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)

Limitless numbers of various genetic structures have been formed in chromosomes and plasmids and numerous bioactive compounds are produced by microorganisms. Therefore, it may be said that compounds useful in treatment of cancer will be found more and more in microbial secondary metabolites and more effective antitumor antibiotics and their derivatives, or more effective products producing immune resistance to cancer, will be discovered. In these studies, as discussed in this paper, the most urgent problem is to establish a rational screening principle or system to select compounds worth clinical examination. This is particularly important in the analog area. Bleomycin is an analog of phleomycin chosen because of lower renal toxicity. It has become an antitumor agent of significant value. Macromycin is a new structure which has been found to bind with animal cells and inhibit growth. Neothramycin is a new benzodiazepine antibiotic which has lower toxicity than other structures studied in this class and is active against L1210, Yoshida sarcoma, and Sarcoma 180. Aclacinomycin A is an analog of adriamycin chosen for clinical study based on its low cardiac toxicity and high distribution in mouse lung and spleen. Coriolins are another new structural class. Diketocoriolin B has activity in L1210 leukemia and has been shown to inhibit Na-K-ATPase. Bestatin is a compound which inhibits aminopeptidase B and leucine aminopeptidase has been shown to increase delayed hypersensitivity. Bestatin also increases the effects of other antitumor agents such as adriamycin, and bleomycin.
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PMID:New microbial secondary metabolites under preclinical development for cancer treatment. 70 7

Ubenimex (Bestatin) is a potent inhibitor of aminopeptidases (APase) including APase N (EC 3.4.11.2), a widely distributed membrane-bound metalloprotease. Binding of Ubenimex (UBX) to cells has been implicated in a variety of its biological activities, while little evidence has yet been provided as to any subsequent mechanisms of intracellular signal transduction. We now examined the possible involvement of protein kinase C (PKC), a key regulator in transmembrane signaling. Human leukemia K562 cells were cultured in the presence or absence of UBX (1 to 50 micrograms.ml-1, 1 to 72 h), and the subcellular distribution as well as phorbol-12, 13-dibutyrate (PDBu)-induced redistribution of PKC activities were assessed. The membrane-bound enzymatic activity tended to increase in the presence of UBX, while a significant loss of the activity was demonstrable upon subsequent exposure to PDBu (100 nM, 10 min) in both the cytosolic and membrane fractions. Specific binding of [3H]PDBu to intact K562 cells was also down-modulated with UBX concentration- and time-dependently, suggesting loss of PKC enzyme protein on the cell surface. Western blot analysis of the total cell extracts disclosed no appreciable alteration in the amount of PKC protein. APase inhibition with UBX was observable independently of PKC modulation. The present findings were discussed with reference to the possible differential mechanisms of PKC-mediated regulation of cellular responses depending on cell types.
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PMID:Ubenimex (Bestatin), an aminopeptidase inhibitor, modulates protein kinase C in K562 cells. 129 52

Graft-versus-host disease (GVHD) in leukemia patients following allogeneic bone marrow transplantation (BMT) has a lot of demerits but it also has a merit, namely graft-versus-leukemia effect. We reported the results of our recent trials on prevention, treatment and induction of GVHD, and prevention of viral infection after BMT. The results were as follows: 1) Twenty-four percent of patients who received prophylactic administration of cyclosporine and short term methotrexate still developed II degree-IV degree acute GVHD. 2) Patients with I degree or II degree acute GVHD showed good clinical courses. But, most patients with III degree GVHD gradually developed chronic GVHD. All patients with IV degree GVHD died of GVHD or infection. 3) Mizoribine and deoxyspergualin were effective for steroid-resistant GVHD. 4) Bestatin was administered to recipients who did not develop GVHD until day 30 after BMT. An interim report suggests that bestatin may induce chronic GVHD and suppress the relapse of leukemia. 5) Oral administration of gamma-globulin may prevent viral enteritis. Intravenous administration of anti-cytomegalovirus monoclonal antibody may prevent cytomegalovirus pneumonia.
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PMID:[Control of graft-versus-host disease and infection associated with immunosuppression]. 190 15

