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)

Relapse of leukemia is the major cause of failure after autologous stem cell transplantation due to reinfusion of residual clonogenic cells and the absence of an immune-mediated graft-versus-leukemia effect. To provide an antileukemia effect, immune-activating cytokines have been given to patients after transplantation. Systemic administration of such cytokines early after transplantation is often accompanied by substantial side effects, and it is unknown whether sufficient concentrations reach the sites of residual disease in the marrow. As a method of site-directed immunotherapy provided early after stem cell transplantation, we have tested in a murine model whether (1) marrow can be retrovirally transduced with the tumor necrosis factor alpha (TNF alpha) gene, (2) local production of TNF alpha by marrow cells after transplantation can be achieved, and (3) adverse effects of TNF alpha occurred. Balb/c mice were treated with 5-fluorouracil and bone marrow (BM) was obtained 4 days later. Whole BM was transduced in the presence of interleukin-3 (IL-3), IL-6, and stem cell factor by coculture with the packaging cell line GP+E-86, producing the cDNA for TNF alpha. Irradiated (1,300 cGy) syngeneic recipient mice were given 10(6) transduced BM cells on day 0. Integration of the TNF alpha gene into the host genome was documented by Southern blotting in spleen and BM cells on days 7 and 12 and in BM on day 40 after marrow infusion, but was no longer found on day 90. Messenger RNA for TNF alpha was present on day 12, but could no longer be shown on day 40 or 90. Although no measurable (L929 bioassay) levels of TNF alpha were found in serum of mice who had received TNF alpha transduced marrow, the supernatant of 10(6) unstimulated BM cells obtained 12 days after marrow infusion was found to have 7 pg of TNF alpha compared with 1.8 pg in nontransduced marrow. Mice that had received TNF alpha transduced marrow showed no side effects suggestive of systemic TNF alpha release, and cellularity of the TNF alpha-transduced marrow was not different from control mice that had received unmanipulated marrow or cells transduced with the neomycin resistance gene only. The studies suggest that gene transfer of immune-activating cytokines into hematopoietic cells could be used as a means to achieve their temporary local production early after transplantation by cells located in the BM.
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PMID:Transfer of the tumor necrosis factor alpha gene into hematopoietic progenitor cells as a model for site-specific cytokine delivery after marrow transplantation. 794 69

In patients with chronic myelogenous leukaemia (CML) treated by allogeneic bone marrow transplantation (BMT), detection of residual leukaemic cells carrying the characteristic bcr/abl rearrangement by highly sensitive techniques, such as qualitative polymerase chain reaction (PCR), is of limited value in predicting disease progression. We have therefore adapted the PCR for quantitative assessment of bcr/abl rearranged cells and applied this technique to the monitoring of residual disease in 28 CML patients during up to 106 months of follow-up after BMT. In 5 patients, quantitative PCR revealed increasing amounts of the pathological bcr/abl message, indicating the presence of a proliferating neoplastic clone, and all 5 had a subsequent relapse of disease. By contrast, the remaining 23 patients have been in maintenance-free complete remission for up to 106 months post-BMT. The monitoring by quantitative PCR of residual leukaemic cells during the post-transplant course of CML patients may allow early detection of relapse and provide a rationale for the timely initiation of treatment.
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PMID:Early detection of relapse after bone marrow transplantation in patients with chronic myelogenous leukaemia. 809 20

