic transformation, the growth-pattern in agar-gel culture, however, turned out to have prognostic importance. Leukemic type of growth, namely always preceded leukemic transformation.
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PMID:[Factors influencing leukemic transformation in myelodysplastic syndrome]. 219 92

Interleukin-1 (IL-1) has hemopoietin-1 (H-1) activity, i.e., it synergizes with macrophage-colony stimulating factor (M-CSF), granulocyte-macrophage-CSF (GM-CSF) and interleukin-3 (IL-3) in stimulating in vitro colony formation of hematopoietic progenitor cells. In this study the synergistic activity of IL-1 was investigated on IL-3 and GM-CSF induced growth of acute myeloid leukemia colony forming cells (AML-CFU) in vitro. Among 12 cases of human AML, IL-1 significantly elevated IL-3 stimulated colony numbers in eight instances and enhanced GM-CSF induced colony growth in five cases. As IL-1 is an inducer of cytokine production and since tumor necrosis factor (TNF) elevates IL-3 or GM-CSF induced proliferation of AML-CFU, we examined whether IL-1 enhanced AML-CFU growth via the induction of TNF production. Neutralizing anti-TNF-alpha antibodies significantly decreased IL-1/IL-3 or IL-1/GM-CSF stimulated colony numbers in six of seven cases studied, whereas anti-TNF-beta had no effect, indicating that endogenously produced TNF-alpha costimulated the growth of AML-CFU. Furthermore, AML blast cells stimulated by IL-1 released increased amounts of TNF-alpha (between 25 and 533 pg/ml; median 255 pg/ml) into the culture medium (TNF-alpha specific radioimmunoassay) as compared with noninduced AML cells (less than 1 to 149 pg TNF-alpha/ml; median 31 pg/ml). Thus, the effect of IL-1 on AML-CFU proliferation is not the result of direct activation of AML progenitors, but IL-1 stimulates the release of TNF-alpha by AML cells and endogenous TNF subsequently synergizes with IL-3 or GM-CSF.
Leukemia 1990 Aug
PMID:Hemopoietin-1 activity of interleukin-1 (IL-1) on acute myeloid leukemia colony-forming cells (AML-CFU) in vitro: IL-1 induces production of tumor necrosis factor-alpha which synergizes with IL-3 or granulocyte-macrophage colony-stimulating factor. 220 34

We have shown that unstimulated and interleukin 2 (IL-2)-activated peripheral blood lymphocytes from both normal donors and cancer patients in remission significantly inhibited the proliferation and granulocyte-macrophage colony formation (granulocyte-macrophage colony-forming cells, GM-CFC) of autologous and allogeneic bone marrow (BM). The inhibition was mediated primarily by CD5+ T cells, although lower levels of inhibition were also displayed by CD56+, CD5- lymphocytes, most of which were CD16-. The CD5+ lymphocytes were also the major effectors responsible for lysis of BM. Inhibition of BM proliferation and GM-CFC colony formation was not dependent on proliferation of the effector cells or cell-to-cell contact, because it was also mediated by a soluble factor produced by IL-2-activated lymphocytes. The relevance of these findings to future approaches to leukemia treatment is discussed.
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PMID:Inhibition of human bone marrow and myeloid progenitors by interleukin 2-activated lymphocytes. 220 62

In the present study the effects of a combined treatment with cytosine-arabinoside (Ara-C) and interleukin-3 (IL-3) on acute myeloblastic leukaemia clonogenic cells and on normal haemopoietic progenitors was investigated, with the aim of improving the tumoricidal effect of cycle specific drugs. Blast cells from 24 acute myeloblastic leukaemia (AML) patients were screened with a short-term proliferative assay based on 3H-thymidine (3H-TdR) uptake for their response to IL-3. To evaluate the synergism between the growth factor and Ara-C, the cells were pretreated for 3 d in liquid culture in the presence or absence of IL-3 (10 U/ml) and for the last 24 h with Ara-C (3 micrograms/ml). The cells were then washed and seeded in semisolid media to assess their clonogenic ability. The results showed that, in those cases which were good responders to IL-3 in the 3H-TdR uptake assay (19 out of 24), Ara-C exposure eliminated a greater proportion of clonogenic cells if pretreated with IL-3 than if untreated (P less than 0.001), while in cases unresponsive to IL-3 this effect was not significant. Moreover, when the same protocol was applied to bone marrow cells from normal donors, it was found that IL-3 pretreatment did not significantly enhance the toxic effect of Ara-C on day 14 granulocyte-macrophage colony forming units (CFU-GM) and erythroid burst forming units (BFU-E). Finally IL-3 pretreatment was also able to increase the cytotoxic effect of Ara-C on leukaemic cells co-cultured, to simulate clinical AML remission, with normal bone marrow cells. The results indicate that IL-3 may improve the therapeutic index of cycle-specific drugs in AML therapy.
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PMID:Different sensitivity of normal and leukaemic progenitor cells to Ara-C and IL-3 combined treatment. 222 44

