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)

The NH2-terminal amino acid sequence of Moloney murine leukemia virus reverse transcriptase was determined to be Thr-Leu-Asn-Ile-Glu-Asp-Glu-Tyr-Arg-Leu-His-Glu-. The comparison of the amino acid analysis data obtained after carboxypeptidase Y digestion with the published nucleotide sequence (T. M. Shinnick, R. A. Lerner, and J. G. Sutcliffe, Nature (London) 293, 543-548, 1981) led to the conclusion that the COOH-terminus is Leu coded by CTC in nucleotide positions 4608-4610, and the tentative COOH-terminal sequence is Pro-Asp-Thr-Ser-Thr-Leu-Leu-OH. In light of these and previously reported results the complexity and map order of the pol gene are discussed.
 ...
PMID:Amino- and carboxyl-terminal sequence of Moloney murine leukemia virus reverse transcriptase. 241 14

SDZ PSC 833, a non-immunosuppressive cyclosporin analogue reverses multidrug resistance (MDR) in vitro by inhibiting P-glycoprotein (P-gp) mediated drug efflux. We performed a dose escalation study of SDZ PSC 833 combined with VAD chemotherapy in refractory multiple myeloma (MM). Twenty-two MM patients who were refractory to doxorubicin/vincristine/dexamethasone (VADr, n=11) or had failed multiple regimens (n=6) or were melphalan-refractory (MELr, n=5), were treated with one to three cycles of VAD combined with oral SDZ PSC 833, which was administered at escalating dosages starting at 5 mg/kg/day to 15 mg/kg/day for 7 days. The median trough and peak blood levels of SDZ PSC 833 ranged from 461/1134 ng/ml at 5 mg/kg/day to 821/2663 ng/ml at 15 mg/kg, respectively. With addition of SDZ PSC 833 (5 mg/kg) the mean plasma AUC 0-->96 h of doxorubicin as compared with control patients treated with VAD increased from 779 to 1510 ng/ml/h (P=0.0071), while the doxorubicin clearance was reduced from 47.6 to 27.8 l/h/m2 (P=0.0002). The clearance of doxorubicinol was reduced accordingly. Because of the increased plasma AUC, the dose of doxorubicin and vincristine had to be reduced in 13 patients to 50% (n=1) or 75% (n=12). A further dose-escalation of SDZ PSC 833 did not lead to a proportional increase of doxorubicin AUC. Toxicity WHO CTC grade 2 or 3 included hypoplasia (18/22), constipation (10/22), hyponatremia (3/22) and infections (6/22). A partial response or stable disease was achieved in eight and six patients, respectively. In 17 evaluable patients the mean percentage of pretreatment bone marrow plasma cells which expressed P-glycoprotein was 40%. The pretreatment in vitro rhodamin retention in CD38++ myeloma cells was reversible by 2 microM SDZ PSC 833 with 15-98% in 7/9 tested patients. In 4/5 responding patients analyzed before and after treatment with VAD + SDZ PSC 833, a reduction of P-gp + plasma cells was observed. It is concluded, that the blood concentrations of SDZ PSC 833 attained in MM patients increase with dose after oral administration. It can be safely combined with VAD chemotherapy. SDZ PSC 833 diminishes the clearance of doxorubicin, leading to an increase of the plasma AUC of doxorubicin. In addition, it is an effective inhibitor of P-gp mediated efflux of doxorubicin in myeloma tumor cells in vitro. Therefore, a proportional dose-reduction of doxorubicin and vincristine is warranted. Phase II/III studies in refractory MM are in progress to evaluate the therapeutic efficacy of SDZ PSC 833 with VAD.
Leukemia 1996 Nov
PMID:Reversal of multidrug resistance by SDZ PSC 833, combined with VAD (vincristine, doxorubicin, dexamethasone) in refractory multiple myeloma. A phase I study. 889 77

