Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A cytokine produced by the subpopulation of activated helper lymphocytes T has been called interleukin-2 (IL-2). The obtaining of recombinant cytokine has facilitated the study of its biological properties and its application in the treatment of certain neoplastic and infectious diseases. IL-2 affects the target cells by means of a receptor of great affinity consisting of three independent chains: alpha, beta, gamma. The cytokine is the most important growth factor of lymphocytes T, conditioning their clonal expansion. Antigen stimulation is the condition for the expression of IL-2 does not, however, affect resting lymphocytes T. The expression of the receptor for this cytokine on NK cells is, however, continuous in character but only a very small percentage of these cells has receptors of great affinity. IL-2 plays a great role in adoptive immunotherapy consisting in intravenous administration of cells with cytotoxic properties. Cells obtained from peripheral blood and grown in vitro are called LAK cells (lymphocyte activated killer cells), while cells obtained from neoplasms and grown in similar conditions are named TIL cells (tumor infiltrated lymphocytes). LAK and TIL cells reveal a similar antineoplastic activity in vivo. At present, however, recombinant IL-2 alone is used more often, either intravenously or subcutaneously. The cytokine is effective in the treatment of patients with disseminate cancer of the kidney and melanoma, and in adjuvant therapy of acute myeloid leukemia. Attempts have been made to apply it in the treatment of AIDS and leprosy. The toxic effect of IL-2 depends on the dose and the mode of administration. In the majority of patients parainfluenza symptoms appear. Most undesirable effects are connected with multisystemic syndrome of capillary vessels hyperpermeability leading to the increased fluid retention into extravascular spaces, oedema, hypotonia and oliguria.
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PMID:[Biological properties and therapeutic use of interleukin 2 (IL-2)]. 865 37

To study prognostic factors in infant acute myeloid leukemia (AML), we analyzed 44 children treated on Childrens Cancer Group protocols for MLL gene rearrangement by Southern blot, cytogenetic 11q23 abnormalities, and reactivity with monoclonal antibody 7.1. This antibody detects the human homologue of the rat NG2 chondroitin sulfate proteoglycan molecule, which has previously been reported to be expressed on human melanoma. NG2 has been found to be expressed on human leukemic blasts but not on other hematopoietic cells. In childhood AML, NG2 cell surface expression correlated with poor outcome and with some but not all 11q23 rearrangements. In childhood acute lymphoblastic leukemia, NG2 expression correlated with poor outcome and with balanced 11q23 translocations. In this study, 29 of 44 (66%) of infants with AML showed MLL rearrangement and, as expected, this group had a high incidence of French-American-British M4/M5 morphology (22/29). Of the cases tested, 35.1% (13/37) were NG2 positive. All (13/13) NG2-positive cases were rearranged at MLL, whereas only 46% (11/24) of NG2-negative cases had MLL rearrangement. NG2 expression did not correlate with poor outcome (P = .31); there was a trend towards a worse outcome with MLL rearrangement (P = .13). Thus monoclonal antibody 7.1 does not detect all cases of MLL rearrangement in infant AML.
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PMID:MLL gene rearrangement, cytogenetic 11q23 abnormalities, and expression of the NG2 molecule in infant acute myeloid leukemia. 916 Jun 87

Despite the importance of bone marrow stromal cells in hemopoiesis, the profile of surface molecule expression is relatively poorly understood. Mice were immunized with cultured human bone marrow stromal cells in order to raise monoclonal antibodies to novel cell surface molecules, which might be involved in interactions with hemopoietic cells. Three antibodies, WM85, CC9 and EB4 were produced, and were found to identify a 100-110 kDa antigen on bone marrow fibroblasts. Molecular cloning revealed the molecule to be MUC18 (CD146), a member of the immunoglobulin superfamily, previously described as a marker of metastatic melanoma. In addition to the expected expression on melanoma cell lines and endothelial cells, a number of human leukemic cell lines were found to express MUC18, including all six T leukemia lines tested, one of five B lineage lines and one of four myeloid lines. Analysis of bone marrow samples from patients revealed positivity in 20% of B lineage ALL (n = 20), one of three T-ALL, 15% of AML (n = 13) and 43% of various B lymphoproliferative disorders (n = 7). No apparent reactivity was observed with mononuclear cells from normal peripheral blood or bone marrow, including candidate hemopoietic stem cells characterized by their expression of the CD34 antigen. However, positive selection of bone marrow mononuclear cells labeled with MUC18 antibody revealed a rare subpopulation (<1%) containing more than 90% of the stromal precursors identified in fibroblast colony-forming assays. The structure and tissue distribution of MUC18 suggest a functional role in regulation of hemopoiesis.
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PMID:MUC18, a member of the immunoglobulin superfamily, is expressed on bone marrow fibroblasts and a subset of hematological malignancies. 952 37