Of 125 children with acute lymphoblastic leukemia (ALL), who had been in continuous remission for three years on chemotherapy, 108 patients received biological response modifiers (BRM) such as Bestatin, N-CWS, OK-432 and/or PSK in order to prevent relapse after treatment suspension. From 20 patients who were treated with PSK, 6 relapsed within 13 months. This relapse rate was quite similar to the rate observed with those children who were off therapy (4 relapses in 17 patients within 13 months). In contrast to these 37 patients, only 3 out of 31 patients who received Bestatin (p less than 0.05) and 8 out of 57 patients who received N-CWS or OK-432 relapsed. Based on these findings, BRMs used in the present study seems to be effective to prevent relapse of leukemia among childhood ALL who have electively stopped chemotherapy.
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PMID:Effects of biological response modifiers on childhood ALL being in remission after chemotherapy. 191 66

Considering the merit and demerit of GVHD in leukemia patients following allogeneic BMT, our strategies for GVHD are as follows; (1) a mild prevention, (2) a treatment to control the severity, if occurred, and (3) an induction of GVHD in recipients who did not develop GVHD. We reported the results of recent trials in prevention, treatment and induction of GVHD. For the prevention, T cells were depleted from bone marrow cells in 11 recipients with the results of graft failure in 5 and death in 9. The data from IBMTR were similar to our data. For the treatment, new drugs, 15-Deoxyspergualin. Mizoribine and anti-human lymphocyte globulin were introduced with compromising outcomes and mild adverse effects. For the induction, Ubenimex, an immunostimulator, was administered to recipients who did not develop GVHD until 30 days after BMT. The interim data suggests that Ubenimex may induce chronic GVHD and suppress the relapse of leukemia. We experienced the sudden onset of GVHD during the tapering of immunosuppressants in two recipients, who were found to have arbitrarily discontinued them. The interruption of drugs for the prevention of GVHD may cause the induction of GVHD.
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PMID:[Control of graft-vs-host disease]. 239 9

The biological activity of the two main metabolites of ubenimex in humans, (-)-N-[(2S,3R)-3-amino-2-hydroxy-4-(4'-hydroxy)phenylbutyryl]-L-leucine (OH-ubenimex) and (2S,3R)-3-amino-2-hydroxy-4-phenylbutyric acid [2S,3R)-AHPA) was examined. OH-Ubenimex was almost identical in inhibitory activity against mouse peritoneal resident macrophage aminopeptidases (APases) and the growth of IMC carcinoma in mice to ubenimex. In contrast, the inhibition of; mouse spleen cell APase activities in vitro, blastogenesis of mouse T and B cells in vitro, delayed cutaneous hypersensitivity in mice, and the growth of C1498 leukemia and HeLa S3 cells in vitro was weaker than ubenimex. Macrophage APase activity was only slightly inhibited by (2S,3R)-AHPA which also had practically no activity in the other biological assays.
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PMID:Biological activity of the main metabolites of ubenimex in humans. 320 78

Ubenimex (Bestatin) was discovered by Umezawa et al. in 1976 from the culture broth of Streptomyces olivoreticuli. Bestatin is a compound of low-molecular weight peptide and inhibits leucine aminopeptidase and aminopeptidase B which localized in cell membrane. Bestatin exhibited antitumor effect against murine syngeneic tumors including mouse colon 26 and C1498 leukemia, and also it was active against MNNG-induced rat tumor by oral administration. Combination treatment of mouse colon 26 with bestatin and mitomycin C, 5-FU or CDDP was effective for the life prolongation of the treated mice compared to mono-therapy alone. Bestatin was found to exhibit the antitumor effect through T lymphocyte stimulation, macrophage activation and bone marrow stem cell stimulation were also observed by bestatin treatment experimentally. Values of T cell subsets in cancer patients recovered to the normal levels by Bestatin treatment. Release of Interleukin-1 and -2 was enhanced by Bestatin treatment in vitro. In the phase I study, clinical optimal daily dose was estimated as 10-100 mg to give 2-3 times weekly or daily continuously. In the comparative clinical trials, Bestatin was found to be effective for the prolongation of survival time of the patients with acute non-lymphocytic leukemia after induction of complete remission in combination with maintenance chemotherapy. Minimal side effects were noted.
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PMID:[A new antitumor drug with immunomodulating activity, ubenimex (bestatin)]. 349 57

