Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that 3F8, a murine IgG3, monoclonal antibody (MoAb) specific for the ganglioside GD2, mediates tumor cell kill in vitro and in vivo. We now describe receptor requirements of polymorphonuclear leukocytes (PMN) in 3F8-mediated cytotoxicity (ADCC) of human GD2 (+) melanoma and neuroblastoma cell lines. PMN from a child with leukocyte adhesion deficiency (LAD) were devoid of CD11/CD18 adhesion molecules and mounted no detectable ADCC. MoAb to CD11b, CD11c, and CD18 each efficiently blocked ADCC by normal PMN. In contrast, a panel of different MoAbs to CD11a had no significant inhibitory effect on ADCC, a finding consistent with the low-to-absent expression of the CD11a ligand, intercellular adhesion molecule-1, on the target cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly increased the expression of CD11b, CD11c, and CD18 on normal PMN, decreased the expression of Fc receptors (FcR), and enhanced ADCC by normal but not by LAD PMN. MoAbs to FcRII and FcRIII each efficiently blocked ADCC; anti-FcRI MoAb had no effect. Flow cytometry using anti-FcRII MoAb versus anti-FcRIII MoAb did not show cross competition, suggesting that inhibition of ADCC was not a steric effect resulting from FcRII proximity to FcRIII. PMN deficient in FcRIII (obtained from patients with paroxysmal nocturnal hemoglobinuria) and PMN depleted of FcRIII by treatment with elastase or phosphatidylinositol (PI)-specific phospholipase C produced low ADCC, supporting a role for the PI-liked FcRIII. Thus, optimal ADCC using human PMN, human solid tumor cells, and a clinically active MoAb (conditions that contrast with the heterologous antibodies and nonhuman or nonneoplastic targets used in most models of PMN ADCC) required CD11b, CD11c, FcRII, and the PI-linked FcRIII. Furthermore, in this clinically relevant system, GM-CSF enhancement of antitumor PMN ADCC correlated with increased expression of CD11/CD18 molecules.
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PMID:Absolute requirement of CD11/CD18 adhesion molecules, FcRII and the phosphatidylinositol-linked FcRIII for monoclonal antibody-mediated neutrophil antihuman tumor cytotoxicity. 134 7

Natural killer (NK) cells are large granular lymphocytes that are able to recognize and lyse a broad spectrum of transformed cells. We report one approach to identify NK surface recognition molecules on human tumor targets. A cloned renal cell carcinoma (RCC) cell line, 5117GB, sensitive to NK activity, was made NK-resistant (5117GBT) by exposure to peripheral blood mononuclear cells. Both cell lines were found to be sensitive to lymphokine-activated killer cells. Both 5117GB and 5117GBT were positive for laminin (25-33%), CD2 (LFA-3 receptor, 95-98%), CD54 (ICAM-1, 99-100%) and CD58 (LFA-3, 100%). 5117GB was positive for HLA-ABC while 5117GBT lost detectable HLA-ABC. F(ab')2 fragments of HLA-ABC were not able to block NK-mediated cytotoxicity of 5117GB. We identified 6 murine monoclonal antibodies that preferentially bind either to sensitive or resistant RCC cells. The role of each of the antigens recognized by these antibodies in NK-mediated lysis is being explored. The development of NK-sensitive and NK-resistant human solid tumor cell lines may allow further exploration of surface molecules involved with NK binding and lysis.
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PMID:The development and characterization of a natural killer cell-resistant human renal cell carcinoma cell line. 135 70

Inosine-5'-phosphate (IMP) dehydrogenase, a regulatory enzyme of guanine nucleotide biosynthesis, may play a role in cell proliferation and malignancy. To assess this role we examined IMP dehydrogenase expression in a series of human solid tumor tissues and tumor cell lines in comparison with their normal counterparts. Increased IMP dehydrogenase gene expression was observed in brain tumors relative to normal brain tissue and in sarcoma cells relative to normal fibroblasts. Similarly, in several B- and T-lymphoid leukemia cell lines, elevated levels of IMP dehydrogenase mRNA and cellular enzyme were observed in comparison with the levels in peripheral blood lymphocytes. These results are consistent with an association between increased IMP dehydrogenase expression and either enhanced cell proliferation or malignant transformation.
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PMID:Increased inosine-5'-phosphate dehydrogenase gene expression in solid tumor tissues and tumor cell lines. 135 21

