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)

From January 1985 to May 1987, we studied 256 adults with newly diagnosed acute leukemia. Acute undifferentiated leukemia (AUL) was diagnosed in 12 of the 256 (4.6%) cases when lineage could not be delineated by light microscopy and light cytochemistry. To further characterize the blasts, immunophenotyping, ultrastructural myeloperoxidase (UMPO), and ultrastructural platelet peroxidase parameters were examined in 10, 11, and 6 of the 12 cases, respectively. Five cases demonstrated UMPO and were reclassified as acute myeloblastic leukemia (AML). Of the six UMPO-negative cases, three had a myeloid and one had a mixed immunophenotype. One UMPO-negative patient with a myeloid immunophenotype was probed for the immunoglobulin heavy chain gene (JH) and the beta chain of the T-cell receptor gene (Tcr beta) with no evidence of rearrangement. Six cases were treated with standard acute lymphoblastic leukemia (ALL) chemotherapy and failed to achieve complete remission (CR). Various AML chemotherapeutic regimens produced CR in only 3 of the 12 cases. One case was treated with gamma interferon and the other 2 with high-dose Ara-C. Our findings indicate a myeloid lineage can be detected by UMPO (5/12) in some cases of AUL. A germline configuration with JH and Tcr beta in one case as well as a myeloid immunophenotype in 3 UMPO-negative cases raises the possibility that myeloid lineage commitment may occur in the absence of myeloid peroxidase (MPO) cytochemical positivity.
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PMID:Heterogeneity in acute undifferentiated leukemia. 319 52

Transient or permanent paraplegia after the use of intrathecal (IT) methotrexate (MTX) or cytosine arabinoside (Ara-C) for treatment or prophylaxis of patients with meningeal leukemia is an unusual complication, with an incidence of less than 3% among such patients. Only 15 cases involving IT MTX have been documented and even fewer with IT Ara-C. Three patients were studied who developed permanent or ascending myelopathy from treatment of their leukemia or rhabdomyosarcoma with IT chemotherapy. The patients' ages ranged from 7 to 62 years. Two of the three patients had electromyographic examinations. These revealed a primary motor neuron degeneration or a polyradiculopathy, superimposed on a mild axonal peripheral neuropathy associated with vincristine therapy. This is consistent with other electromyographic studies. Two of the patients showed an elevation of the cerebral spinal fluid (CSF) protein before development of paraplegia; one also showed a rise in myelin basic protein associated with his myelopathy. Neuropathologic findings suggest demyelination as the primary process leading to myelopathy. Increasing evidence has shown that total CSF protein, or more specifically, the myelin basic protein, may be elevated before development of paraplegia. Routine serial testing of the CSF for total protein could be used as a screening test during therapy.
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PMID:Paraplegia and quadriplegia after intrathecal chemotherapy. 321 64

Human DNA ligase was purified from different kinds of immunocompetent cells: thymocytes, normal and stimulated lymphocytes, blasts from ALL (Burkitt and non-T, non-B) and ANLL (M1, M2, and M5). Based upon the protocol for the treatment of these leukemias, the purified enzymes were assayed in the presence of routinely used combinations of antileukemic drugs. At the range of concentration tested (between 0.1 and 5 microM) some drugs taken separately were totally inactive on the enzyme from the different sources. For those being inhibitory, when used in combination their effect was always different from what was observed when the compound was tested alone. Some combinations were more effective in inhibiting the enzyme from leukemic than from normal cells (vincristine + cyclophosphamide + prednisone in ALL and rubidazone + Ara-C, Ara-C + m-AMSA, in ANLL). However, some combinations of drugs are without effect on ligase from leukemic cells at this dose range (vincristine + rubidazone + Ara-C + prednisone and adriamycin + asparaginase + Ara-C in ALL or etoposide + Ara-C, adriamycin + cyclophosphamide in ANLL). This is the first direct observation of the effect of cytostatic drugs on DNA ligase, a key enzyme of the DNA replication and repair process. The clinical consequences of these observations are discussed in an attempt to selectively inhibit replication, thereby division, of cancer cells.
Leukemia 1988 Jun
PMID:Effects of clinical combinations of antileukemic drugs on DNA ligase from human thymocytes and normal, stimulated, or leukemic lymphocytes. 325 60

