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)

Eleven leukemia patients who had undergone bone marrow transplants from HLA-A, B, DR genotypically mismatched unrelated donors received FK506 and short-term methotrexate as prophylaxis for graft-versus-host disease (GVHD). Grade III-IV acute GVHD developed in 2 of the patients, and chronic GVHD developed in 4 of the other patients. Adverse drug reaction included reversible nephrotoxicity, hyperglycemia (all patients) and hypertension (9 patients). Hyperglycemia and hypertension of grade 3 or higher occurred mostly in the patients who were on supplemental steroids. However, severe nephrotoxicity was not observed. Complications included cystitis (4 patients), cytomegalovirus colitis (3 patients), Interstitial Pneumonitis (IP) (3 patients), tuberculosis (1 patient), and thrombotic microangiopathy (1 patient). None of patients relapsed. Although close monitoring of FK506 blood concentration and patient clinical signs are required, we concluded that FK506 is effective for GVHD prophylaxis after bone marrow transplantation from HLA-A, B, DR genotypically mismatched unrelated donors, and that adverse reactions due to FK506 are controllable. To determine the long-term effectiveness of this drug, it will be necessary to conduct prospective randomized studies that compare it wiht cycloporin A as a preventive treatment against GVHD in patients who receive bone marrow transplants from HLA genotypically mismatched unrelated donors.
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PMID:[FK506 for the prophylaxis of graft-versus-host-disease after bone marrow transplantation from HLA-genotypically mismatched unrelated donor]. 978 75

Thirty patients (median age of 32 years; range, 6-61) with hematologic disorders received unmanipulated peripheral blood stem cell transplants from HLA-matched or one-antigen-mismatched related donors following myeloablative therapy for acute lymphoblastic leukemia (7), acute myelogenous leukemia (6), chronic myelogenous leukemia (8), myelodysplastic syndrome (3), or other disorders (6). Granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood stem cells were collected from donors in 1 to 3 aphereses. The apheresis products contained mean counts of 11.3 x 10(8) (range, 3.8-17.2) nucleated cells/kg and 6.7 x 10(6) (range, 1.3-16.7) CD34+ cells/kg. Graft-versus-host-disease (GVHD) prophylaxis consisted of cyclosporin A plus methotrexate, or FK506 plus methotrexate. All patients received G-CSF following their transplant. Although 1 patient died of pneumonia 6 days after transplantation, the others demonstrated rapid engraftment. Median days to recovery to 500/microliter neutrophils and 20,000/microliter platelets were 13 (range, 8-21) and 14 (range, 1-23) days, respectively. The incidence of acute GVHD grade II-IV was 33%; chronic GVHD developed in 57% of the assessable patients. There were no episodes of graft failure or rejection. Nineteen patients (63%) were alive and in complete remission from 147 to 839 days following their transplant (median follow-up of 560 days). Further follow-up study will be required to assess the incidence of chronic GVHD and graft-versus-leukemia (GVL) effects.
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PMID:[Allogeneic peripheral blood stem cell transplantation in 30 patients with hematologic disorders]. 986 19

Thirty adults with leukemia or lymphoma transplanted with marrow or blood stem cells from 1-antigen mismatched related donors received tacrolimus and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 42 years (range 18-56 years). Twenty-seven patients had advanced disease, and 13 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/day i.v. by continuous infusion from day -2, converted to oral at four times the i.v. dose following engraftment, and continued to day 180 post-transplant. Methotrexate 5 mg/m2 was given i.v. on days 1, 3, 6 and 11. Mild nephrotoxicity was common before day 100; 69% of patients had a doubling of creatinine, 56% had a peak creatinine greater than 2 mg/dl, and two patients were dialyzed. Other toxicities prior to day 100 thought to be related to tacrolimus included hypertension (45%), hyperkalemia (17%), hyperglycemia (14%), seizures (13%), headache (3%) and hemolytic uremic syndrome (3%). Grades 2-4 GVHD occurred in 59% (95% CI, 38-70%), and grades 3-4 GVHD in 17% (95% CI, 1-32%). Overall survival at 1 year was 29% (95% CI, 12-45%). We conclude that tacrolimus and minidose methotrexate is active post-transplant immunosuppression for patients with 1-antigen mismatched donors.
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PMID:Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after HLA-mismatched marrow or blood stem cell transplantation. 1051 80

Histamine release and cytokine production by mast cells and basophils are thought to be closely involved in the pathogenesis of allergic diseases. Some reports show that FK506 (tacrolimus hydrate) inhibited histamine release and cytokine production by mast cells and basophils. However, as the effects of FK506 has not been compared with those of clinically used drugs in those reports, the clinical relevancy of FK506 inhibition remained unclear. In this paper, we compared the actions of FK506 with those of steroids or disodium cromoglycate (DSCG) which has been clinically used. FK506 inhibited histamine release by Brown-Norway rat peritoneal mast cells more potently than steroids and especially DSCG. FK506 also inhibited histamine release by a mast rat basophilic leukemia (RBL)-1 cell line and human peripheral blood basophils, whereas steroids failed to inhibit histamine release by human basophils. FK506 as well as steroids inhibited TNF-alpha and IL-4 production by RBL-1 cells. FK506 was therefore more effective than steroids and DSCG in inhibiting histamine release, and it also had the ability of inhibiting cytokine production by mast cells as steroids do. We concluded that FK506 might regulate allergic diseases via these actions, judging from the viewpoint of clinical relevancy.
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PMID:FK506 inhibition of histamine release and cytokine production by mast cells and basophils. 1068 2

