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)

Although commonly expressed human melanoma-associated antigens recognized by CD8+ cytolytic T cells have been described, little is known about CD4+ T-cell recognition of melanoma-associated antigens. Epstein-Barr virus-transformed B cells were used to present antigens derived from whole cell lysates of autologous and allogeneic melanomas for recognition by melanoma-specific CD4+ T-cell lines and clones cultured from tumor-infiltrating lymphocytes. HLA-DR-restricted antigens were detected in the lysates on the basis of specific release of cytokines from the responding T cells. Antigen sharing was demonstrated in the majority of melanomas tested, as well as in cultured normal melanocytes, but not in other normal tissues or nonmelanoma tumors. T-cell clones manifested a single recognition pattern, suggesting the presence of an immunodominant epitope. This epitope was identified as a product of the tyrosinase gene, which has also been shown to encode class I-restricted epitopes recognized by CD8+ T cells from melanoma patients. Identification of commonly expressed tumor-associated protein molecules containing epitopes presented by both class I and class II major histocompatibility molecules may provide optimal reagents for cancer immunization strategies.
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PMID:Human CD4+ T cells specifically recognize a shared melanoma-associated antigen encoded by the tyrosinase gene. 793 89

Previously we have demonstrated safe and effective transfer of the HSVtk cytotoxic gene to primary murine melanoma tumors by direct injection of plasmid and retroviral vectors in which the HSVtk gene is driven by the tissue-specific tyrosinase promoter. However, for general clinical application such forms of therapy should, ideally, be effective against disseminated metastases. We report here that the number of recently established lung metastases of B16 melanoma in C57BL mice treated with ganciclovir is reduced compared to controls after multiple i.v. administrations of high titer retroviral supernatant encoding the HSVtk gene, but not after administration of liposome-complexed plasmid DNA. Using polymerase chain reaction analysis, integration of the provirus was observed in metastasis-bearing lungs (4 of 6 mice) and in the spleens of some ganciclovir-treated animals (2 of 6 mice) but not in the testes, brain, heart, liver, or kidney. The reduction in the number of experimental metastases in C57BL mice exceeded the anticipated extent of transduction of tumor cells, which is indicative of a marked bystander effect. This magnitude of reduction was not observed in immunodeficient athymic mice, suggesting that the immune system plays some part in the bystander effect. In support of these data, we show that, whereas the parental tumor cells are only poorly immunogenic, an effective antitumor immune response is generated following the killing of neoplastic cells in vivo as a result of treatment with ganciclovir. These effects may be responsible for augmenting the efficacy of retroviral infection. The combination of local cell killing by the HSVtk/ganciclovir system and the induction of antitumor immunity suggests new opportunities for the design of vectors for the gene therapy of cancer.
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PMID:Systemic gene therapy of murine melanoma using tissue specific expression of the HSVtk gene involves an immune component. 795 71

Cigarette smoke polyphenolic agents (catechol and hydroquinone) that generate oxidants have been shown to be tumor promoters. Furthermore, oxidants can influence protein kinase C (PKC)-mediated signal transduction. Since terpenoid tumor promoters, phorbol esters, increase invasion and metastasis by activating PKC, we have determined whether polyphenolic agents present in the cigarette smoke condensate (CSC) could also influence these events. Hydroquinone (50 microM), catechol (500 microM), or CSC (50 micrograms/ml) induced an initial cytosol-to-membrane translocation of PKC in LL/2 lung carcinoma cells, followed by a later down-regulation of the enzyme. LL/2 cells treated with these CSC-related agents for a limited time (45 min) and exhibiting high membrane-associated PKC activity, when injected into mice through the tail vein, produced an increase in metastatic nodules in the lungs after 20 days. However, cells treated with CSC-related agents for a prolonged period did not exhibit an increase in metastasis. Agents that decrease the rate of production of reactive oxygen species, such as catalase either alone or in combination with superoxide dismutase, and a cell-permeable iron-chelator, o-phenanthroline, inhibited CSC-mediated membrane association of PKC and metastasis. Prior treatment of CSC with tyrosinase to modify polyphenols resulted in a partial loss of CSC stimulation of metastasis. Furthermore, a cell-permeable Ca2+ chelator and diverse PKC inhibitors, such as calphostin C, hypericin, chelerythrine, and bisindolylmaleimide, inhibited CSC-enhanced metastasis. CSC increased in vitro tumor cell adhesion to endothelial monolayers and to reconstituted basement membrane (Matrigel) and also enhanced the invasion through Matrigel coated on the polycarbonate filters in Transwells. All these CSC effects were found to be temporary and were blocked by the above mentioned antioxidant systems and PKC inhibitors. Thus, these results suggest that the oxidants generated by autooxidation of polyphenolic agents present in tobacco smoke increase tumor cell invasion and metastasis, at least in part by activation of Ca2+/PKC signal transduction. Conceivably, cigarette smoke constituents not only promote tumorigenesis but also may increase the spread of cancer in the body.
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PMID:Tobacco smoke tumor promoters, catechol and hydroquinone, induce oxidative regulation of protein kinase C and influence invasion and metastasis of lung carcinoma cells. 799 11

