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)

Expression of an extended panel of cytokine genes was investigated by reverse polymerase chain reaction (PCR) in 10 freshly excised melanoma metastases infiltrated by lymphocytes (TIL). cDNA encoding for CD3-delta and tyrosinase could be amplified in all samples, confirming the presence of T lymphocytes and melanoma cells. Cytokine genes possibly transcribed by both cell types, such as GM-CSF, IL-6 and IL-10 could be amplified from 5, 2 and 2 samples respectively. In contrast, IL-1 beta and TNF-alpha mRNA were never detectable, IL-1 alpha, IL-3 and IL-7 mRNA could be observed only in one case each. Transcripts encoding for TGF-beta 1 were observed in 8 samples, while TGF-beta 2 and 3 mRNA were detectable in only 2 specimens. mRNA encoding for cytokine genes typically transcribed by antigen-stimulated T lymphocytes, such as IL-2, IL-4 and IFN-gamma were rarely or never detectable (none, none and 1 of the samples respectively). In one case, where no cytokine gene transcription was detectable at the time of surgery, we addressed the question of the antigenicity of the tumor and of the functional competence of TIL. A primary tumor cell line was generated and cultured TIL were induced to transcribe IL-2 and IFN-gamma genes by incubation with the autologous irradiated tumor cell line, but not with autologous EBV-transformed cells. In these conditions, tumor-specific cytotoxic T lymphocytes (CTL) could be generated only after 3 weekly re-stimulations. In contrast, if autologous irradiated EBV-transformed cells were added to the cultures, specific CTL could be detected after one single tumor stimulation. Thus, signs of active responsiveness in terms of lymphokine gene mRNA are seldom detectable in melanoma metastases. Tumor-specific responses, however, including IL-2 and IFN-gamma gene expression and generation of CTL can be produced in vitro from specimens in which no cytokine gene mRNA is detectable ex vivo.
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PMID:The pattern of cytokine gene expression in freshly excised human metastatic melanoma suggests a state of reversible anergy of tumor-infiltrating lymphocytes. 818 65

The inhibition by different p-alkoxyphenol derivatives of the growth-regulating enzyme ribonucleotide reductase (RR) in purified Escherichia coli and mouse R2 protein preparations was studied by EPR spectroscopy. The inhibitor-induced inactivation of the catalytic subunit protein R2 was measured at 77 degrees K by observing the decrease of the typical EPR signal from the functionally essential protein-linked tyrosyl free radical. p-Methoxy-, p-ethoxy-, p-propoxy-, and p-allyloxyphenol were about 2 orders of magnitude more effective in inhibiting mouse R2, compared with E. coli R2. Among the p-alkoxyphenols studied, p-propoxyphenol was the most effective inhibitor of mouse R2 (IC50, 0.7 microM) and p-methoxyphenol was the least effective (IC50, 11 microM); p-ethoxy- and p-allyloxyphenol were intermediate. The observed half-maximal inhibition values characterized p-alkoxyphenols as a new class of strong inhibitors of the R2 protein of mammalian RR. p-Propoxy-, p-ethoxy-, and p-allyloxyphenol could be considered as new candidates for anticancer drugs. A special cellular inhibition assay of RR in proliferating tumor cells, in which the tyrosyl radical of R2 at natural concentration was monitored by EPR, showed that the four para-substituted alkoxyphenols also inhibited the enzyme with high efficiency in tumor cells (IC50, between 0.5 microM and 5 microM). Our results with inactivation of protein R2 of RR imply that the cytostatic effect of p-alkoxyphenols on melanoma cells, which has been hitherto explained by inhibition of tyrosinase [Melanoma Res. 2:295-304 (1992)], may be caused at least partly by inhibition of RR. Protein R2 of RR may be considered as an additional target that could be used for future cancer chemotherapy.
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PMID:p-Alkoxyphenols, a new class of inhibitors of mammalian R2 ribonucleotide reductase: possible candidates for antimelanotic drugs. 818 56

The observation that allogeneic melanoma cells matched for particular HLA class I alleles stimulate T-cells isolated from patients suggests that widely shared antigens exist on these tumors. A transient expression system was developed for screening a melanoma complementary DNA library using the highly transfectable human kidney cell line 293. Using this system, large numbers of complementary DNA clones can be rapidly screened for the expression of antigens which stimulate T-cells. Tumor-infiltrating lymphocytes from patient 888, which recognized melanoma in the context of HLA-A24, were used to screen a complementary DNA library made from the autologous melanoma. Our results demonstrate that these tumor-infiltrating lymphocytes recognize tyrosinase, a gene previously shown to be recognized by T-cells only in the context of HLA-A2. These data demonstrate that a single antigen can be recognized in the context of two different class I HLA alleles. In addition, this study suggests that recognition of tyrosinase by antigen-specific T-cells may be involved in tumor rejection.
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PMID:Recognition of tyrosinase by tumor-infiltrating lymphocytes from a patient responding to immunotherapy. 820 28

