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)

Bestatin, a chemically defined immunostimulant of low molecular weight, suppressed the gradually-occurring lymph node metastasis of P388 leukemia in CDF1 mice when administered i.p. at the doses of 1 approximately 30 micrograms/mouse. It could not, however, suppress the established large metastasis of P388 leukemia. Lymph node cells isolated from the mice given bestatin i.p. at 1 and 30 microgram/mouse showed cytostatic activity against P388 leukemic cells in vitro than those from the untreated mice.
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PMID:Inhibition of lymph node metastasis of P388 leukemia by bestatin in mice. 732 59

We investigated the effect of ubenimex on the growth and differentiation of U937 cells, a histiocytic lymphoma cell line. Ubenimex is a dipeptide ((2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl-L-leucine) and an inhibitor of aminopeptidase B produced by Streptomyces olivoreticuli. Ubenimex inhibited the proliferation of U937 cells in a dose-dependent manner. Ubenimex-treated U937 cells showed condensation of nuclear chromatin, increase of cytoplasmic vacuoles and more intense nonspecific esterase staining compared with untreated U937 cells. Expression of CD13 and CD68 detected by monoclonal antibodies My7 and EBM11, respectively, was enhanced by ubenimex, but the expression of CD4 detected by MT310 was significantly decreased. The effects of ubenimex on U937 cell growth inhibition and enhancement of monocytic cell surface marker expression on U937 cells were reversible when cultivated without ubenimex for more than 6 days. In addition, the bactericidal activity of U937 cells was increased by ubenimex treatment, and was further enhanced by treatment with macrophage colony-stimulating factor (M-CSF). Furthermore, ubenimex augmented the expression of M-CSF receptors by U937 cells and enhanced the tyrosine kinase activity of cellular pp60c-src. These findings indicated that ubenimex inhibited the proliferation of U937 cells and induced morphological, cytochemical and functional differentiation into monocyte/macrophages.
Leukemia 1994 Dec
PMID:Effect of ubenimex on the proliferation and differentiation of U937 human histiocytic lymphoma cells. 752 60

A 65-year-old female with acute myelomonocytic leukemia (AMMoL) developed from myelodysplastic syndrome (MDS), successfully treated with cytarabine ocfosfate (SPAC) is reported. Ubenimex, calcitriol and corticosteroid had a minor effect on her MDS. Since she had severe anemia and congestive heart failure on developing leukemia, she was treated with oral administration of SPAC, a cytidine deaminase resistant derivative of Ara-C. After the second course of SPAC (200 mg/day, for 14-28 days), marked erythroid bursts were found and she entered complete remission. The samplings of SPAC and its metabolites of SPAC were investigated in 2 cases including this case, but there seemed to be no relation between their content and effects. In AML patients, especially in cases developed from MDS, SPAC might be useful because it can be given orally even in an outpatient.
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PMID:[Successful treatment of acute myelomonocytic leukemia developed from MDS with cytarabine ocfosfate (SPAC)]. 788 Jan 11

Ubenimex (Bestatin, Ubx) has been shown to have anti-tumor activity and immuno-modulating activities. Ubx has been used in immuno-therapy in combination with remission maintenance chemotherapy after induction of complete remission for adult acute non-lymphocytic leukemia (ANLL, AML). Daunomycin (DNR), arabinosylcytosine (Ara-C) and 6-mercaptopurine (6-MP) are used for the standard chemotherapy for ANLL. It is, however, believed that emergence of resistant cells to chemotherapy cause minimal residual leukemia resulting in poor prognosis. Ubx has been administered in combination with these chemotherapeutic agents. We examined the combinatorial effect of Ubx with DNR, Ara-C, 6-MP and etoposide on K562 leukemic cell line and the chemotherapeutic agent resistant cells derived from K562 cell line. Ubx showed growth inhibitory effects on these cell lines. A synergistic effect was observed on growth inhibition and with colony formation of parent k562 cell line when DNR and Ubx were used in combination. A combination of Ubx with Ara-C or etoposide showed additional effects on parent cells and other resistant cell lines. The combined growth inhibitory effect of 6-MP and Ubx was stronger than the effect of 6-MP alone. These results show that Ubx has a direct growth inhibitory effect on leukemic cells and additional or synergistic effects are obtained on K562 leukemic cell line and on chemotherapeutic agent resistant cells derived from the K562 cell line when Ubx is used combination with the above chemotherapeutic agents.
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PMID:[Growth inhibitory effects of ubenimex on leukemic cell lines resistant to chemotherapeutic agents]. 903 97

