Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown in a murine acute myelogenous leukemia (AML) model that leukemic mice can be cured with a B7 vaccine if immunized early in the disease and that CD8+ T cells are necessary for tumor rejection. However, when B7 vaccine is administered 2 weeks after leukemia inoculation, the effect is only prolonged survival, ending in death virtually of all the mice. To distinguish between tumor kinetics and tumor-induced immunosuppression as potential mechanisms eliminating the therapeutic potential of late B7 vaccines, we performed in vitro T-cell studies during leukemia progression and in vivo studies on the clinical outcome of late B7 vaccines in combination with prior cytoreductive chemotherapy. Our results show that CD8+ T cells from leukemic mice 1 and 2 weeks after leukemia inoculation proliferate more vigorously in response to in vitro activation than cells from normal mice and produce Th1-type cytokines interleukin-2 and interferon-gamma. Cytotoxic T lymphocyte (CTL) assays demonstrate that cells from week-2 vaccinated mice (which succumb to their leukemia), surprisingly develop a stronger CTL activity than cells from week-1 vaccinated mice (which reject their leukemia). Finally, the combination of late chemotherapy and late B7 vaccine administration can cure only 20% of leukemic mice, whereas early chemotherapy and the same late B7 vaccine administration cure 100% of leukemic mice. These results demonstrate that in murine AML tumor growth does not induce T-cell anergy or a Th2 cytokine profile and suggest that tumor growth is most likely to be the limiting factor in the curative potential of late B7 vaccines.
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PMID:CD8+ T cells activated during the course of murine acute myelogenous leukemia elicit therapeutic responses to late B7 vaccines after cytoreductive treatment. 910 12

In an attempt to explore novel treatment modalities in acute myeloid leukemia (AML), we studied the role of costimulatory and cytokine gene immunotherapy in murine AML. We have previously shown that leukemic mice can be cured with CD80 transfected leukemic cells (B7. 1-AML vaccine) administered early in the course of the disease and that the failure B7.1-AML vaccines administered late cannot be attributed to immunosuppression induced by tumor growth. CD8+ T cells, which are necessary for tumor rejection, are activated rather than suppressed during the first half of the leukemic course in nonvaccinated mice. In this report, we question whether CD86 (B7.2) or the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4), or tumor necrosis factor-alpha (TNF-alpha) can improve the vaccination potential of AML cells. The choice of cytokines was based on their combined and alone as well ability to direct the differentiation of CD34+ cells into potent antigen-presenting dendritic cells in vitro. Our studies show that (1) mice vaccinated with a leukemogenic number of AML cells engineered to express B7.2 (B7.2-AML) or to secrete GM-CSF, IL-4, or TNF-alpha (GM-, IL-4-, TNF-alpha-AML) do not develop leukemia; (2) GM-AML cells are tumorigenic in sublethally irradiated SJL/J mice but not in Swiss nu/nu mice, indicating that killing of tumor cells is not T-cell-dependent; (3) vaccines with irradiated GM-AML, but not B7.2-, IL-4-, or TNF-alpha-AML cells, can elicit leukemia-specific protective and therapeutic immunity; and (4) in head-to-head comparison experiments, vaccination with irradiated GM-AML is more potent than B7.1-AML, curing 80% and providing 20% prolonged survival of the leukemic mice at week 2, as opposed to cures only up to 1 week with B7.1-AML vaccines. These preclinical data emphasize that GM-CSF gene immunotherapy deserves clinical evaluation in AML.
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PMID:Gene immunotherapy in murine acute myeloid leukemia: granulocyte-macrophage colony-stimulating factor tumor cell vaccines elicit more potent antitumor immunity compared with B7 family and other cytokine vaccines. 941 88

Interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) are potent activators of natural killer (NK) cells and other anti-tumor effector cells, but the results obtained in clinical trials with these cytokines have proved disappointing in many forms of cancer. It may be that IL-2 and IFN-alpha are often not sufficiently effective because intratumoral monocytes/macrophages (MO) inhibit the cytokine-induced activation of cytotoxic effector lymphocytes such as NK-cells at the site of tumor growth. An essential part of this inhibitory signal is conveyed by MO-derived reactive oxygen species (ROS), which potently inhibit NK-cell-related functions, including the constitutive and cytokine-induced cytotoxicity against tumor cells. Histamine, a biogenic amine, inhibits ROS formation in MO; thereby, histamine synergizes with IL-2 and with IFN-alpha to induce killing of NK-cell-sensitive human tumor cells in vitro. Furthermore, treatment of tumor-bearing mice with histamine potentiates cytokine-induced killing of NK-cell-sensitive murine tumor cells in vivo. In ongoing clinical trials, histamine has been added to IL-2 or IFN-alpha in immunotherapy of human neoplastic disease. The results of two pilot trials in metastatic melanoma suggest that the addition of histamine to IL-2/IFN-alpha prolongs survival time and induces regression of tumors, such as liver melanoma, which are considered refractory to immunotherapy with IL-2 or IFN-alpha. In acute myelogenous leukemia (AML), histamine and IL-2 have been given in order to protect patients in remission against relapse of leukemic disease. The potential benefit of histamine therapy in melanoma and AML will be evaluated in randomized trials.
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PMID:Histamine and cytokine therapy. 974 56

As a result of its transforming abilities, activated Ras is expressed in a great number of cancers. The ras mutation frequency varies between 95% in pancreatic cancer and 5% in breast cancer. In leukemia, the highest frequency (30%) is found in acute myeloid leukemia. The presence of ras mutations has been correlated with a poor prognosis and negative clinical outcome. This suggests that mutated Ras activates mechanisms, which favor tumor growth, enhance the metastatic capacity of tumors or modulate tumor-specific immune responses. Several new functions of Ras, such as downregulation of major histocompatibility complex molecules, upregulation of certain cytokines, growth factors and degradative enzymes have been uncovered in the last decade. Additionally, mutated Ras can also serve as a primary target for the development of immunotherapy or drug therapy. This review will discuss the mechanisms by which Ras expressing tumors are able to evade destruction by the immune system and enhance their growth and metastatic potential. It will further elaborate on the attempts to develop successful immunotherapy and drug therapy targeting Ras expressing tumors.
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PMID:Modulation of the immune response and tumor growth by activated Ras. 1021 54

Interleukin-12 (IL-12) is a heterodimeric cytokine mediating a dynamic interplay between T cells and antigen-presenting cells (APCs). Preclinical studies have demonstrated that recombinant murine IL-12 (rmIL-12) promotes specific antitumor immunity mediated by T cells in several types of tumors. However, the in vivo antitumor properties of IL-12 in acute myeloid leukemia (AML) have not been previously reported. We show here in a murine AML model that systemic administration of rmIL-12 significantly delays tumor growth but is incapable of rescuing mice from lethal leukemia. In contrast, AML cells genetically modified to express IL-12 (IL12-AML) using murine stem cell virus (MSCV) p40 + p35 elicit very potent antileukemic activity. Vaccines with lethally irradiated IL12-AML cells protect naive mice against challenge with wild-type AML cells and, more importantly, can cure mice bearing a considerable leukemic burden. Immunized mice show no signs of systemic IL-12 toxicity and their spleen histology is comparable with naive mice spleen. In vivo depletion of IL-12, interferon-gamma (IFN-gamma), or CD8(+) T cells after injections with live IL12-AML cells abrogates completely the antileukemia immune responses. Studies on the in vitro effects of IFN-gamma on AML cells demonstrate enhanced expression of major histocompatibility complex (MHC) and accessory molecules and induction of the costimulatory molecules B7.1 and B7.2, but no significant direct antiproliferative effect. (51)Cr release assays show that rejection of live IL12-AML cells supports the development of long-lasting leukemia-specific cytotoxic T lymphocyte (CTL) activity. In conclusion, our results demonstrate that IL12-AML vaccination is a safe and potent immunotherapeutic approach that has a great potential to eliminate minimal residual disease in patients with AML.
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PMID:Vaccines with interleukin-12-transduced acute myeloid leukemia cells elicit very potent therapeutic and long-lasting protective immunity. 1059 71