Hexamethylene bisacetamide (HMBA; NSC 95580) is a potent polar-planar differentiating agent of leukemia and solid tumor cell lines in vitro at clinically achievable concentrations. HMBA is currently being studied in patients with myelodysplastic syndrome. Previous phase I trials have demonstrated that HMBA produces hematologic toxicity in morphologically normal bone marrows of patients with solid tumors. Because of concern that HMBA may produce more severe myelotoxicity in patients with myelodysplastic syndrome since these patients have limited hematopoietic reserves, we studied the effects of HMBA on myelodysplastic and normal hematopoietic progenitors in vitro. HMBA concentrations that are optimal for differentiation in vitro (2 to 5 mmol/L) and HMBA concentrations that are being achieved in clinical trials (1 to 2 mmol/L) inhibited the growth of granulocyte-macrophage colony-forming units and erythroid burst-forming units from all 15 patients with myelodysplastic syndrome and all 4 normal subjects, HMBA did not induce proliferation of myelodysplastic or normal progenitors at any concentration; rather, it produced nearly identical inhibition of normal and myelodysplastic hematopoietic progenitors. HMBA also produced quantitatively similar inhibition of clonogenic leukemic growth of two myeloid leukemia cell lines. For a differentiating agent to be effective, it will likely have to either produce both differentiation and proliferation of abnormal hematopoietic progenitors or show selective inhibitory effects on abnormal as compared with normal progenitors. Although the mechanisms responsible for the antiproliferative effects of HMBA cannot be determined from this study, similar inhibitory effects of HMBA on normal and abnormal hematopoietic progenitors suggest that HMBA may be of limited utility in producing and sustaining elevations of peripheral blood cell counts in patients with myelodysplastic syndrome.
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PMID:Effects of the differentiating agent hexamethylene bisacetamide on normal and myelodysplastic hematopoietic progenitors. 225 Mar 14

The retroviral vector N2, which is derived from the Moloney murine leukemia retrovirus, was used to transfer the bacterial NeoR gene (conferring resistance to the neomycin analogue G418) into hematopoietic progenitor cells from fetal, neonatal, and adult dogs and cats. Infection of canine and feline bone marrow cells with the N2 vector resulted in resistance of granulocyte-macrophage colony-forming units (CFU-GM) to G418. Approximately 2%-4% of fetal liver, fetal bone marrow, and adult bone marrow day-7 CFU-GM were resistant to 1.75 mg/ml G418, a dose toxic to cells not expressing the NeoR gene, after infection with the N2 retrovirus. In sharp contrast to the low rate of infectivity of both fetal and adult marrow samples, the mean +/- SD of G418-resistant CFU-GM was 11.7% +/- 14.1% and 14.0% +/- 18.1% for neonatal dog and cat marrow samples, respectively. The neomycin phosphotransferase enzyme activity was detected in G418-resistant CFU-GM, confirming that G418-resistant CFU-GM expressed the NeoR gene. The increased efficiency of retroviral vector-mediated gene transfer into neonatal hematopoietic progenitor cells was not due to an increased fraction of actively dividing cells, as determined by tritiated thymidine suicide. Understanding the basis for increased gene transfer into neonatal hematopoietic progenitor cells may be helpful in designing effective retroviral vectors/gene transfer protocols for gene therapy.
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PMID:Increased efficiency of gene transfer with retroviral vectors in neonatal hematopoietic progenitor cells. 230 10

Using an in vitro model, we studied whether combining 4-hydroperoxycyclophosphamide (4HC) with other drugs could improve its effectiveness as an ex vivo purging agent for autologous bone marrow transplantation. 4HC was incubated simultaneously with vincristine and etoposide, and sequentially with methylprednisolone, in various combinations. Compared to 4HC alone, all drug combinations increased the kill of the leukemia cell lines K562 and CEM without increasing the kill of granulocyte-macrophage colony-forming units (CFU-GM). The combination of 4HC, vincristine and methylprednisolone was the most active, and this drug combination was also the only combination which showed improved selective cytotoxicity (compared to 4HC alone) toward REH cells. This combination inhibited at least 8 logs of clonogenic leukemia cells from all three cell lines at doses which spared 1% of CFU-GM. This was an increase of 1.7 to 6.6 logs of clonogenic leukemia cell kill over 4HC alone. This drug combination displayed similar differential activity between fresh clonogenic leukemia cells and CFU-GM cultured from the bone marrows of seven patients about to undergo autologous bone marrow transplantation for acute lymphocytic leukemia.
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PMID:In vitro evaluation of combination drug purging for autologous bone marrow transplantation. 235 Jun 26

The in vitro cytotoxic properties of acetaldoifosphamide, a new chemically stable bis-acetate analogue of aldoifosphamide that requires enzymatic activation by cellular carboxylate esterases, has been compared with that of 4-hydroperoxycyclophosphamide (4-HC). On a molar basis, acetaldoifosphamide was 8-10 times more potent than 4-HC against two different human leukemic myeloid cell lines, but only twice as potent as 4-HC against normal bone marrow granulocyte-macrophage colony-forming cells (GM-CFC). Acetaldoifosphamide retained its activity against leukemic cell lines that were highly resistant to the antileukemic drugs doxorubicin and m-AMSA. GM-CFC doubling times after exposure of bone marrow to high concentrations of acetaldoifosphamide in suspension cultures were 6-12 hours. Similar doubling times were obtained after incubation of marrow with 4-HC. Acetaldoifosphamide has a sparing effect on hematopoietic stem cells that is similar to that found for 4-HC; however, it is considerably more potent than 4-HC. Acetaldoifosphamide is different from 4-HC in its chemical stability and its unique requirement for carboxylate esterase activation. We conclude that acetaldoifosphamide may have advantages over 4-HC for in vitro purging of leukemic cells from human bone marrow.
Leukemia 1990 Jun
PMID:Suitability of a new stable acetal analogue of aldoifosphamide for purging leukemic cells from human bone marrow. 235 43


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