The feasibility of adding both the multidrug resistance modulator cyclosporin (CsA) and granulocyte colony-stimulating factor (G-CSF) to a standard salvage regimen of idarubicin (IDA) and cytarabine was evaluated in patients with resistant or relapsed acute myeloid leukemia and myelodysplastic syndrome. Three patients received IDA 12 mg/m2/day, the next four patients 9 mg/m2/day. The dose of CsA was 16 mg/kg/day. Six patients showed Pgp expression and none MRP1 expression. Grade III or IV toxicity (CTC-NCIC criteria) was registered in six patients for gastrointestinal, two patients for cardiovascular and one patient for neurological complications. Three patients died in hypoplasia and three patients showed leukemic regrowth. Three control patients were treated with IDA 12 mg/m2/day and cytarabine, but no CsA and G-CSF. The plasma IDA and idarubicinol (ida-ol) area under the curve's of patients treated with IDA 12 mg/m2 plus CsA were higher (P< 0.05) than in controls. Cellular IDA concentrations were almost similar, but cellular ida-ol concentrations were significantly higher (P < 0.05) in the presence of CsA than in controls. We conclude that the toxicity either with IDA 12 or 9 mg/m2/day was too high. The modulating effect of CsA was mainly based on changes in plasma kinetics of IDA and ida-ol, although ida-ol cellular clearance was delayed in the presence of CsA.
Leukemia 2001 Jan
PMID:Cyclosporin increases cellular idarubicin and idarubicinol concentrations in relapsed or refractory AML mainly due to reduced systemic clearance. 1124 4

Disease recurrence following stem cell transplantation (SCT) remains a major problem. Despite the sensitivity of leukaemias to chemotherapy and irradiation, conventional conditioning before SCT is limited by significant organ toxicity. Targeted irradiation of bone marrow and spleen by radioimmunotherapy may provide considerable dose escalation, with limited toxicity to non-target organs. In this study, 27 patients with high-risk or relapsing leukaemia were treated with rhenium-188-labelled CD66a,b,c,e radioimmunoconjugates (188Re-mAb) specific for normal bone marrow in addition to conventional conditioning with high-dose chemotherapy and 12 Gy total body irradiation prior to SCT. A mean activity of 10.2+/-2.1 (range 6.9-15.8) GBq 188Re-mAb was administered intravenously. Acute side-effects were assessed according to the CTC classification and patient outcome was determined. Mean radiation doses (Gy; range in parentheses) to relevant organs and whole body were as follows: 13.1 (6.5-22) to bone marrow, 11.6 (1.7-31.1) to spleen, 5.0 (2.0-11.7) to liver, 7.0 (2.3-11.6) to kidneys, 0.7 (0.3-1.3) to lungs and 1.4 (0.8-2.1) to the whole body. Stem cells engrafted in all patients within 9-18 days post SCT. Acute organ toxicity of grade II or less was observed. During follow-up for 25.4+/-5.3 (range 18-34) months, 4/27 (15%) patients died from relapse, and 9/27 (33%) from transplantation-related complications. Fourteen patients (52%) are still alive and in ongoing complete clinical remission. Radioimmunotherapy with the bone marrow-seeking 188Re-labelled CD66 mAb can double the dose to bone marrow and spleen without undue extramedullary acute organ toxicity, when given in addition to high-dose chemotherapy and 12 Gy TBI before allogeneic SCT. This intensified conditioning regimen may reduce the relapse rate of high-risk leukaemia.
 ...
PMID:Targeted bone marrow irradiation in the conditioning of high-risk leukaemia prior to stem cell transplantation. 1150 76

Following a human leucocyte antigen (HLA)-identical allogeneic stem cell transplantation (allo-SCT), minor histocompatibility antigens (mHags) play an important role in the induction of graft-versus-leukaemia (GvL) and graft-versus-myeloma (GvM). Many mHags show ubiquitous tissue expression and are associated with GvL and graft-versus-host disease. Here we describe a cytotoxic CD4(+) T lymphocyte line and a cytotoxic, CD4(+) T cell clone (CTC), 3AB11, which recognized a tissue-restricted mHag. This CTC was isolated from a multiple myeloma patient with clinical GvM following an HLA-matched allo-SCT. CTC 3AB11 was activated in a HLA-DP*0401 restricted fashion and the antigen was expressed by 27% of HLA-DP*0401 positive Epstein-Barr virus (EBV)-transformed B-cell lines (EBV-B). Tissue distribution analysis of antigen 3AB11 showed it to be expressed by patient-derived EBV-transformed B cell lines (EBVp), the myeloma plasma cell-line UM9 and monocytes. It was weakly expressed by peripheral blood-derived phytohaemagglutinin-induced T-cell blasts and absent on CD40L stimulated peripheral B (CD40L B) cells and stromal cells. The relatively high prevalence of the HLA class II-restricted 3AB11 antigen, together with its apparent haematopoietic-restricted expression, makes it an antigen of interest for cellular immunotherapy.
 ...
PMID:A class II-restricted cytotoxic T-cell clone recognizes a human minor histocompatibility antigen with a restricted tissue distribution. 1560 52