In order to define the antigens recognized by cytolytic T lymphocytes (CTLs) on autologous tumors, we derived tumor-specific CTL clones from autologous mixed lymphocyte tumor cell cultures. The gene coding for a tumor rejection antigen expressed on a melanoma was isolated by transfecting genomic DNA of the tumor into an antigen-loss variant of the melanoma. Transfectants were identified on the basis of their ability to stimulate tumor necrosis factor release by the CTL clone. The gene that transferred the expression of the antigen was named MAGE-1. It is a new gene, silent in normal tissues with the exception of testis, but expressed in several types of tumors. The antigen recognized by the CTL clone is a nonapeptide derived from the protein encoded by gene MAGE-1, and presented by the HLA class I molecule HLA-A1. Using two other antimelanoma CTL clones, we identified the tyrosinase gene as coding for an antigen presented by HLA-A2 on this type of tumors. The identification of these tumor rejection antigens open new possibilities for the specific immunotherapy of cancer.
J Immunother Emphasis Tumor Immunol 1993 Aug
PMID:Genes coding for tumor antigens recognized by human cytolytic T lymphocytes. 828 Jul 1

The adoptive transfer of tumor-infiltrating lymphocytes (TILs) with interleukin-2 (IL-2) has antitumor activity in some patients with metastatic melanoma. We have analyzed molecular mechanisms of TIL recognition of human melanoma. Some cultured TILs specifically lysed autologous and some allogeneic melanomas sharing a variety of class I major histocompatibility complex (MHC) molecules. HLA-A2-restricted melanoma-specific TILs lysed many HLA-A2+ melanoma cell lines from different patients but failed to lyse HLA-A2- melanoma and HLA-A2+ nonmelanoma cell lines. However, these TILs were capable of lysing many naturally HLA-A2- melanomas after introduction of the HLA-A2.1 gene by vaccinia virus. These results indicate that shared melanoma antigens (Ag) are expressed in melanomas regardless of their human leukocyte antigen types. In order to identify these shared melanoma Ags, we have tested some known proteins expressed in melanoma. Expression of tyrosinase or HMB45 Ag correlated with lysis of TILs. We are also attempting to isolate antigenic peptides by high performance liquid chromatography separation and genes encoding melanoma Ag by cDNA expression cloning. The T-cell component of the antimelanoma response was also analyzed by determining the genetic structure of the T-cell receptor (TCR) used by melanoma TILs. However, we did not observe common TCR variable region usage by different melanoma TILs. We could establish melanoma cell clones and lines resistant to TIL lysis due to the absence of or defects in the expression of Ag, MHC, or beta 2-microglobulin molecules. These data indicate multiple mechanisms for melanoma escape from T-cell immunosurveillance.(ABSTRACT TRUNCATED AT 250 WORDS)
J Immunother Emphasis Tumor Immunol 1993 Aug
PMID:T-cell recognition of human melanoma antigens. 828 Jul 5

Lymphocytes of melanoma patients can be restimulated in vitro with autologous tumor cells to generate antitumor cytolytic T lymphocytes (CTL). Previous reports have indicated that, when such CTL are obtained from HLA-A2 melanoma patients, they often display broad reactivity on A2 melanoma cell lines. Such antitumor CTL clones, which appeared to recognize the same antigen, were isolated from two patients. We report here the cloning of a cDNA that directs the expression of the antigen recognized by these CTL. This cDNA corresponds to the transcript of the tyrosinase gene. The gene was found to be active in all tested melanoma samples and in most melanoma cell lines. Among normal cells, only melanocytes appear to express the gene. The tyrosinase antigen presented by HLA-A2 may therefore constitute a useful target for specific immunotherapy of melanoma. But possible adverse effects of antityrosinase immunization, such as the destruction of normal melanocytes and its consequences, will have to be examined before clinical pilot studies can be undertaken.
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PMID:The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. 834 Jul 55

We report here the use of the 5' flanking region of the murine tyrosinase gene to direct expression of the herpes simplex virus thymidine kinase (tk) gene specifically to murine melanoma cells, whilst not permitting expression in a range of other cell types. Expression of the herpes simplex virus tk gene from the tyrosinase promoter in melanoma cells rendered them sensitive to killing by ganciclovir (100% cell death of a tk-expressing B16 clone after 12 days in culture at 1 microgram/ml ganciclovir). We also observed a substantial bystander killing effect when expressing cells were mixed with nontransfected parental B16 cells. When transfected murine melanoma cells expressing tk were injected into syngeneic mice both their tumorigenicity and experimental metastatic potential were abrogated completely when the mice were treated with ganciclovir (27 of 28 mice treated with water developed progressively growing tumors versus 1 of 30 in the ganciclovir-treated group). Direct injection of the tk gene under control of the tyrosinase promoter into established tumors in mice, followed by treatment with ganciclovir, led to significant reductions in resultant tumor size relative to the size of tumor developing in mice treated with water (median tumor weight, 1.65 g versus 2.75 g). Therefore, direct transfer of recombinant genes by injection of DNA can significantly reduce established tumor burden in vivo.
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PMID:Use of tissue-specific expression of the herpes simplex virus thymidine kinase gene to inhibit growth of established murine melanomas following direct intratumoral injection of DNA. 839 31