The curability of pediatric cancer has been improved to nearly seventy percent. This change has been achieved by refinements in treatment strategy and supportive care. More than seventy percent of patients with ALL can be cured by modern chemo-radiotherapy with reduced late effects. The stratification of the patients by risk factor, introduction of CNS prophylaxis, shortening of the duration of chemotherapy and intensification of the chemotherapy with agents such as HD-MTX have contributed to this remarkable success. Burkitt's lymphoma is a tumor for which the curability has improved from almost zero to ninety percent. With Wilms' tumor, clinical trials have been used to optimally refine the treatment strategy. The NWTS first compared the efficacy of combined VCR and Act-D with the single use of each drug. The difference was significant. The results of the systematic trials were then used to improve the survival rate of patients with Wilms' tumor from twenty to ninety percent and shorten the duration of chemotherapy to six months. On the other hand, tumors remain with which less than half of patients can survive for long. Advanced neuroblastoma and AML are typical such tumors. With these diseases, refinements in the treatment based on evidence derived from clinical trials have been insufficient. Further intensification of the treatment or novel approaches to control tumor growth are warranted for these diseases. In this article, I would like to describe the "standard" therapy for each tumor and the evidence on which improvements in those strategies have been based.
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PMID:[Evidence based chemotherapy for pediatric cancers]. 1070 Aug 90

The potential benefit of immunotoxin (IT) for cancer therapy has mostly been limited by the fact that only a small portion of injected dose ever reaches the cancer target. Thus, we set out to determine whether antigen-specific CTLs would be suitable vehicles to deliver IT to the site of cancer cells in vivo. A retroviral vector was constructed for gene therapy with (interleukin 4) IL-4 positioned downstream of its 20-amino-acid leader sequence that permitted cotranslational protein synthesis of IT along with truncated diphtheria toxin (DT). IL-4 was chosen as a ligand based on the expression of IL-4 receptor (IL-4R) on most acute myeloid leukemia cases. The first-time expression and secretion of a cytokine/DT fusion toxin was accomplished in mammalian NIH.3T3 cells, and then a retroviral vector was assembled. The retroviral IT was used to transiently transduce T15, a CD8+ CTL T cell line that specifically recognized C1498 (a lethal murine acute myeloid leukemia cell line). Transduced T15 T cells expressed intracellular DT and IL-4 as determined by immunofluorescence. Secreted IT supernatants collected from T15 had enzymatic activity and killed IL-4R+ C1498 cells, but not IL-4R- EL4 cells. Intravenous injection of transduced T15, but not nontransduced T15, into mice with s.c. tumors significantly inhibited tumor growth. In contrast, systemic therapy with a bacterial preparation of the same IL-4 IT given at its maximum tolerated dose did not protect. Retroviral IT-treated mice showed no sign of the renal or hepatic toxicity that is common to this class of IT. Together, these data indicate that retroviral IT may solve problems relating to systemic IT therapy by delivering reagent more directly to the site of cancer in vivo and may impart new anticancer defense mechanisms to antigen-specific T cells.
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PMID:Retroviral immunotoxin gene therapy of acute myelogenous leukemia in mice using cytotoxic T cells transduced with an interleukin 4/diphtheria toxin gene. 1070 13

The Wilms' tumor (WT1) gene participates in leukemogenesis and is overexpressed in most types of leukemia in humans. WT1 is also detectable in many types of lung, thyroid, breast, testicular, and ovarian cancers and melanoma in humans. Initial studies evaluated whether immune responses to murine WT1 can be elicited in mice. Murine and human WT1 are similar. Thus, mouse models might lead to resolution of many of the critical issues for developing WT1 vaccines. C57/BL6 (B6) mice were injected with synthetic peptides from the natural sequence of WT1 containing motifs for binding to major histocompatibility (MHC) class II molecules. Immunization induced helper T-cell responses specific for the immunizing WT1 peptides and antibody responses specific for WT1 protein. Screening of multiple murine cancer cell lines identified 2 murine cancers, TRAMP-C and BLKSV40, that "naturally" overexpress WT1. Immunization with MHC class I binding peptides induced WT1 peptide-specific cytotoxic T-lymphocyte (CTL) that specifically lysed TRAMP-C and BLKSV40. WT1 specificity of lysis was confirmed by cold target inhibition. No toxicity was noted by histopathologic evaluation in the WT1 peptide-immunized animals. WT1 peptide immunization did not show any effect on TRAMP-C tumor growth in vivo. Immunization of B6 mice to syngeneic TRAMP-C elicited WT1-specific antibody, demonstrating that WT1 can be immunogenic in the context of cancer cells. To evaluate whether WT1 might be similarly immunogenic in humans, serum from patients with leukemia was evaluated for pre-existing antibody responses. Western blot analyses showed WT1-specific antibodies directed against the N-terminus portion of the WT1 protein in the sera of 3 of 18 patients with acute myeloid leukemia (AML). (Blood. 2000;96:1480-1489)
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PMID:Immunity to WT1 in the animal model and in patients with acute myeloid leukemia. 1094 95