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

We determined the expression of a newly recognized drug resistance gene, the multidrug resistance-associated protein (MRP) gene, [Cole et al., Science (Washington DC), 258: 1650-1654, 1992], in normal human tissues and in >370 human tumor biopsies using a quantitative RNase protection assay and immunohistochemistry. MRP mRNA appeared to be ubiquitously expressed at low levels in all normal tissues, including peripheral blood, the endocrine glands (adrenal and thyroid), striated muscle, the lymphoreticular system (spleen and tonsil), the digestive tract (salivary gland, esophagus, liver, gall bladder, pancreas, and colon), the respiratory tract (lung), and the urogenital tract (kidney, bladder, testis, and ovary). The human cancers analyzed could be divided into three groups with regard to MRP expression. Group 1 consists of tumors that often exhibit high to very high MRP mRNA levels (e.g., chronic lymphocytic leukemia). Group 2 comprises the tumors that often exhibit low, but occasionally exhibit high MRP mRNA expression (e.g., esophagus squamous cell carcinoma, non-small cell lung cancer, and acute myelocytic leukemia). Group 3 comprises the tumors with predominantly low levels of MRP mRNA, comparable to the levels found in normal tissues (e.g., other hematological malignancies, soft tissue sarcomas, melanoma, and cancers of the prostate, breast, kidney, bladder, testis, ovary, and colon). Using the MRP-specific mAbs MRPr1 and MRPm6, we confirmed the elevated MRP mRNA levels in tumor tissues by immunohistochemistry. We conclude that hyperexpression of MRP is observed in several human cancers, and that additional studies are needed to assess the clinical relevance of MRP.
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PMID:Expression of the multidrug resistance-associated protein (MRP) gene in human cancers. 981 25

Gene transfer is a potentially powerful tool for the treatment of a wide variety of diseases. The transfer of these genes is achieved by utilizing a variety of vectors, including retroviral, adenoviral, adeno-associated virus (AAV) and a number of non-viral mechanisms. Numerous studies have successfully demonstrated transduction of genes into target cells with a variety of vectors, and have provided 'proof-in-principle' that gene transfer can result in prolonged in vivo expression of transduced genes, albeit at low quantities. Furthermore, gene marking studies in acute myeloblastic leukemia (AML), chronic myeloid leukemia (CML) and neuroblastoma have elegantly demonstrated that gene-marked tumor cells contribute to relapse following autologous transplantation. However none of the studies examining the therapeutic benefit of gene therapy has definitively demonstrated a clinically meaningful benefit. Nonetheless, the results of studies involving gene transfer for severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), melanoma and lung cancer highlight the potential benefit of this strategy. This review will discuss mechanisms of achieving gene transfer into target cells. It will examine some of the pre-clinical and clinical results to date and will discuss some of the potential uses of gene transfer for therapeutic purposes.
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PMID:Gene transfer: a review of methods and applications. 983 7

The receptor tyrosine kinase Flt3 is expressed on the blasts of a high proportion of AML cases. We were interested in the expression and function of Flt3 on various human tumors. human tumor cell lines were tested for Flt3 expression by northern blot analysis and RT-PCR using head/neck (n=3), breast (n=4), ovarian (n=4), small cell lung (n=2), non-small cell lung (n=2), gastric (n=1), colon (n=3), pancreatic (n=1) and prostate carcinoma (n=1), choriocarcinoma (n=1), glioblastoma (n=5), neuroblastoma (n=1), melanoma (n=3), lymphoma (n=1), Hodgkin's disease (n=2), and leukemic (n=6) cell lines. With no expression on the other cell samples, 3 of 6 leukemic cell lines showed expression of Flt3 mRNA. The cDNA region corresponding to the juxtamembrane domain did not show any mutation as determined by sequence analysis. In all 3 positive cell lines, protein expression was verified by immunoprecipitation followed by immunoblot analysis. Although Flt3 is functional in these cell lines, as judged by ligand-dependent receptor autophosphorylation, it only mediates a proliferative response in 2 of the 3 cell lines. In conclusion, Flt3 is expressed exclusively in hematopoietic malignancies. Although early signalling events are detectable in all Flt3-positive cell lines tested, the expression of Flt3 does not predict a proliferative response of the cell lines. No internal tandem duplication of the juxtamembrane domain can be observed.
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PMID:Expression and function of Flt3/flk2 in human tumor cell lines. 1008 27

