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)

Graft-versus-host disease (GvHD), a major complication of allogeneic bone marrow transplantation, has been ascribed to mature T cells in the graft. Because T cells play an important role in engraftment of the bone marrow and decrease the probability of relapse of leukemia, a treatment strategy was developed to preserve the benefits of T cells in the graft and to control the severe complications of GvHD. This can be accomplished by the genetic modification of donor T cells with a suicide gene that allows their selective in vivo elimination and subsequently the abrogation of GvHD. For clinical benefit the alloreactivity of herpes simplex virus thymidine kinase (HSV-TK) gene-transduced T cells should be retained. Therefore, we investigated the influence of gene transduction and the selection procedure on T cells. We demonstrated that activation and culturing of T cells reduce their capacity to induce lethal GvHD in an allogeneic rat bone marrow transplantation model. Furthermore, positive immunomagnetic selection of gene-transduced T cells resulted in loss of the GvHD-inducing capacity of HSV-TK(+) T cells directly after MACS (magnetic cell sorting) selection; this loss could be recovered by a 1-day expansion of the selected T cells. No effect on alloreactivity was observed to be caused by the gene transduction procedure. Our study resulted in the development of an optimized culture and gene transduction protocol with preservation of T cell alloreactivity. Treatment of transplanted rats with ganciclovir resulted in a rapid reduction in the number of HSV-TK(+) T cells in the peripheral blood and in increased survival of the animals.
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PMID:Reduced graft-versus-host disease-inducing capacity of T cells after activation, culturing, and magnetic cell sorting selection in an allogeneic bone marrow transplantation model in rats. 1181 76

A retrospective cohort mortality study was conducted among Italian commercial flight personnel for the period 1965-1996. The cohort was composed of 3,022 male cockpit crew members and 3,418 male and 3,428 female cabin attendants. Cause-specific standardized mortality ratios (SMRs) and exact 95% confidence intervals (CIs) were calculated as estimates of the relative risk. Mortality from all cancers was less than expected for all categories (SMRs of 0.58 for male cockpit crew, 0.67 for male cabin attendants, and 0.90 for female cabin attendants). Among male flight personnel, the SMR for leukemia was somewhat elevated (SMR 1.73; 95% CI: 0.75-3.41) based on eight deaths, with a positive trend by length of employment (p = 0.046). Additionally, an excess of death by suicide was seen among female cabin attendants (SMR 3.38; 95% CI: 1.24-7.35). Other Italian studies of flight personnel are under way, including a detailed assessment of cosmic radiation exposure and investigations of non-radiation occupational risk factors and prevalence of nonfatal outcomes.
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PMID:A retrospective cohort mortality study of Italian commercial airline cockpit crew and cabin attendants, 1965-96. 1201 85

Elevated magnetic field exposures are associated with increased childhood leukaemia risk. A link with breast and other cancers has been postulated via modified melatonin activity. Other illnesses have been linked to electricity distribution, by association or mechanistic considerations. For selected illnesses, this paper estimates the annual number of excess cases that might occur near high-voltage powerlines in the UK. Within 150m of powerlines, magnetic field exposures above 0.1 microT are postulated to result in 9000 excess cases of depression in adults and 60 cases of suicide. Electric field effects can mediate increased exposure to air pollution. Within 400m of powerlines, this may result annually in 200-400 excess cases of lung cancer, 2000-3000 cases of other illnesses associated with air population and 2-6 cases of childhood leukaemia. Seventeen cases of non-melanoma skin cancer might occur by exposure directly under powerlines.
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PMID:Does our electricity distribution system pose a serious risk to public health? 1216 Jun 79

Clinical data indicate that after allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies, the graft-versus-leukemia (GVL) effect is in large part mediated by the graft-versus-host reaction (GVHR), which also often leads to graft-versus-host disease (GVHD). Controlling alloreactivity to prevent GVHD while retaining GVL poses a true dilemma for the successful treatment of such malignancies. We reasoned that suicide gene therapy, which kills dividing cells expressing the thymidine kinase (TK) "suicide" gene using time-controlled administration of ganciclovir (GCV), might solve this dilemma. We have previously shown that after infusion of allogeneic TK T cells along with HSCT to an irradiated recipient, an early and short GCV treatment efficiently prevents GVHD by selectively eliminating alloreactive T cells while sparing nonalloreactive T cells, which can then contribute to immune reconstitution. Nevertheless, it remained to be established that this therapeutic strategy retained the desired GVL effect. Hypothesizing that a contained GVHR would be essential, we evaluated the GVL effect using different protocols of GCV administration. We were able to show that when the GCV treatment is initiated at, or close to, the time of grafting, GVHD is controlled but GVL is lost. In contrast, when the onset of GCV administration is delayed until day 6, a potent GVL effect is retained while GVHD is still controlled. These data emphasize that, by a time-optimized scheduling of the administration of GCV, this TK/GCV strategy can be tuned to efficiently treat malignant hemopathies.
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PMID:Graft-versus-leukemia effect after suicide-gene-mediated control of graft-versus-host disease. 1220 Mar 61