Taxol has been demonstrated in numerous laboratories worldwide to have broad-spectrum antitumor activity against many tumor models. The susceptible tumors include murine leukemias and solid tumors, and human solid tumor xenografts. The initial findings of taxol's ineffectiveness against most distal site tumor models was probably a consequence of the insolubility of taxol in nearly all the vehicles used in those early studies. On the occasions when an ethanol-based vehicle was used to dissolve taxol, substantial distal site antitumor activity was observed. Although no definitive schedule dependency data have evolved, once-a-day or every-other-day i.v. injections for several treatments have proved to be reproducibly effective in stringent s.c. tumor models. Attempts to discern a therapeutically synergistic cytotoxic drug combination was made on two occasions without success. In the manner evaluated, taxol plus either adriamycin, cisplatin, cyclophosphamide or etoposide (VP-16) were not meaningfully more efficacious than the more effective drug in each of those combination settings.
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PMID:Taxol: a review of its preclinical in vivo antitumor activity. 135 64

The frequent occurrence of TF gene involvement in translocations associated with leukemia is remarkable, although not yet explained. The wide variety of TFs involved in these translocations and the different stages of cellular maturation argue against a unifying mechanism. Recombinases, active during B-cell and T-cell development, have been implicated in gene arrangements involving TCR genes and in the SIL/SCL rearrangement, which involves two genes not normally rearranged. However, other mechanisms must clearly be active in generating these molecular abnormalities and perhaps they relate to the multistep maturation and differentiation processes and continuous cell turnover seen in hematopoietic cells. The difficulties in obtaining human solid tumor samples may make it more difficult to identify translocations involving TF genes in solid tumors. Recently, the cytogenetic analysis of solid tumors has improved and specific cytogenetic abnormalities have been associated with specific types of tumors. With advanced techniques, such as fluorescent in situ hybridization (a technique that does not depend on cell growth) and PCR, abnormalities involving TF genes will be discovered. Abnormalities of TF genes, other than translocations, have been seen in a broad variety of nonhematopoietic malignancies. The p53 protein has been shown to bind DNA in a sequence-specific fashion and interact with a variety of DNA tumor virus oncoproteins. The broad range of cell types that harbor p53 abnormalities suggests that TF abnormalities will likely be implicated in many solid tumors. We have detailed several examples of how gene rearrangements that accompany chromosomal translocations in acute leukemia can alter the expression or activity of cellular TFs. Several translocations generate fusion RNA transcripts and fusion TF proteins with altered functional characteristics. Other translocations result in the expression of a gene not normally detectable in hematopoietic cells or alter the level of its expression, or affect the promoter usage or exon structure of the gene (Table 2). Studies are underway in many laboratories to characterize the biologic activity of these abnormal TFs and it remains to be proven that these molecular abnormalities are directly linked with leukemogenesis. The identification of abnormal fusion transcripts and proteins may allow specific therapies to be directed against "tumor-specific" DNA, mRNA, or protein targets. Therapeutic strategies based on antisense or ribozyme technology may be used to turn off expression of these genes and inhibit leukemia cell growth. Immunologic methods can also be used to direct therapy against the malignant cells.
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PMID:Transcription factors, translocations, and leukemia. 136 70

Solid tumor growth can be modulated through inhibition of vascularization elicited by angiogenic factors. With the objective to complex these factors, new derivatives of distamycin A were synthesized and evaluated in vitro [1] and in vivo for their ability, after i.v. administration, to inhibit bFGF-induced vascularization and the growth of M5076 murine reticulosarcoma implanted i.m. The tested compounds were able to block angiogenesis with inhibition values ranging between 70-100%. Moreover, they were found to be capable of inducing tumor inhibition with values ranging between 40% and 95% at non-toxic doses.
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PMID:In vivo activity of novel sulphonic derivatives of distamycin A. 137 72

Experimental and clinical evidence is here assembled in support of the concept that the development of a solid tumor progresses from a prevascular phase to a vascular phase. The prevascular tumor does not induce angiogenesis, is limited in size, and rarely metastasizes. The vascularized tumor induces host microvessels to undergo angiogenesis, has the potential to rapidly expand its cell population, and has a propensity to metastasize. Thus, angiogenesis is necessary but not sufficient for tumor growth and metastasis. Neovascularization of a tumor requires that a critical number of its cells have switched to the angiogenic phenotype. The mechanisms by which tumor cells become angiogenic, subjects of current study, are reviewed here. At least two general categories are recognized: (i) angiogenic activity arises from the tumor cell itself in the form of the release of angiogenic molecules such as basic fibroblast growth factor; (ii) angiogenic activity arises from host cells recruited by the tumor (e.g. macrophages), or is mobilized from the extracellular matrix, or requires concomitant loss of physiological inhibition of endothelial cell proliferation. Accumulating evidence indicates that for most tumors, the switch to the angiogenic phenotype depends upon the outcome of a balance between angiogenic stimulators and angiogenic inhibitors, both of which may be produced by tumor cells and perhaps by certain host cells.
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PMID:The role of angiogenesis in tumor growth. 137 11