It has been reported previously that antitumor cytolytic T lymphocyte (CTL) clones can be isolated from blood lymphocytes of HLA-A2 melanoma patients, after stimulation in vitro with autologous tumor cells, and that some of these CTL clones lyse most HLA-A2 melanomas. A first antigen recognized by such CTL clones was previously shown to be encoded by the tyrosinase gene. We report here the identification of another gene that also directs the expression of an antigen recognized on most melanomas by CTL clones that are restricted by HLA-A2. The gene, designated Melan-A, is unrelated to any known gene. It is 18 kb long and comprises five exons. Like the tyrosinase gene, it is expressed in most melanoma tumor samples and, among normal cells, only in melanocytes.
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PMID:A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. 800 76

Transplantation experiments have demonstrated that most mouse tumors express antigens that can constitute targets for rejection responses mediated by syngeneic T lymphocytes. For human tumors, autologous cultures mixing tumor cells and blood lymphocytes or tumor-infiltrating lymphocytes have produced CD8+ and CD4+ cytolytic T cell (CTL) clones that recognize tumor cells specifically. Attempts to identify the target antigens by biochemical fractionation of tumor cells up to now have failed, with the important exception of the identification of underglycosylated mucins present on breast and pancreatic carcinomas. Gene transfection approaches have proved more successful. A gene family named MAGE codes for antigens recognized by autologous CTL on a melanoma tumor. These genes are not expressed in normal tissues except for testis. They are expressed in many tumors of several histological types. Differentiation antigens coded by genes such as tyrosinase are also recognized on human melanoma by autologous CTL. The identification of human tumor rejection antigens opens new possibilities for systematic approaches to the specific immune therapy of cancer.
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PMID:Tumor antigens recognized by T lymphocytes. 801 Dec 85

Malignant melanoma is a tumor that offers unique possibilities for approaches to targeted therapy by virtue of the pigment biosynthesis pathway. Such approaches may seek to use the incorporation of toxic intermediates or to use the natural transcriptional control of genes coding for enzymes involved in melanin formation to regulate gene therapy. In this paper, we describe how the 5'-flanking sequences of the genes for tyrosinase or tyrosinase-related protein 1 can be used to drive expression of complementary DNA, coding for immunity-stimulating proteins or for drug-activating enzymes, specifically in melanoma cells. The combination of the tissue specificity resulting from these techniques, coupled with innovative delivery systems, should provide the maximum available therapeutic index and lead to the design of new treatments with limited side effects.
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PMID:Targeted therapy for malignant melanoma. 801

2-Thiouracil (TU), an antithyroid drug, is generally recognized as a highly specific melanoma seeker owing to its capability of being selectively accumulated into active melanin-producing tissues. We recently reported evidence that in vitro TU is capable of reacting with dopaquinone (DQ), an early intermediate in melanin biosynthesis, to give an addition product characterized as 6-S-thiouracildopa (TD). However, several aspects of the mechanism of the uptake of TU into melanin in vivo still need to be clarified. We report here the extremely rapid incorporation of [2-14C]thiouracil into melanoma tumors growing subcutaneously in mice and show its selective accumulation into melanin by isolation and purification of the pigment fraction. Formation of the TD adduct in the tumor was examined by HPLC analysis of the soluble fractions of the tissue homogenates: however, no trace of TD could be detected on account of its rapid oxidation by the melanogenic enzyme tyrosinase, as evidenced by in vitro kinetic measurements. Monitoring the course of the tyrosinase-catalyzed oxidation of 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) in the presence of TU, at various molar ratios, provided evidence for the ability of the drug to affect melanogenesis by interaction with biosynthetic intermediates beyond the DQ stage, suggesting other possible modes for its chemical binding to the growing pigment.
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PMID:Specific incorporation of 2-thiouracil into biological melanins. 806 12