In allogeneic hematopoietic cell transplantation, donor lymphocytes play a central therapeutic role in both graft-versus-leukemia and immune reconstitution. However, their use is limited by the risk of severe graft-versus-host disease (GVHD). Different strategies have been investigated to obtain all the benefits derived from donor lymphocytes while avoiding the risk of GVHD. Infusions of donor lymphocytes transduced with the herpes simplex virus thymidine kinase (HSV-tk) suicide gene resulted in anti-tumor activity in a substantial number of patients. Acute GVHD could be effectively controlled by ganciclovir-induced elimination of the transduced cells. Haplo-identical stem cell transplantation (haplo-SCT) is a promising therapeutic option for patients with high-risk hematologic malignancies lacking an HLA-matched donor. However, the intensive T-cell depletion required to overcome the risk of lethal GVHD has been associated with a delayed immune recovery with a prolonged risk of posttransplantation viral, fungal, and other opportunistic infections. Donor lymphocyte infusions of HSV-tk represent a promising tool for preventing disease relapse and promoting immune reconstitution after haplo-SCT, and a unique tool for the control of GVHD. The genetic manipulation of donor lymphocytes with a suicide gene is a promising strategy to increase feasibility and safety of allogeneic bone marrow transplantation.
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PMID:Suicide-gene-Transduced donor T-cells for controlled graft-versus-host disease and graft-versus-tumor. 1246 92

Donor T cells are able to effect a graft-vs-leukemia (GVL) response but also induce graft-vs-host disease (GVHD) after allogeneic bone marrow transplantation. We used an AKR leukemia murine transplant model, analogous to human acute lymphoblastic leukemia, in which donor T cells expressed a thymidine kinase suicide gene, to test whether separation of GVL and graft-vs-host (GVH) responses was feasible by selectively eliminating alloactivated donor T cells at defined time points posttransplant. Under experimental conditions where untreated mice could not be cured of disease without dying from GVHD, mice transplanted with thymidine kinase-positive T cells and subsequently administered ganciclovir (GCV) could eliminate leukemia without lethal GVHD. Timing of GCV administration, donor T cell dose, and preexisting leukemia burden were observed to be critical variables. Eradication of leukemia without lethal GVHD in GCV-treated mice implied that the kinetics of GVL and GVH responses were asynchronous and could therefore be temporally dissociated by timely GCV administration. That this strategy was feasible in a murine leukemia model in which GVHD and GVL reactivity are tightly linked suggests that this approach may be relevant to the treatment of selected human leukemias where similar constraints exist. This strategy represents an alternative approach to separating GVL and GVH reactivity and challenges the current paradigm that separation of these responses is dependent upon the administration of donor T cells with restricted specificity for leukemia as opposed to host Ags.
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PMID:Elimination of leukemia in the absence of lethal graft-versus-host disease after allogenic bone marrow transplantation. 1262 59

Gene transfer into T lymphocytes is currently being tested for the treatment of lymphohematologic disorders. We previously showed that suicide gene transfer into donor lymphocytes infused to treat leukemic relapse after allogeneic hematopoietic stem cell transplantation allowed control of graft-versus-host disease. However, the T-cell receptor (TCR) activation and sustained proliferation required for retroviral vector transduction may impair the half-life and immune competence of transduced cells and reduce graft-versus-leukemia activity. Thus, we tested lentiviral vectors (LVs) and stimulation with cytokines involved in antigen-independent T-cell homeostasis, such as interleukin 7 (IL-7), IL-2, and IL-15. Late-generation LVs transduced efficiently nonproliferating T cells that had progressed from G0 to the G1 phase of the cell cycle on cytokine treatment. Importantly, IL-2 and IL-7, but not IL-15, stimulation preserved physiologic CD4/CD8 and naive-memory ratios in transduced cells with only minor induction of some activation markers. Functional analysis of immune response to cytomegalovirus (CMV) showed that, although CMV-specific T cells were preserved by all conditions of transduction, proliferation and specific killing of autologous cells presenting a CMV epitope were higher for IL-2 and IL-7 than for IL-15. Thus, LV transduction of IL-2 or IL-7 prestimulated cells overcomes the limitations of retroviral vectors and may significantly improve the efficacy of T-cell-based gene therapy.
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PMID:Human T lymphocytes transduced by lentiviral vectors in the absence of TCR activation maintain an intact immune competence. 1264 46