The locus for Tyrosinase-Positive Oculocutaneous Albinism (ty-pos OCA) has not yet been localised. The search for the ty-pos OCA locus has included a search for linkage to candidate pigment loci and a candidate chromosomal region, as well as a random search using highly polymorphic markers in 42 families, including 271 individuals of whom 79 are affected. The lod scores for the tyrosinase (TYR) locus (11q14-q21), homologous to the albino locus, c, in the mouse and the CAS2/TRP1 locus (9p22-pter), homologous to the brown locus, b, in the mouse were -5.89 and -7.22, respectively, at a recombination fraction of theta = 0.01, thus excluding them from being the ty-pos OCA locus. In the candidate chromosomal region, 11p, four loci (probes) were tested, SAA (pSAA82), CALC (pHC36), HBB (Gamma-globin haplotype) and an AC repeat polymorphism at the Wilm's Tumour locus (WT1). A portion of 11p was excluded with the following lod scores: pSAA82 lod = -2.05 at theta = 0.10; pHC36 lod = -3.87 at theta = 0.05; gamma-globin haplotype lod = -2.80 at theta = 0.10; and WT1 lod = -2.34 at theta = 0.10. Thirty-three polymorphic markers randomly distributed on 13 different chromosomes were all excluded from close linkage to ty-pos OCA.
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PMID:Exclusion of two candidate pigment loci, c and b, part of chromosome 11p, and 33 random polymorphic markers as the locus for tyrosinase-positive oculocutaneous albinism. 842 54

The activities of catechol-O-methyltransferase (COMT) and tyrosinase were measured in subcellular fractions obtained from transplantable melanotic and amelanotic hamster melanoma. The results showed that there was a substantial difference between the localization of these enzymes. Whereas tyrosinase was localized mainly in the large granule fraction, the highest COMT activity was found to be in fractions abundant in microsomal structures. As expected, subcellular fractions obtained from amelanotic melanoma contained low or undetectable tyrosinase activity. On the other hand, the same fractions exhibited higher COMT activity than those from the pigmented tumor. Relatively low specific activity of COMT in fractions containing coated vesicles does not support the idea that this enzyme could be responsible for the inhibition of melanin polymerization in these structures. Because melanogenic intermediates, such as 5,6-dihydroxyindole and 5,6-dihydroxyindole-2-carboxylic acid, are compartmentalized within membraneous structures, the preferential localization of COMT in cytosol and cytosolic membrane network might be advantageous for a detoxification role in (melanotic) melanocytes that produce dihydroxyindoles.
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PMID:Differences in subcellular distribution of catechol-O-methyltransferase and tyrosinase in malignant melanoma. 843 11

Human malignant melanoma represents a difficult therapeutic challenge to both medical scientists and practicing physicians. However, the biologic uniqueness of the tumor may provide opportunities for exploitation in therapeutics. This study proposed to undertake a systemic approach to the chemotherapy of malignant melanoma based upon the uniqueness of pigment-cell metabolic pathway pertaining to conversion of tyrosine and dopa with subsequent formation of melanin by tyrosinase and its related enzymes. The sulphur homologue of tyrosine, cysteinylphenol (CP), its amine derivative, cysteaminylphenol (CAP), and their N-acetyl and alpha-methyl derivatives have been synthesized and tested in in vivo and in vitro melanocytotoxicity and antimelanoma effects. These phenolic thioethers (PTEs) and phenolic thioether amine (amides) (PTEAs), which are substrates of tyrosinase, showed significant cytotoxicity that is selective to melanocytes and melanoma cells. Most previous attempts to impair the melanin pathway as a therapeutic strategy have been of limited success because they have been directed to catecholic compounds that are unstable and insufficient in lethality at physiologically tolerable doses. By contrast, our approach relies on phenolic compounds, PTEs and PTEAs, which are more stable than catechols and become toxic only after oxidation by tyrosinase. We found PTEA as the most promising agent for the future development of chemotherapeutic agents. The possible biologic, chemical, and pharmacologic reactions of these synthetic compounds within the melanoma cells are studied and discussed.
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PMID:Exploitation of pigment biosynthesis pathway as a selective chemotherapeutic approach for malignant melanoma. 843 13


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