Angiogenesis has been associated with the growth, dissemination, and metastasis of solid tumors. The aims of this study were to evaluate the vascularity and the levels of angiogenic factors in patients with acute and chronic leukemias and myelodysplastic syndromes (MDS). The numbers of blood vessels were measured in 145 bone marrow biopsies and the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis growth factor-alpha (TNF-alpha), tumor growth factor-alpha (TGF-alpha), and hepatocyte growth factor (HGF) were determined in 417 plasma samples. Except for chronic lymphocytic leukemia (CLL), vascularity was significantly higher in all leukemias and MDS compared with control bone marrows. The highest number of blood vessels and largest vascular area were found in chronic myeloid leukemia (CML). VEGF, bFGF, and HGF plasma levels were significantly increased in acute myeloid leukemia (AML), CML, CLL, chronic myelomonocytic leukemia (CMML), and MDS. HGF, TNF-alpha, and bFGF but not VEGF were significantly increased in acute lymphoblastic leukemia (ALL). TNF-alpha levels were significantly increased in all diseases except for AML and MDS. No significant increase was found in TGF-alpha in any leukemia or MDS. The highest plasma levels of VEGF were in CML, and the highest plasma levels of bFGF were in CLL. The levels of HGF were highest in CMML. These data suggest that vascularity and angiogenic factors are increased in leukemias and MDS and may play a role in the leukemogenic process.
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PMID:Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. 1097 72

Cancer in the older person has become an increasingly common problem with the aging of the population. The goal of this paper is to review the influence of age on cancer biology and cancer management. Specific interactions of cancer and aging include: Increased incidence of cancer with the age: This association may be reported to three factors: duration of carcinogenesis; increased susceptibility of older tissues to late stage carcinogens, and systemic effects of aging, including immune-senescence and enhanced cytokine production. Biological behavior of cancer: With aging, the prognosis of certain neoplasms, including acute myelogenous leukemia and large-cell non-Hodgkin's lymphoma worsens, whereas the behavior of other tumors becomes more indolent. In these biologic variations one may recognize both a 'seed" effect (different tumor cells) and a "soil" effect (different ways in which the older tumor host handles tumor growth. Goals of prevention and treatment: Given the limited life-expectancy of older individuals and reduced tolerance of clinical intervention, the main goal is compression of morbidity, rather than prolongation of survival. Cancer prevention in the older person: In virtue of increased susceptibility to environmental carcinogens, the older person appears an ideal candidate for primary prevention of cancer, including chemoprevention; though randomized controlled studies have not been performed, the older person may benefit from secondary prevention (screening), when the average life-expectancy is 3 years or longer. Cancer treatment: The risk of surgical complications increases only slightly with age for elective surgery, but increases dramatically for emergency surgery. Radiation therapy appears a valuable method of cancer treatment in patients of all ages. Chemotherapy can be made safer by the following provisions: use of hemopoietic growth factors for patients aged 70 and older receiving moderately toxic chemotherapy (CHOP and CHOP-like); maintenance of hemoglobin levels at 12 g/dl with erythropoietin; adjustment of the dose of renally excreted agents to the glomerular filtration rate; selection of the best candidates for chemotherapy based on comprehensive geriatric assessment.
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PMID:Cancer and age in the USA. 1116 87


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