To test the concept that a replication-competent retrovirus carrying a suicide gene could have potential utility in the control of the natural virus infection in mammalian species, we constructed derivatives of a feline leukemia virus (FeLV) that is commonly associated with leukemia-lymphomas in this species. The FeLV, Rickard strain, subgroup A (FRA) genome contained at the 3' end of the envgene, an insert of an internal ribosomal entry site (IRES) linked to cDNA sequence of either herpes simplex virus thymidine kinase (HSV-TK) or a truncated HSV-TK (HSV-ATK) or yeast cytosine deaminase (CD). These constructs were transfected into feline fibroblast cells (H927). The viruses produced were determined to be replication-competent. The stable propagation of the full-length transgene was, however, dependent on the size of the insert, IRES-CD being the smallest in size (1031 bp) exhibiting maximal stability for at least up to six months. The protein products of the transgenes could be detected, despite the appearance of deleted proviruses at late passages. The transduced cells were susceptible to cytotoxic killing when the appropriate prodrug, ganciclovir (GCV), acyclovir (ACV) or 5-fluorocytosine (5-FC) was added to the culture medium. H927 cells, infected with another subgroup of FeLV, namely, FeLV-B or FeLV-C, could be superinfected by the FRA-suicide gene viruses and thus, subjected to killing. Interestingly, at an early stage of infection by the parental FRA, H927 cells could also be reinfected by the same subgroup FRA constructs to induce the suicide effect. Among the three constructs, the vector with the CD gene was determined to be superior to others in terms of stability, therapeutic index and bystander effect in the cell culture test system. While the in vivo correlates of the therapeutic effect in the feline model remain to be determined, our results do encourage investigation of the same concept in the control of HTLV and, perhaps even, HIV infection in humans.
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PMID:A potential therapeutic strategy to combat leukemia virus infection. 1267 28

The understanding of the use of donor lymphocyte infusions (DLI) for graft-versus-leukaemia (GVL) in the treatment of chronic myeloid leukaemia (CML) post haemopoietic stem cell transplant (HSCT) has advanced during the last years. In relapsed leukaemia post-stem cell transplant, DLI can achieve durable remissions in 60-73% patients. Technical improvements in molecular methods of detection of the BCR-ABL transcripts permit the prediction of relapse with increased sensitivity and reproducibility. Use of DLI early at relapse is important since responses to DLI are less likely in the face of bulky or blast-phase disease. Exogenous interleukin-2 may enhance the response to DLI but total cell dose is also relevant to the efficacy of DLI with the effective cell dose (ECD) required being lower in HLA matched unrelated DLI donors compared to siblings. Donor T-lymphocytes target minor histocompatibility (H) antigens and the relative tissue distribution of these may influence the toxicity of DLI, which includes graft-versus-host-disease (GVHD). Modified methods of delivery such as selective deletion of CD8+ cells or escalating cell dosage regimens have reduced the incidence of serious morbidity due to GVHD without compromising the GVL effect mediated by DLI. These approaches have not removed the risk of GVHD entirely and conditional suicide protocols utilising the HSV-tk or fas receptor derived genes are being developed in the clinic. Since significant morbidity and mortality is attributable to the conditioning regimen used prior to HSCT, awareness of the potency of DLI has driven the development of reduced intensity conditioning (RIC) regimens. The purpose of RIC is to enhance tolerisation of the host to the graft while permitting the establishment of donor haemopoiesis. DLI may then be used subsequently to enhance the GVL effect.
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PMID:Donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukaemia. 1269 Nov 39

In the case of hematopoietic malignancies, direct approach of gene therapy [gene transfer to cancer cells in order to obtain direct therapeutic effects (cell damage)] is difficult, because malignant cells are distributed in the whole body. As for indirect approaches, immuno-gene-therapy is investigated: As a unique approach, suicide gene therapy is applied to donor lymphocyte infusion for relapsed leukemia after bone marrow transplantation. The purpose of gene therapy is to eliminate donor lymphocytes quickly when severe side effects (GVHD) appeared. HSV-TK gene is generally utilized as a suicide gene. Basic studies are conducted to determine whether anti-tumor-angiogenesis therapy is also effective for hematological malignancies. In addition, leukemia development in 2 patients with X-linked severe combined immunodeficiency who underwent hematopoietic stem cell gene therapy is currently a serious problem in the field of gene therapy. In both cases, LMO2 gene was activated through insertional mutagenesis which was caused by retroviral vectormediated gene transfer. This genetic event is considered to be a trigger of T-lymphocytic leukemia development. Further basic studies are needed in terms of safety for stem cell gene therapy.
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PMID:[Hematopoietic malignancies and gene therapy]. 1272 77


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