Human recombinant GM-CSF (rGM-CSF) is under investigation as a growth-protective agent for normal hematopoietic elements in phase I trials of myelosuppressive chemotherapy and in bone marrow transplantation. We determined the effect of rGM-CSF on the metabolism of high dose Ara-C in bone marrow mononuclear cells (BMMCs) from healthy volunteers and patients with ANLL. Cells were incubated with rGM-CSF alone, Ara-C alone, or a combination of the two drugs. Treatment with rGM-CSF alone yielded approximately a twofold increment in intracellular dCTP pools in normal BMMCs but not in leukemic blasts. Exposure to rGM-CSF in conjunction with Ara-C corrected Ara-C-mediated declines in dCTP levels and decreased cytosine arabinoside triphosphate (Ara-CTP) accumulation in normal BMMCs but not in their leukemic counterparts. Furthermore, when exposure to Ara-C was preceded by treatment with rGM-CSF for 18 hr, an even greater reduction in the Ara-CTP/dCTP pool ratio was observed in normal versus leukemic elements; however, this did not significantly change Ara-C DNA incorporation in the two cell types. The differential effect of rGM-CSF on the phosphorylation of Ara-C in normal BMMCs versus leukemic blasts has potential implications for the use of a regimen consisting of rGM-CSF and high dose Ara-C in the treatment of ANLL with chemotherapy or autologous bone marrow transplantation.
Leukemia 1988 Dec
PMID:Effect of recombinant GM-CSF on the metabolism of cytosine arabinoside in normal and leukemic human bone marrow cells. 326 63

High doses of cytosine arabinoside (ara-C) were administered by continuous infusion to 24 patients with acute leukemia in relapse or blast phase of chronic myelogenous leukemia (CML). Ara-C was infused at a dose rate of 250 mg/M2/hr for 36 to 72 hr. The major toxicities were myelosuppression, diarrhea, and abdominal pain. Other toxicities included pulmonary edema, neurotoxicity, and liver function abnormalities. The gastrointestinal toxicity was dose-limiting and a phase II dose was established at 250 mg/M2/hr for 60-72 hr. Four patients treated with this dose schedule had objective responses. Two patients with CML in blast phase returned to chronic phase and have remained stable without maintenance therapy for 12 and 18 months. Two patients with acute myelogenous leukemia in relapse entered complete remissions which continued unmaintained for 4 and 6 months. Steady-state plasma ara-C levels ranged between 7 and 24 x 10(-6) M, while ara-U levels were as high as 4.5 x 10(-4) M. There was no detectable accumulation of ara-C or ara-U during the infusion period. These findings would suggest that the continuous infusion of high dose ara-C may be useful in the treatment of acute leukemia and CML in blast crisis.
Leukemia 1988 May
PMID:Prolonged high dose ARA-C infusions in acute leukemia. 328 17

In this article, the clinical effects of rH-TNF on various cancer patients and the mechanism of self-induction of defense against rH-TNF cytotoxicity in tumor cells and the counter measures against this are reviewed. 1) Clinical effects of rH-TNF Intratumoral administration of rH-TNF was performed in 7 patients and clinical efficacy (PR + MR) was observed in 3/7 (42.9%). Also a reduction of leukemia cells in peripheral blood was observed in all 4 leukemia patients following intravenous (i.v.) administration of rH-TNF. Furthermore, in 2 multiple myeloma patients, the myeloma protein and plasma cells in bone marrow were reduced by i.v. administration of rH-TNF. 2) Self-induction of defense against rH-TNF cytotoxicity Investigation of the effect of TNF on RNA and protein synthesis by tumorigenic and normal cell lines showed that their synthesis in tumor cells was increased at 12 h and peaked at 24 h of incubation with TNF, while that in normal diploid fibroblast (HEL) cells was apparently unaffected by the presence of TNF. Artificial inhibition of either RNA or protein synthesis by L-M cells, upon addition of Act D or CHI increased the cytotoxic effect of TNF, thus suggesting that the elevated RNA and protein synthesis is related not to the cytotoxic reaction itself but rather to a defense mechanism. Similar incubation of HEL cells with TNF in the presence of either inhibitor resulted in the occurrence of cytotoxicity not observed with TNF alone, thus suggesting the existence of a defense mechanism in normal, TNF-resistant cells which is absent or greatly weakened in tumor cells. 3) Combination therapy of rH-TNF with various anticancer drugs. A synergistic increase in the cytotoxic effects of rH-TNF and anti-cancer drugs was demonstrated in vitro The cytotoxicity of rH-TNF against L-M cells in combination with MMC, ADM, Ara-C, ACD, DM, CDDP, VCR and 5-FU was 4 to 347 times as high as that of rH-TNF alone. These results suggest that combination therapy including rH-TNF and anti-cancer drugs may be of value in the treatment of malignancy in human patients.
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PMID:[Anti-tumor effect of human recombinant TNF]. 329 72