This is a preliminary feasibility study to assess the pharmacokinetics and efficacy of pentostatin in a patient undergoing dialysis. Pentostatin is a safe and well-tolerated medication, but a dose reduction is required for patients with renal insufficiency. We present a patient with chronic adult T-cell leukemia, whose white blood cell count exceeded 100 X 10(9)/l, and end-stage renal disease, receiving long-term thrice-weekly dialysis. The initial treatment with oral cyclophosphamide or with oral etoposide resulted in no response. After informed consent was obtained, pentostatin (1, 2, or 3mg/m2) was administered. 1 or 2 hours after injection, the patient received hemodialysis over 4 hours to remove any of the drug remaining in his system. Plasma concentrations of pentostatin were calculated with the known pharmacokinetics parameters. The differential equations describing a 2-compartment open-infusion pharmacokinetic model were fitted to the measured concentration-time data. Tumor lysis syndrome occurred 4 days after the course of the highest dose (3mg/m2), and the patient achieved complete remission. Anorexia, graded as 2 according to the NCI-CTC classification system, occurred and continued for four weeks. Pentostatin therapy consisting of the decreased dose (2mg/m2) was then administered every other week and provided a transient partial response with mild anorexia. Consequently, pentostatin can be considered as one of the chemotherapeutic regimens available for a patient undergoing dialysis.
 ...
PMID:[Pentostatin treatment for a patient with chronic type adult T-cell leukemia undergoing hemodialysis]. 1644 Aug 2

Increased angiogenesis, mediated by vascular endothelial growth factor (VEGF), was associated with poor prognosis in acute myeloid leukaemia (AML) patients. The current study investigated the impact of VEGF gene (VEGFA) single nucleotide polymorphisms (SNPs) on treatment outcomes for AML. Four VEGFA SNPs were analysed for -2578C>A (rs699947), -460T>C (rs833061), +405G>C (rs2010963) and +936 C>T (rs3025039) loci in 138 AML patients. The +936 CC/CT genotype showed strong correlation with favourable leukaemia-free survival (LFS) at 2 years (51.3%) versus with +936 CC genotype (33.6%, P = 0.03). Strong linkage disequilibrium was noted among loci -2578, -460 and +405, but not with +936. Accordingly, four haplotypes were generated based on the genotypes of -2578, -460 and +405 as follows: CTC (40.2%), CTG (35.0%), ACG (22.0%) and ATC (1.2%). The LFS and event-free survival (EFS) inversely correlated with CTG haplotype (P = 0.03 for LFS; P = 0.05 for EFS). We scored the VEGFA polymorphism marker based on +936 C>T genotype and CTG haplotype for -2578, -460 and +405, which demonstrated a good correlation with the treatment outcomes: LFS (P = 0.01), EFS (P = 0.03) and overall survival (P = 0.01). The VEGFA +936 C>T genotype and CTG haplotype seemed to have an additive effect to predict the prognosis in AML patients.
 ...
PMID:Vascular endothelial growth factor (VEGF) gene (VEGFA) polymorphism can predict the prognosis in acute myeloid leukaemia patients. 1798 59