Murine L1210 leukemia cells resistant to the antineoplastic agent L-phenylalanine mustard have a 1.5-2.0-fold elevation in their cellular GSH and GSSG content as compared to drug-sensitive cells. Cellular uptake of L-[U-14C]cystine and its incorporation into GSH of the resistant tumor are correspondingly elevated. Synthesis of gamma-glutamylcysteine, GSH, and GSSG is elevated 1.5-2.0-fold in cell-free preparations of the resistant tumor. This increased synthesis of GSH is attributed to increased cellular content (1.6-fold) of gamma-glutamylcysteine synthetase. GSH synthetase activity is equivalent in both drug-sensitive and -resistant cells. Investigation into the hydrolysis of selected peptides by cell-free preparations of both sensitive and resistant tumors suggest that aminopeptidase M participates in the formation of L-cysteine from L-Cys-Gly. This is supported by the observation that these preparations readily degrade L-Leu-p-nitroanilide and L-Ala-L-Ala-L-Ala, known substrates for aminopeptidase M, but not dipeptidase. The failure of the tumors to degrade Gly-D-Ala, a dipeptidase substrate, and the marked inhibition of L-Ala-Gly, L-Cys-Gly, and L-Ala-L-Ala-L-Ala hydrolysis by Bestatin further support a role for aminopeptidase M in the generation of L-cysteine from L-Cys-Gly. These results suggest that the drug-resistant tumor cell has developed an efficient mechanism for maintenance of elevated GSH which involves both gamma-glutamyl transpeptidase-initiated catabolism of GSH to cysteine and its reutilization by gamma-glutamylcysteine synthetase.
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PMID:Elevation of glutathione in phenylalanine mustard-resistant murine L1210 leukemia cells. 366 23

Umezawa initiated the study of low molecular weight enzyme inhibitors produced by microorganisms and discovered more than 50 inhibitors which had various pharmacological activities. An extensive search was begun for inhibitors of enzymes on cell surfaces. Bestatin, amastatin, arphamenine, forphenicine, ebelactone thus found bound to cells and enhanced immune responses. The immunity enhancing effects of bestatin, forphenicinol (a derivative of forphenicine) and arphamenine have been studied in detail. The effect of bestatin in suppressing relapses and prolonging the survival period of patients were confirmed by randomized clinical tests with leukemia, melanoma, etc....
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PMID:Low molecular weight immunomodifiers produced by microorganisms. 384 96

Currently, the most probable theory of tumor surveillance is neither the existence of any tumor-specific, antigen-dependent, T-cell-mediated cytotoxic effect that could eliminate spontaneous tumors in man and that could be used for some kind of vaccination against tumors, nor the complete absence of any surveillance or defense systems against tumors. What is probable is the cooperation of a number of antigen-independent, relatively weakly cytotoxic or possibly only cytostatic humoral and cellular effects, including nutritional immunity, tumor necrosis factor, certain cytokines, and the cytotoxic effects mediated by macrophages, NK cells, NK-like cells, and certain stimulated T-cells. One question remaining to be solved is why these antigen-independent effects do not attack normal cells. A number of plausible hypotheses are discussed. The hypothetical surveillance system is modulated both by traditional cancer treatment and by attempts at immunomodulation. Radiotherapy reduced the T-helper cell function for almost a decade, but not those of macrophages or NK cells. T-cell changes have no prognostic implication, supporting, perhaps, the suggestion of a major role for macrophages and NK cells. Cyclic adjuvant chemotherapy reduces the peripheral lymphocyte population and several lymphocyte functions but not NK activity. Most of the parameters were normalized some years following treatment, but NK activity remained elevated and Th/Ts cell ratio was still decreased. This might possibly be taken to support the surveillance role of NK cells. Bestatin increases the frequency of lymphocytes forming rosettes with sheep red blood cells (but not their mitogenic responses), enhances NK activity, and augments the phagocytic capacity of granulocytes and monocytes (but not their cytotoxic activity). Improved survival with Bestatin treatment following chemotherapy has been observed in patients with melanoma Stages 1b and II and in patients with acute nonlymphatic leukemia, where BCG also seems active, although possibly only in patient groups with less than 49% complete remissions.
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PMID:Cells responsible for tumor surveillance in man: effects of radiotherapy, chemotherapy, and biologic response modifiers. 391 61


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