Multidrug resistance, mediated by the overexpression of an energy-dependent transport protein, P-glycoprotein, has been one of the major targets of interest in solving the mechanisms of clinical drug resistance of malignant cells. To evaluate the correlation between P-glycoprotein overexpression and the response to chemotherapy, we analysed cytospin preparations of gradient-separated blood or bone marrow mononuclear cells from 79 patients with acute leukaemia by means of the P-glycoprotein-directed monoclonal antibody JSB-1 and immunocytochemistry using the alkaline phosphatase-antialkaline phosphatase technique. P-glycoprotein expression was detected in all disease phases of acute leukaemia. Thirteen out of 51 patients at diagnosis, 10/29 patients in relapse or during residual disease and 8/27 patients in remission overexpressed P-glycoprotein. Seven out of the 8 positive remission samples were collected between the cycles of consolidation treatment. Our results suggest that increased P-glycoprotein expression in samples collected between the cycles of consolidation treatment during remission may be induced in normal leukocytes by cytotoxic drug treatment, infections, or by some physiological mechanisms related to the disease. Patients older than 45 years of age were significantly more often P-glycoprotein-positive (11/25) at diagnosis than younger patients (2/26). P-glycoprotein expression at diagnosis was significantly correlated with a low remission rate after the first cycle of induction therapy. Of 34 P-glycoprotein-negative patients, 25 achieved remission after the first cycle as compared to 4/12 of the P-glycoprotein-positive patients. Our results indicate that the method used is specific and sensitive enough for the analysis of P-glycoprotein expression and that the expression at initial presentation is inversely correlated with the outcome of induction therapy.
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PMID:Clinical significance of P-glycoprotein expression in acute leukaemia as analysed by immunocytochemistry. 810 May 37

High, myeloablative doses of chemoradiotherapy represent the treatment of choice for a large number of malignant hematological diseases that cannot be successfully treated with conventional chemotherapy. Residual tumor cells following high dose chemotherapy represent the most common treatment failure, resulting in frequent relapse following autologous bone marrow transplantation (ABMT) and even allogeneic bone marrow transplantation (BMT). Graft vs leukemia (GVL) effects mediated by immunocompetent donor lymphocytes represent a major therapeutic potential of allogeneic BMT which results in reduced rate of relapse, especially when immune interactions between immunocompetent donor's T lymphocytes and host allogantigens is apparent, a reaction which might result in graft vs host disease (GVHD). Recent experiments in animal models of murine leukemias suggest that post-transplant immunotherapy may be successfully accomplished by lymphokine-mediated immunotherapy (LMI) and cell-mediated immunotherapy (CMI). Following allogeneic BMT, provided GVHD can be prevented by T-cell depletion, CMI may be amplified by repeated administration of immunocompetent donor's lymphocytes in graded increments following successful induction of chimerism and sustained hematopoiesis. GVL effects induced by CMI may be further potentiated by in-vivo administration of a short course of recombinant human interleukin-2 (rhIL2). Taken together, our data suggest that post-transplant immunotherapy by cytokines and adoptive cell therapy may successfully prevent relapse in patients at high-risk and even result in complete elimination of tumor cells following overt relapse. Thus, immunotherapy may represent an optimal approach for prevention and treatment of minimal residual disease.
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PMID:Prevention and treatment of relapse by bone marrow transplantation. 812 59

Emergence of drug resistance with conventional cytotoxic therapy is a major challenge towards the curability of many cancers, especially in patients undergoing autologous BMT with ex-vivo purged hematopoietic support. We have explored the potential role of photoradiation therapy in purging hematopoietic stem cells of various hematological malignancies. Benzoporphyrin derivative, monoacid ring A (BPD-MA), dihematoporphyrin ether (DHE), and MC-540 were evaluated for the "ex-vivo" purging of residual tumor cells from autologous bone marrow (BM) grafts. BPD-MA and DHE photosensitizing activity was tested against two human large cell lymphoma cell lines and colony forming-unit leukemia (CFU-L) derived from patients with acute myelogenous leukemia (AML). In mixing experiments four log elimination of tumor cell lines was observed after 1 hr of incubation with BPD-MA or DHE followed by white light exposure. By comparison, using the same concentration of BPD-MA or DHE, the mean recovery of normal BM progenitors was 4-5.2% for granulocyte-macrophage colony forming unit (CFU-GM) and 5-9.8% for burst forming unit erythroid (BFU-E). The T lymphoblastic leukemia cell line CEM and its vinblastine (VBL)-resistant subline CEM/VBL100, along with the acute promyelocyte leukemia cell line HL-60 and its vincristine (VCR)-resistant subline HL-60/VCR, were also tested. Our results demonstrated the preferential cytotoxicity of BPD-MA and DHE toward neoplastic cell lines and CFU-L from AML patients. In addition, DHE was slightly more effective in purging tumor cells expressing the p-170 glycoprotein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Newer options for treating drug-resistant (MDR+) cancer cells using photoradiation therapy. 818 Jun 6