A hybrid human protein was produced in E. coli by fusing the genes encoding human pancreatic RNase1 (hpRNase1) and human IL-2 (hIL-2). The recombinant hpRNase1-hIL-2 inhibited protein synthesis in HTLV-1-infected, malignant T cells, which hyperproduce high affinity IL-2 receptors, with an IC(50)of 2x10(-8) M, whereas no inhibition was detectable in control cells with lower affinity receptors. HpRNase1 alone had an IC(50)of almost 10(-3) M. A molar excess of hIL-2 blocked the protein synthesis inhibition dose-dependently. In a human mixed lymphocyte culture, hpRNase1-hIL-2 inhibited the proliferation of responder cells with potency comparable to that of cyclosporine, while non-effective doses of FK506 importantly improved its potency. Despite its short half-life in animals, hpRNase1-hIL-2 rapidly enters cells in a few minutes and arrests the protein translation in less than 10 h. Thus, hpRNase1-hIL-2 may be useful to selectively eliminate activated lymphocytes hyperproducing high affinity IL-2 receptors, as in allograft rejection, graft-versus-host disease, autoimmune disorders, adult T cell leukaemia and other lymphoproliferative or retroviral malignancies including HIV infection, without inducing general immunosuppression. As an entirely human "immunotoxin analogue" it may alleviate the dose limiting toxicity and immunogenicity of conventional immunotoxins.
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PMID:Targeting activated lymphocytes with an entirely human immunotoxin analogue: human pancreatic RNase1-human IL-2 fusion. 1084 65

Fv-4 is a mouse gene that dominantly confers resistance to infection with Friend murine leukemia virus (F-MuLV) (S. Suzuki, Jpn. J. Exp. Med. 45:473-478, 1975). However, the resistance caused by Fv-4 is recessive in nude mice, which suggests that immunological effects play important roles in this resistance in vivo (K. Higo, Y. Kubo, Y. Iwatani, T. Ono, M. Maeda, H. Hiai, T. Masuda, K. Kuribayashi, F. Zhang, T. Lamin, A. Adachi, and A. Ishimoto, J. Virol. 71:750-754, 1997). To determine the immunological effect on the resistance in vivo, we infected immunologically immature newborn mice homozygous (Fv-4(r/r)) and heterozygous (Fv-4(r/-)) for Fv-4. Although the Fv-4(r/r) mice showed complete resistance to F-MuLV whether infected neonatally or as adolescents, the Fv-4(r/-) mice showed high sensitivity to viral proliferation and disease induction when infected as newborns but complete resistance when infected as adolescent mice. To confirm the immunological effect on the resistance in adolescent mice with the Fv-4(r/r) and Fv-4(r/-) genotypes, we examined the effect of an immunosuppressant drug, FK506, on the resistance. The mice with the Fv-4(r/r) genotype treated with FK506 still showed resistance, but the mice with the Fv-4(r/-) genotype became highly sensitive to F-MuLV infection. Flow cytometric analysis to detect the Fv-4 gene product showed that the Fv-4 gene product was expressed on the cells from newborn and adolescent mice. The Fv-4 gene product was also detected on the cells from the FK506-treated mice as well as on those from untreated mice. However, a quantitative difference in the gene product between the cells with the Fv-4(r/r) and Fv-4(r/-) genotypes was detected by indirect staining for flow cytometry. These results show that the resistance to F-MuLV infection conferred by the Fv-4 gene is originally recessive, but it looks dominant in adolescent mice mainly because of the effect of the immune system.
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PMID:Resistance to Friend murine leukemia virus infection conferred by the Fv-4 gene is recessive but appears dominant from the effect of the immune system. 1084 5

1. The combined effects of the macrolide antibiotics erythromycin, josamycin, clarithromycin and YM17K (3,4'-dideoxy mycaminosyl tylonolide hydrochloride) on in vitro intracellular accumulation of vinblastine or cyclosporine (Cs)A and on the in vivo antitumour activity of vinblastine were investigated using mouse leukaemia P388 cells (P388/S) and anticancer drug-resistant (P388/ADR) cells. These effects were compared with those of a calcium antagonist (verapamil) or immunosuppressants (FK506 and CsA). 2. All tested macrolide antibiotics increased the accumulation of both vinblastine and CsA in P388/ADR cells in a dose-dependent manner, but their potency was lower than that of verapamil, CsA or FK506. 3. When vinblastine (200 microg/kg) was administered intraperitoneally with each of the macrolide antibiotics (10 or 100 mg/kg) or with verapamil (25 mg/kg) once a day for 10 days in P388/ADR-bearing mice, combined effects of vinblastine with the macrolide antibiotics (erythromycin, clarithromycin and YM17K) or verapamil were observed. 4. The present study suggests that macrolide antibiotics may overcome anticancer drug resistance by inhibiting the binding of vinblastine or CsA to P-glycoprotein in P388/ADR cells. 5. We believe that these results are encouraging for combination chemotherapy to overcome P-glycoprotein-dependent anticancer drug-resistant tumours in clinical practice.
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PMID:Reversal of anticancer drug resistance by macrolide antibiotics in vitro and in vivo. 1090 87