We studied fifteen patients older than 80 years of age with acute myelogenous leukemia (AML) treated between 1984 and 1996. Among 15 cases of AML including 7 de novo cases and 8 from myelodysplastic syndrome (MDS) or hypoplastic leukemia, 14 patients had complications, including cardiovascular disease, diabetes mellitus or other malignancies. Although patients with de novo AML showed high peripheral WBC counts and higher cellularity of bone marrow than those from MDS or hypoplastic leukemia, it was difficult in some cases to distinguish these types of AML from hematological findings. Of the 6 AML cases, three had entered complete remission (CR) by a standard dose of combination chemotherapy (BHAC-DMP). One CR patient has had CR for more than 9 years now with good QOL. Among the 3 patients treated by low-dose Ara-C, one attained CR but only for a short period. Four other patients received BRM, such as G-CSF or Ubenimex, and 2 patients died without chemotherapy. Since AML at more than 80 years of age is a highly heterogenous disease, it would be reasonable to give antileukemic agents according to the individual patient's condition.
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PMID:[Treatment of acute myelogenous leukemia in patients more than 80 years old]. 923 61

We investigated the growth inhibitory activity of bestatin, an inhibitor of aminopeptidase N (CD13), on six human leukemic cell lines. Proliferation of all the cell lines except KG1 was inhibited by bestatin. P39/TSU, HL60 and U937 were highly sensitive, with 50% growth inhibitory concentrations (IC50) close to the maximum serum concentration when bestatin was orally administered at 30 mg in clinical application. All cell lines except for K562 highly expressed CD13, but a clear correlation between the sensitivity to bestatin and expression of CD13 was not observed. Other aminopeptidase inhibitors such as amastatin A, arphamenine B and WM15 antibody showed no growth inhibitory effects. To confirm the growth inhibitory effects of bestatin, we quantitatively examined DNA fragmentation in five bestatin-sensitive cell lines. Bestatin dose-dependently induced DNA fragmentation in those cell lines. In case of U937, bestatin induced DNA fragmentation quantitatively and DNA ladder and enhanced caspase-3 activity. Furthermore, the growth inhibition by bestatin was reduced by the caspase inhibitor Z-Asp-CH2-DCB. These results suggested that bestatin exhibits direct antileukemic effects against human leukemic cell lines through the induction of apoptosis.
Leukemia 1999 May
PMID:Induction of apoptosis by bestatin (ubenimex) in human leukemic cell lines. 1037 77

We previously reported that the aminopeptidase inhibitor bestatin induced apoptosis in several human leukemia cell lines. The present study was performed to examine whether bestatin can also induce apoptosis in solid tumor cell lines. Bestatin alone exhibited neither direct growth inhibition nor induction of apoptosis in the tumor cell lines examined. However, it significantly augmented the growth-inhibitory effect and induction of apoptosis by agonistic anti-Fas antibody (CH11). The augmentation by bestatin was also observed with other death ligands including tumor necrosis factor-alpha (TNF-alpha) in EBC-1 cells, a cell line sensitive to these death ligands. However, the HeLa S3 cell line, which is insensitive to TNF-alpha, showed no growth inhibition even by combination treatment. Bestatin methyl ester, a more cell-permeable derivative of bestatin with similar inhibitory activity to cytosolic neutral aminopeptidase, potentiated cell growth inhibition of CH11 more efficiently than bestatin. Other cytosolic neutral aminopeptidase inhibitors such as actinonin and puromycin also augmented cell growth suppression by CH11, while an enantiomer of bestatin lacking aminopeptidase inhibitory action did not increase the growth-inhibitory effects of CH11. The combination of 10 microg/ml of bestatin with CH11 promoted processing of caspase 3 to the active form p17 and efflux of mitochondrial cytochrome c into the cytosol more quickly and more intensely than CH11 alone. Inhibition of aminopeptidase was not involved in dATP- and cytochrome c-dependent caspase 3-activation in a cell-free system. Bestatin significantly augmented activation of caspase 8, which is upstream of cytochrome c efflux in the apoptosis cascade. These results suggested that intracellular neutral aminopeptidase might play an important role in Fas- or TNF-alpha-induced solid tumor cell apoptosis.
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PMID:Augmentation of death ligand-induced apoptosis by aminopeptidase inhibitors in human solid tumor cell lines. 1174 33