Cell lineage-specific cellular proteins, oncogenes from viral or cellular origin and tumor suppressor genes encode tumor-specific/associated antigens. Such antigens can elicit an major compatibility complex (MHC) class I-restricted cytotoxic T lymphocyte (CTL) response, either naturally in cancer patients or following appropriate immunostimulation (in vitro or in vivo). The reported immune responses in humans to the melanoma-associated MAGE gene products, GP100 and tyrosinase, all self-proteins, support the idea to use wild-type p53 products as targets for T cells. An important step towards this goal is identification of potential p53 CTL epitopes. We identified the wild-type p53 peptides with the highest affinity to the HLA-A*0201 molecule using two assays: the previously described MHC peptide-binding assay and the peptide competition assay. We obtained CTL against four p53 peptides with a high affinity for the HLA-A*0201 molecule. These findings are discussed next to a short review concerning the p53 literature.
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PMID:p53, a potential target for tumor-directed T cells. 808 74

B16 melanoma sublines (B16-F10-BL6 and B16-F1) exhibited elevated adenosine 3',5'-cyclic monophosphate (cAMP) levels when cultured in Dulbecco's modified Eagle's medium (DMEM) in comparison to cells in RPMI-1640 medium. In parallel, cells cultured in DMEM had increased tyrosinase activity, melanization and dendrite formation, all markers of melanoma differentiation. Also, the proliferative rates of both cell lines were decreased by 80-85% when cultured in DMEM relative to cells maintained in RPMI-1640 medium. In these studies, elevated levels of the melanin precursors tyrosine (Tyr) and phenylalanine (Phe) found in DMEM were shown not to be solely responsible for the phenotypic changes observed with DMEM. Both BL6 and B16-F1 cell lines formed more experimental pulmonary tumor metastasis in syngeneic C57BL/6 mice when maintained in DMEM vs RPMI-1640 medium. Analysis of metastasis formation in nude mice with normal and depleted natural killer (NK) cell activity revealed that the enhanced lung colonizing capacity of the BL6 cells maintained in DMEM was independent of the function of T-cell or NK-cell-mediated immunity. A close association between metastatic ability of tested lines and the expression of the membrane-associated enzyme gamma-glutamyltranspeptidase (gamma-GTPase, EC 2.3.2.2) was observed. The highly metastatic BL6 cell line had 20-fold higher levels of gamma-GTPase activity than the weakly metastatic B16-F1 cell line. Both cell lines, when grown in DMEM, had elevated gamma-GTPase activity that paralleled augmentation of metastatic ability. The dramatic changes in lung-colonizing capacity of the variant B16 melanoma cells maintained in DMEM in contrast to those grown in RPMI-1640 medium may serve as a useful model in understanding certain steps involved in triggering cell differentiation as well as metastasis development.
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PMID:Enhancement of pulmonary metastasis formation and gamma-glutamyltranspeptidase activity in B16 melanoma induced by differentiation in vitro. 809 41

N-Methyl-N-nitrosourea (MNU) is a potent carcinogen that causes the development of murine thymic lymphomas. MNU-induced tumor incidence varies considerably among different inbred mouse strains. In particular, the AKR strain is highly susceptible, whereas the C57L strain is highly resistant to MNU-induced lymphoma formation. Crosses between AKR and C57L mice were established to investigate the genetic basis for the differential susceptibility of these inbred strains. A strong association between MNU-induced lymphoma development and coat color was observed in (AKR x C57)F2 and AKR x (AKR x C57)F1 progeny such that albino mice developed a higher tumor incidence than nonalbino animals. These data suggest that a locus on chromosome 7 influences tumor development. Analysis of four additional polymorphic loci (D7Rp2, Fes, Hbb, and Int-2) on chromosome 7 in AKR x (AKR x C57)F1 backcross mice revealed a significant linkage between high tumor incidence and homozygous inheritance of AKR alleles at the albino (tyrosinase) and Hbb loci. Thus, inheritance of at least one C57L allele at the albino or Hbb loci was associated with protection against MNU-induced lymphoma development. There was no association between tumor incidence and genotype at the D7Rp2, Fes, or Int-2 loci. Taken together, the data suggest that whereas C57L mice contain a dominant tumor suppressor gene on chromosome 7, in the AKR strain both alleles at this locus are defective resulting in enhanced susceptibility to MNU-induced lymphomagenesis.
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PMID:Localization of a novel chromosome 7 locus that suppresses development of N-Methyl-N-nitrosourea-induced murine thymic lymphomas. 809 17


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