With its broad spectrum of activity and better tolerability profile than conventional amphotericin B, liposomal amphotericin B (L-AmB) may be the drug of choice for antifungal prophylaxis in haematological patients. An open-label, multicentre, prospective, pilot study was conducted in adult patients receiving chemotherapy for acute leukaemia (AL) or myeloablative allogeneic stem cell transplantation (SCT). Patients received weekly 10mg/kg infusions of L-AmB for 4 weeks for AL and 8 weeks for SCT. The primary objective was safety, with particular attention to infusion-related reactions and nephrotoxicity. Twenty-nine adult patients were included: 21 AL (median age 52 years) and 8 SCT (median age 37 years). The most frequent adverse events (AEs) related to study drug were infusion-related reactions, 12 of which (from a total of 76 infusions) led to increased infusion duration for better tolerance. No AE related to the study drug led to discontinuation of prophylactic treatment in AL patients. In SCT patients, eight AEs (in six patients) reported to be related to study treatment led to treatment discontinuation. Enrolment was discontinued in the SCT group as recommended by the independent data review committee in accordance with the 10% limit of AEs (CTC grade 3-4) fixed by the protocol. The appropriate timing of high-dose prophylactic L-AmB remains to be determined in the SCT setting to optimise the safety profile of this regimen. For AL, a 10mg/kg weekly dose appears to be well tolerated during chemotherapy and may represent an important tool towards improving AL patient outcome.
 ...
PMID:Safety of a weekly high dose of liposomal amphotericin B for prophylaxis of invasive fungal infection in immunocompromised patients: PROPHYSOME Study. 1816 75

The receptor for hyaluronic acid-mediated motility (RHAMM) is a tumor-associated antigen in chronic lymphocytic leukemia (CLL). CD8(+) T cells primed with the RHAMM-derived epitope R3, which is restricted by human leukocyte antigen (HLA)-A2, effectively lyse RHAMM(+) CLL cells. Therefore, we initiated a phase I clinical trial of R3 peptide vaccination. Six HLA-A2(+) CLL patients were vaccinated four times at biweekly intervals with the R3 peptide (ILSLELMKL; 300 microg per dose) emulsified in incomplete Freund's adjuvant; granulocyte-macrophage colony stimulating factor (100 microg per dose) was administered concomitantly. Detailed immunological analyses were conducted throughout the course of peptide vaccination. No severe adverse events greater than CTC I degrees skin toxicity were observed. Four patients exhibited reduced white blood cell counts during vaccination. In five of six patients, R3-specific CD8(+) T cells were detected with the corresponding peptide/HLA-A2 tetrameric complex; these populations were verified functionally in four of five patients using enzyme-linked immunosorbent spot (ELISpot) assays. In patients with clinical responses, we found increased frequencies of R3-specific CD8(+) T cells that expressed high levels of CD107a and produced both interferon-gamma and granzyme B in response to antigen challenge. Interestingly, vaccination was also associated with the induction of regulatory T cells in four patients. Thus peptide vaccination in six CLL patients was safe and could elicit to some extent specific CD8(+) T-cell responses against the tumor antigen RHAMM.
Leukemia 2010 Apr
PMID:Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia. 2022 Jul 77

Novel treatment schedules of induction therapy for acute lympoblastic leukaemia (ALL) use combinations of immunosuppressive and cytotoxic drugs that are associated with neutropenia and acquisition of invasive fungal infections. It has been described that posaconazole, a triazole antifungal drug, is active against a variety of Candida and Aspergillus species in vitro. Moreover, large clinical trials using posaconazole in severely immunosuppressed patients provided data on efficacy against Aspergillus in vivo. As patients with ALL are also affected by difficult-to-treat Aspergillus infections, we conducted a pilot study to prove the safety of posaconazole in patients undergoing intensified induction phase treatment. We report on eight patients receiving prophylactic (200 mg t.i.d.) dose of posaconazole and demonstrate good tolerability of the drug. The most obvious side effect was liver toxicity as defined by abnormal serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase and bilirubin levels (<CTC grade 3) documented in three of eight patients. However, side effects were not life-threatening and appeared without clear relationship to posaconazole applications. During the study, one patient developed possible aspergillosis of the lung. Therefore, the observations indicate a favourable toxicity profile of posaconazole in ALL therapy. Efficacy of the drug has to be further validated in prospective clinical trials.
 ...
PMID:Posaconazole prophylaxis during induction therapy of patients with acute lymphoblastic leukaemia. 2033 42


1 2 Next >>