Central nervous system (CNS) relapse confers a poor prognosis in children with acute lymphoblastic leukemia (ALL). It is uncertain whether morphologically undetectable leukemia is present in the bone marrow at the time of CNS relapse, or whether the CNS acts as a 'sanctuary' site to allow reseeding of the marrow at a later time. We examined DNA from bone marrow samples from six patients with T-cell ALL with isolated CNS relapse using sensitive polymerase chain reaction (PCR) assays to detect minimal residual disease. One of these PCR assays was based on amplification of leukemia-specific TCR-delta gene rearrangements, while the other assay relied upon detection of the c-tal deletion. In four patients, where bone marrow samples were taken at the time of CNS relapse, residual disease was detectable in every sample at a level below morphological detection. In addition, three patients had residual disease detected in their subsequent bone marrow when CNS disease was not evident. Our findings, although preliminary, suggest that relapse of leukemia in the CNS reflects resurgence of the disease in the bone marrow that is first detected clinically in the CNS. The concomitant molecular detection of bone marrow leukemia at time of 'isolated' CNS relapse in children with T-cell ALL explains subsequent bone marrow relapse in some of these children, and argues for intensive systemic therapy of these patients.
Leukemia 1994 May
PMID:Molecular evidence for minimal residual bone marrow disease in children with 'isolated' extra-medullary relapse of T-cell acute lymphoblastic leukemia. 818 34

Twenty-two B-cell chronic lymphocytic leukemia (CLL) patients were investigated to evaluate residual disease in clinico-hematological remission. Residual disease was determined by monotypy of surface light-chain expression and by dual-color staining with CD5 and CD19 markers. Samples were analyzed on flow cytometer. Total CD19+ cells above 25%, the CD5+CD19+/total CD19+ cells ratio above 0.25, clonal excess above 0.4 were considered positive for residual disease. According to these immunological criteria, only four cases achieved phenotypic remission. Our data confirm that dual marker analysis is more sensitive than clonal excess and may predict an early relapse. Ig gene rearrangements were studied by Southern blot analysis using IGHJ and IGKC probes in fifteen cases. All 12 cases that retained a detectable rearrangement displayed a phenotypic residual disease. Conversely, in two cases, DNA analysis failed to detect the residual disease characterized by flow cytometry. In conclusion, this study suggests that in B-CLL, dual marker analysis is sensitive in predicting an early relapse in sequential evaluations of residual disease, whereas rearranged bands are undetectable when the proportion of malignant cells is low.
Leukemia 1994 Jun
PMID:Residual disease in B-cell chronic lymphocytic leukemia patients and prognostic value. 820 75

The translocation t(1;19)(q23;p13) in pediatric patients with acute lymphoblastic leukemia (ALL) was demonstrated in early reports to result in a consistent fusion between the E2A and PBX1 gene sequences and in the expression of a uniform, chimeric E2A/PBX1 mRNA with transforming potential. More recent observations suggested that cytogenetically identical t(1;19) translocations can result in the transcription of different mRNA species and that expression of the E2A/PBX1 message may be restricted to patients with the t(1;19) who display a pre-B phenotype of ALL. To further assess the correlation between the immunologic subtypes of the disease and specific genetic alterations, we have performed cytogenetic and molecular analyses in 221 children with B-lineage ALL. Expression of the chimeric E2A/PBX1 message was detected in 21 patients. Out of 14 patients, in whom cytoplasmic immunoglobulin (cig) analyses were available, no less than four had a cig- B-cell precursor ALL, whereas 10 displayed a cig+ B-ALL immunophenotype. These findings are at variance with a recent report in which expression of the E2A/PBX1 message was linked exclusively to a subset of patients who displayed a cig+ pre-B-cell precursor phenotype of ALL. In seven cases diagnosed before 1986, cig analyses were not available, and consequently E2A/PBX1 expression could not be correlated to a particular immunological subtype of B-cell precursor ALL. Our results have important implications for the detection of residual disease in pediatric patients where expression of the typical E2A/PBX1 mRNA may occur both in cig+ (pre-B) and cig- (early pre-B) immunologic subtypes of ALL.
Leukemia 1993 Dec
PMID:Expression of identical E2A/PBX1 fusion transcripts occurs in both pre-B and early pre-B immunological subtypes of childhood acute lymphoblastic leukemia. 825 5