Both harringtonine (Harr) and Ara-C are effective for treatment of ANLL. Since it was suggested that Harr could induce leukemic cells to differentiate and Ara-C might be a weak inducer of leukemic cell differentiation, we investigated the effect of Harr in combination with Ara-C on inducing differentiation of leukemic cells. Ten patients with ANLL were treated with low dose Harr in combination with low dose Ara-C. Complete remission was achieved in 8 of the 10 patients. After therapy, severe pancytopenia and moderate myelosuppression occurred in two patients who achieved remission. Four patients demonstrated a decrease in blast cells with an associated transient increase in mature granulocytes during therapy. Auer bodies appeared in 7-8% mature granulocytes in peripheral blood and in bone marrow on the 14th day of combination therapy in one patient. Freshly isolated leukemic cells from six pretreatment patients were cultured in liquid in the presence of Harr in combination with Ara-C. Apparent evidence of differentiation of leukemic cells and Auer bodies in the cytoplasm of mature granulocytic cells were observed in two of the six patients. The above results seem to suggest that the therapeutic effect of low dose Harr plus low dose Ara-C may result from both differentiation induction and cytotoxicity of the leukemic cells.
Leukemia 1988 Aug
PMID:A study on the induction of differentiation of human leukemic cells by harringtonine combined with cytarabine. 341 24

The effect of retinoic acid (RA) alone and in combination with cytosine arabinoside (Ara-C) on differentiation of fresh human myeloid leukaemic cells from patients with AML was studied. Cells from six patients: three with acute myelomonocytic leukaemia AMMoL and three with acute monoblastic leukaemia AMoL with a percentage of blasts greater than 70, were treated in an in vitro primary suspension culture with retinoic acid (10(-7) M), cytosine arabinoside (100 ng/ml) or both in combination. Non-adherent mononuclear cells were seeded at a concentration of 5 x 10(5) cells/ml in RPMI 1640 culture medium supplemented with 20 per cent fetal bovine serum and 10 per cent (PHA-LCM) phytohaemagglutinin leucocyte conditioned medium and incubated for 6 days at 37 degrees C in a humidified incubator containing 5 per cent CO2 in air. Morphological and functional differentiation into terminal mature elements was induced in all leukaemia cells of the six patients following exposure to the combination of both agents. These results suggest the potential usefulness of the combination of a differentiating agent (retinoic acid) and an antileukaemic drug (cytosine arabinoside) in the treatment of acute myeloid leukaemias: AMMoL and AMoL. This combination warrants a clinical trial.
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PMID:Retinoic acid alone and in combination with cytosine arabinoside induces differentiation of human myelomonocytic and monoblastic leukaemic cells. 342 32

A patient with acute leukaemia was treated with i.v. 2-h infusions of Ara-C at a dose of 3.0 g/m2 every 12 h. During 6 d of therapy the concentrations of the metabolite Ara-U in the CSF reached rather high levels of between 60 and 70 mumol/l from d 2-6 due to high levels of Ara-U in the plasma. The concentration of Ara-C in the CSF after the first infusion was 10.8 mumol/l. After repetitive doses on d 2-6 the drug concentrations increased from about 3 mumol/l just before infusion to about 8 mumol/l at the end of infusion, indicating inhibition of Ara-C influx into the CSF during prolonged treatment. We suggest that the high levels of Ara-U in the plasma interfere with Ara-C transport across the blood-brain barrier.
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PMID:Does the metabolite uracil arabinoside inhibit cytosine arabinoside (Ara-C) penetration into the cerebrospinal fluid during high-dose Ara-C therapy? 345 31

Two patients with acute myelomonocytic leukemia in central nervous system relapse developed clinical signs and computerized tomographic evidence of leukoencephalopathy five to seven days after intravenous high dose Ara-C therapy. The first patient had received 30 gm of intravenous Ara-C with cranial irradiation (1680 rad in 2 fractions) and intrathecal Ara-C (100 mg X twice) for an intracerebral chloroma and leptomeningeal leukemia. In this patient the leukoencephatlopathy was probably a result of a synergistic effect of the concomitant triple therapy. The second patient had received intrathecal administration of Ara-C and methotrexate for five and one-half months prior to intravenous Ara-C therapy. He developed altered mental status after 24 gm of intravenous Ara-C infusion. CT scan showed changes in the white matter compatible with leukoencephalopathy. In this patient the intravenous Ara-C probably was the precipitating factor of the development of leukoencephalopathy. The possible mechanism of the Ara-C induced leukoencephalopathy is discussed.
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PMID:High dose Ara-C related leukoencephalopathy. 345 3


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