Human stem cell factor (SCF) acts in the presence of other growth factors to stimulate the growth of primitive hematopoietic progenitor cells. These effects are performed by activation of the SCF receptor, c-kit. Because of the potential use of SCF in patients undergoing chemotherapy and bone marrow transplantation, the effect of SCF on nonhematopoietic tumors requires investigation. To determine whether human tumor cell lines display c-kit receptors, we performed binding experiments with 125I-SCF on a breast carcinoma cell line (Du4475), a gastric carcinoma cell line (KATO III), a melanoma cell line (HTT144), as well as two small cell lung carcinoma cell lines (H69 and H128). The biologic effect of SCF on tumor cell lines was assessed by its ability to stimulate tritiated thymidine uptake and to enhance colony growth in methylcellulose. The breast carcinoma cell line, Du4475, as well as two small cell lung carcinoma cell lines, H69 and H128, exhibit high-affinity c-kit receptors with approximate binding affinities of 40, 100, and 90 pmol/L, respectively. The number of high-affinity receptors per cell ranged from 700 to 9,500. The gastric carcinoma cell line, as well as the melanoma cell line, showed trace binding of 125I-SCF. In the presence of SCF alone, or in combination with granulocyte-macrophage colony-stimulating factor or interleukin-3, there was less than a 17% increase in the colony growth of Du4475, H69, or H128 cell lines. Postulating that the lack of growth response could be secondary to endogenous SCF production by the tumor cell lines, we used an RNAse protection assay to determine whether the tumor cell lines contain SCF messenger RNA (mRNA). In addition, we tested tumor cell line supernatants for the presence of secreted SCF protein by enzyme immunoassay, and analyzed the tumor cell lines for membrane-bound SCF by indirect immunofluorescence. Our results show that the Du4475, H69, and H128 cell lines, as well as a melanoma cell line (HTT144), have multiple copies of SCF mRNA. Soluble SCF protein was detected in the cell supernatants in the Du4475 and H69 cell lines and SCF was found on the surface of all four cell lines. These data show that some human solid tumor cell lines display high-affinity c-kit receptors and produce SCF, which can be detected on the cell surface. These results suggest the possibility that autocrine production of SCF by c-kit receptor-bearing tumor cells may enhance cell growth in tumor cell lines.
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PMID:Nonhematopoietic tumor cell lines express stem cell factor and display c-kit receptors. 137 16

The distributions of acidic fibroblast growth factor (aFGF) and basic FGF (bFGF) in extracts of various cultured mammalian cells were determined from their elution profiles on heparin-affinity chromatography, and assay of activity as ability to stimulate DNA synthesis in BALB/c3T3 cells. Only aFGF was found in extracts of mouse melanoma B 16 cell and rat Morris hepatoma cell (MH1C1) lines. Other tumor cell lines established from solid tumors and some normal cells contained bFGF as a main component, but blood tumor cell lines contained no aFGF or bFGF. The FGFs in extracts of solid tumor tissues derived by transplantations of these cultured tumor cells and various normal tissues of mice were also examined. Tumors formed by all cell lines, regardless of whether they produced aFGF, bFGF, or neither, contained bFGF that was probably derived from host cells including capillary endothelial cells, in addition to the tumor-derived aFGF or bFGF, if produced. The content of bFGF, possibly derived from the host, in these tumor tissues was comparable to those of various mouse organs other than thymus, lung, spleen, and testis, which have higher bFGF contents. Tumor tissues derived from cultured cells producing bFGF had relatively higher bFGF contents. Like bFGF, aFGF was distributed almost ubiquitously in normal mouse tissues.
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PMID:Distribution of fibroblast growth factors in cultured tumor cells and their transplants. 137 29

Neuroblastoma is the second most common solid tumor in infants and children. Improvement of therapy for stage IV patients remains the major goal of research in treatment of neuroblastoma. New approaches under study are focused in four main areas: (a) phase II studies; (b) mega-therapy procedures; (c) targeted therapy; and (d) immunotherapy. Future approaches will be closely linked to progress in laboratory investigation and more efficient use of currently available drugs. Of all the childhood malignancies, this is the one tumor where such an approach is most likely to be effective.
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PMID:Overview of current treatment of neuroblastoma. 138 90


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