After the transplantation of unmodified marrow from human leukocyte antigen-matched unrelated donors receiving cyclosporine (CSP) and methotrexate (MTX), the incidence of acute graft-versus-host disease (GVHD) is greater than 75%. Tacrolimus is a macrolide compound that, in previous preclinical and clinical studies, was effective in combination with MTX for the prevention of acute GVHD. Between March 1995 and September 1996, 180 patients were randomized in a phase 3, open-label, multicenter study to determine whether tacrolimus combined with a short course of MTX (n = 90), more than CSP and a short course of MTX (n = 90), would reduce the incidence of acute GVHD after marrow transplantation from unrelated donors. There was a significant trend toward decreased severity of acute GVHD across all grades (P =.005). Based on the Kaplan-Meier estimate, the probability of grade II-IV acute GVHD in the tacrolimus group (56%) was significantly lower than in the CSP group (74%; P =.0002). Use of glucocorticoids for the management of GVHD was significantly lower with tacrolimus than with CSP (65% vs 81%, respectively; P =. 019). The number of patients requiring dialysis in the first 100 days was similar (tacrolimus, 9; CSP, 8). Overall and relapse-free survival rates for the tacrolimus and CSP arms at 2 years was 54% versus 50% (P =.46) and 47% versus 42% (P =.58), respectively. The combination of tacrolimus and MTX after unrelated donor marrow transplantation significantly decreased the risk for acute GVHD than did the combination of CSP and MTX, with no significant increase in toxicity, infections, or leukemia relapse.
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PMID:Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. 1097 48

The RGS (regulator of G-protein signalling) proteins are GTPase-activating proteins for activated Galpha subunits. We investigated the effects of protein kinase C (PKC) on RGS proteins in various T cell lines by treating them with PMA. mRNA levels of both RGS16 and tumour necrosis factor alpha (TNFalpha) were found to be up-regulated in CEM leukaemia cells in a PKC-dependent manner. Mezerein, a non-phorbol-ester activator of PKC, also elevated RGS16 and TNFalpha mRNA levels, while the specific PKC inhibitor Go6983 abrogated their expression. In view of the slower kinetics of PMA-induced RGS16 expression and the tight correlation between TNFalpha and RGS16 mRNA induction among the cell lines studied, we suggest that activation of PKC up-regulates RGS16 via TNFalpha. Indeed, addition of recombinant TNFalpha to CEM cells rapidly stimulated RGS16 mRNA expression independently of PKC. Furthermore, mobilization of calcium by A23187 and thapsigargin blocked the TNFalpha-mediated induction of RGS16, which was reversed by EGTA and by the immunosuppressants FK506 and cyclosporin A, suggesting that the calcineurin/NF-AT (nuclear factor of activated T cells) pathway may repress the up-regulation process. Our results demonstrate for the first time that activation of PKC induces RGS16 expression via TNFalpha in a calcium-sensitive manner, thereby implicating RGS16 in the regulation of T cell responses to inflammation.
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PMID:Specific induction of RGS16 (regulator of G-protein signalling 16) mRNA by protein kinase C in CEM leukaemia cells is mediated via tumour necrosis factor alpha in a calcium-sensitive manner. 1110 82

The immunosuppressant rapamycin can regulate the translation of a subset of messenger RNAs, a phenotype which has been linked to the presence of a polypyrimidine motif [C(N)(4-14)] downstream of the mRNA cap structure. T-cell clones naturally infected with transcriptionally active human T-cell leukaemia virus, type I (HTLV-I) undergo autologous proliferation; this phenotype is inhibited by rapamycin but not FK506, which reverses the rapamycin effect. Within the R region of the HTLV-I 5' long terminal repeat (LTR) there are seven polypyrimidine motifs. We sought to determine if these were involved in the sensitivity of proliferation to the presence of rapamycin. Here we illustrate the generation of an in vitro model of this rapamycin-sensitivity and the analysis of LTR mutants which were created to determine the importance of the polypyrimidine motifs. Reporter gene assays suggest the effect is independent of the polypyrimidine motifs in the virus leader sequence.
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PMID:The rapamycin sensitivity of human T-cell leukaemia virus type I-induced T-cell proliferation is mediated independently of the polypyrimidine motifs in the 5' long terminal repeat. 1116 Dec 83


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