IL-2 has been used after autologous BMT (ABMT) with the aim of inducing graft versus leukemia (GVL) effect. Our studies in mice have shown that IL-2 therapy induces GVL effect when employed after BMT with bone marrow (BM) that has been activated with IL-2 in vitro (ABM). The present study was carried out to define the time of optimal GVL effect after BMT so that the immunomodulatory approaches could be concentrated at the time of maximum GVL effect. Our data show that GVL effect was induced if IL-2 was instituted immediately after BMT with ABM in mice with acute myeloid leukemia; institution of IL-2 1 week after BMT with ABM did not induce GVL effect. IL-2 therapy instituted immediately or 1 week after BMT with fresh bone marrow (FBM) did not induce any GVL effect. A significant increase in the NK activity was noticed whether IL-2 was instituted immediately or 1 week after BMT, either with FBM or with ABM. To evaluate the ability of IL-2 in the eradication of residual disease from the autograft and the host, BM with variable infiltration with leukemia was activated with IL-2 and used for BMT in leukemic mice. The GVL effect of BM with minimal leukemic infiltration (absence of morphologically demonstrable disease) was comparable to the GVL effect of normal BM. These findings suggest that: (a) maximum GVL effect after BMT with ABM is concentrated in the early post-transplant period possibly because of minimal residual disease during this time; (b) an increase in the NK activity induced by IL-2 therapy may not predict for an improved GVL effect; and (c) for optimum GVL effect, BM with minimal leukemic infiltration should be activated with IL-2 before BMT.
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PMID:Graft versus leukemia effect after transplantation with interleukin-2-activated bone marrow. Correlation with eradication of residual disease. 833 64

We have studied 61 patients who underwent allogeneic bone marrow transplantation (BMT) for chronic myeloid leukaemia (CML) in first chronic phase. Minimal residual disease was detected by the amplification of the leukaemia-specific BCR-ABL fusion mRNA with the polymerase chain reaction (PCR) using a highly sensitive nested primer strategy. As a general pattern, patients often had detectable BCR-ABL (PCR positive) for up to 6 or 9 months post BMT after which time BCR-ABL became undetectable (PCR negative). The conversion from PCR positive to PCR negative was not associated with the time at which cyclosporin A treatment was stopped. Six patients (10%) have relapsed during the period of this study, two within 1 year and four more than 1 year after transplant. The relationship between PCR positivity more than 1 year post transplant and relapse was significant (P = 0.036) but 15 patients who were PCR positive beyond 1 year remain in complete clinical and cytogenetic remission. Thus late positivity identifies a group of patients at increased risk of relapse but is of little predictive value for individual patients. Of the four late relapses, two had been persistently PCR positive and two were initially PCR positive, converted to negative and subsequently to positive again. Although all relapses were preceded by PCR positivity, relapse may occur only 12 months after a PCR negative result. The proportion of patients PCR negative at 3/4 months after BMT was found to increase significantly with the severity of acute GVHD (P = 0.002) but no relationship was found between acute GVHD and subsequent PCR results. There was no clear association between severity of chronic GVHD and PCR result.
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PMID:Minimal residual disease after allogeneic bone marrow transplantation for chronic myeloid leukaemia in first chronic phase: correlations with acute graft-versus-host disease and relapse. 833 80


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