Paclitaxel is a promising drug for the treatment of breast and ovarian cancer. It also may play a role in mobilization of peripheral blood stem cells (PBSC), as an alternative to cyclophosphamide (Cy). We investigated the PBSC-mobilizing potential of paclitaxel compared to Cy in a murine model. C57B1/6 mice were primed with intraperitoneal injections of Cy (200 mg/kg) or paclitaxel (60 mg/kg) and were sacrificed 4, 6, 8, or 10 days later. Spleens were harvested and processed to obtain low-density mononuclear cells that were used as PBSC. The number of hematopoietic progenitors (CFU-C) on day 4 was significantly higher in the paclitaxel group when compared to mice receiving Cy (72.0 +/- 1.8 vs 9.8 +/- 2.8, p < 0.001). By day 6, CFU-C became significantly higher in the Cy-treated group compared to the paclitaxel-treated group (195.6 +/- 31.9 vs 95.8 +/- 20.7, p < 0.05) and this trend was maintained. However, the total number of CFU-C recovered per spleen was greater in the paclitaxel-treated group (1.27 x 10(5) +/- 0.53 x 10(5) vs 1.06 x 10(5) +/- 0.36 x 10(5), NS). In contrast to paclitaxel, mobilization with Cy was associated with marked perturbation in the proportion of lymphoid cell subsets in the PBSC population along with functional impairment of lymphocytes. After 24 hours of in vitro IL-2 activation, the cytotoxic effector cell function of the Cy-mobilized PBSC population was lower than that of paclitaxel-mobilized cells when tested against three tumor cell lines (B16, melanoma; C1498, AML; and Yak-1, lymphoma). These results indicate that paclitaxel is an efficient mobilizer of PBSC, leading to early (day 4 to 6) mobilization of PBSC when compared to Cy (day 6 to 8). In addition, paclitaxel was associated with less perturbation of phenotypic and functional characteristics of cells contained within the mobilized PBSC population.
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PMID:Paclitaxel vs cyclophosphamide in peripheral blood stem cell mobilization: comparative studies in a murine model. 1008 19

The aim of this study was to examine the occurrence of additional, unrelated primary cancers in patients with melanoma. Data from the hospital-based, melanoma registry of a specialist unit (the Melanoma Unit at Charing Cross Hospital, London, UK) were compared with the incidence rates in a population-based cancer registry (the Thames Cancer Registry). In total, 2076 patients with the histological diagnosis of melanoma established between 1960 and 1997 who were registered with the Melanoma Unit at Charing Cross Hospital, were included in the study. Patterns in time and in the tumour type of the additional cancers were analysed in the cohort. The relative risk of subsequent cancers was evaluated, the number of expected cancers being calculated by applying incidence rates in the population of south-east England to the person-years of follow-up in the cohort. Sixty-six (3%) of the 2076 evaluable patients had a history of, or developed, 69 histologically verified additional cancers, the commonest being colorectal, breast and lymphoma. Twenty-six additional cancers preceded the diagnosis of melanoma by 1-42 years, 16 were diagnosed within 12 months and 27 followed the diagnosis of melanoma, 1-28 years later. Seven cancers occurred after chemotherapy for metastatic melanoma: two colorectal, one bladder, one renal, two myelodysplasias and one acute myeloid leukaemia. The relative risk of additional cancers developing after the diagnosis of melanoma during the 8537 evaluable years-at-risk was 0.64 (95% confidence interval 0.41-0.96; P = 0.0006). Thus, the risk of additional cancers following treatment for metastatic melanoma in this cohort is small. The potential influence of other factors on the occurrence of additional cancers observed overall in this study requires further investigation.
Melanoma Res 2000 Apr
PMID:Melanoma and additional primary cancers. 1080 15

The functions of intratumoral lymphocytes in many human malignant tumors are inhibited by reactive oxygen species (ROS), generated by adjacent monocytes/macrophages (MO). In vitro data suggest that immunotherapeutic cytokines such as interleukin-2 (IL-2) or interferon-alpha (IFN-alpha) only weakly activate T cells or natural killer (NK) cells in a reconstituted environment of oxidative stress and that inhibitors of the formation of ROS or scavengers of ROS synergize with IL-2 and IFN-alpha to activate T cells and NK cells. In this review, we focus on the immunoenhancing properties of histamine, a biogenic amine. Histamine inhibits ROS formation in MO via H2-receptors; thereby, histamine protects NK cells from MO-mediated inhibition and synergizes with IL-2 and IFN-alpha to induce killing of NK cell-sensitive human tumor cells in vitro. Histamine also optimizes cytokine-induced activation of several subsets of T cells by affording protection against MO-inflicted oxidative inhibition. The putative clinical benefit of histamine as an adjunct to immunotherapy with IL-2 and/or IFN-alpha is currently evaluated in clinical trials in metastatic malignant melanoma and acute myelogenous leukemia.
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PMID:Histamine: a novel approach to cancer immunotherapy. 1080 71


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