A 20-month-old boy with infantile leukemia was treated with total body irradiation, etoposide, cyclophosphamide and unrelated cord blood transplantation with a one-antigen mismatch. He relapsed on day 100 and achieved remission after ubenimex administration, and also developed chronic graft-versus-host disease of the skin. He remained in remission for 22 months with repeated courses of ubenimex. Ubenimex may be an alternative to donor lymphocyte transfusion and may be useful for the treatment of a patient who has relapsed after cord blood transplantation.
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PMID:Induction of graft-versus-host disease and a graft-versus-leukemia effect using ubenimex in a patient with infantile leukemia relapsing after an unrelated cord blood transplant. 1236 60

All-trans retinoic acid (ATRA) induces the differentiation of acute promyelocytic leukemia (APL) cells into neutrophils. We found that bestatin, an inhibitor of CD13/aminopeptidase N, enhanced the sensitivity of APL NB4 cells to ATRA at concentrations of 0.1-1000ng/ml. A structurally different aminopeptidase N inhibitor, actinonin, also increased the effect of ATRA on differentiation, but an inactive stereoisomer of bestatin, (2R,3S)-AHPA-(R)-Leu, did not. Bestatin synergistically enhanced the cytostatic effect of ATRA on NB4 cells. Masking of the cell-surface CD13 by anti-CD13 antibody WM15 blocked the synergistic effect of bestatin and ATRA on differentiation. Thus bestatin, an immunomodulator clinically used for nonlymphocytic leukemia, synergistically increased the ATRA-induced differentiation of NB4 cells by inhibiting CD13/aminopeptidase N on the cell-surface.
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PMID:Enhancement of sensitivity by bestatin of acute promyelocytic leukemia NB4 cells to all-trans retinoic acid. 1244 82

OBJECTIVE: To study the mechanism of inhibitory effect of Ubenimex on human leukemic cells. METHODS: K562 and HL60 cells were treated with Ubenimex at different concentrations, and the growth inhibition was analysed by MTT assay. Cell apoptosis was evaluated by light microscopy, agrose gel electrophoresis, TUNEL labeling method and flow cytometry (FCM) assay. RESULTS: (1)Treatment with Ubenimex remarkably inhibited the growth of HL60 cells, the IC(50) of Ubenimex for HL60 cells was 13.03&mgr;g/ml. But K562 cells were less sensitive than HL60. Ubenimex inhibited the growth of HL60 and K562 cells in a dose-dependent manner. (2)Apoptosis of leukemic cells was induced by Ubenimex, which was shown by the changes in morphology, DNA ladder on agrose gel, TUNEL labeling,typical peak before G1 phase of cell cycle and the positive of Annexin V(FITC) on the cells membrane with FCM. (3)Ubenimex induced apoptosis of K562 and HL60 cells in a dose-and-time-dependent manner. (4)The cell cycle analysis by FCM showed that the HL60 cells were blocked in G1 phase after treated by Ubenimex. Conclution Ubenimex can efficiently induce apoptosis of HL60 and K562 cells, this may be one of the mechanisms for inhibiting effect of Ubenimex on leukemia.
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PMID:[Mechanisms of inhibitory effect of Ubenimex on human leukemic cells] 1260 5


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