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)

This study was designed to develop a safe, effective gene therapy for disseminated melanoma. We constructed retroviral vectors containing a tyrosinase promoter-cytosine deaminase expression cassette (Tyr/CD), and demonstrated that the tyrosinase promoter conferred a selective expression of cytosine deaminase (CD) gene in B16 melanoma cells, especially when the Tyr/CD cassette inserted in 3'LTR region of a retroviral vector. In vivo gene therapy for the intraperitoneally disseminated melanoma using Tyr/CD retrovirus-producing cells and 5-fluorocytosine (5-FC) showed that retroviruses produced in situ were capable of infecting tumor xenografts and bone marrow cells in animal model, and survival rates were prolonged significantly as compared with those treated with CD2 retrovirus-producing cells and 5-FC. Importantly, the treatment-related bone marrow suppression was not observed in the former treatment, while profound bone marrow suppression was observed in the latter treatment. In vivo gene therapy using retrovirus-producing cells containing suicide gene under the control of a tissue-specific promoter and 5-FC administration is safer and more effective for the treatment of disseminated melanoma, as compared with retrovirus-producing cells containing the gene under the control of a universal promoter and 5-FC.
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PMID:A safe, effective in vivo gene therapy for melanoma using tyrosinase promoter-driven cytosine deaminase gene. 1036 76

We described the occurrence of 4 transcripts differentially displayed between syngeneic murine B16F10 (metastatic melanoma) and Melan-a (immortalised melanocytes) cell lines. We now report that one such transcript, which is B16F10-specific, represents a protein phosphatase-2A B' regulatory subunit. No expression of this transcript was detected in the weakly metastatic B16F1 by Northern blotting. Moreover, the transcript was not expressed by spontaneously immortalised, non-tumorigenic, melanocytes (Melan-Ab and Melan-a2), nor was it expressed by ras-transformed, tumourigenic melanocytes (Melan-Ab-LTR-ras). Cloning of the 5'-end region of this transcript (termed band 8A) from B16F10 cells revealed an intracisternal A-particle insertion, including the long terminal repeat region, which could account for the observed high expression in B16F10 cells. Single cell clones of B16F10 manifested an experimental metastasis capacity, which correlated with band 8A expression with the lowest expressors being least metastatic. The human homologue of the B' regulatory subunit, B56gamma, is expressed preferentially at the mRNA level in human melanoma cell lines compared with normal epidermal melanocytes. In situ hybridisation studies on human clinical samples detected high expression of this gene in a number of malignant melanomas. Our results imply strongly that this protein phosphatase-2A regulatory subunit may have a role in melanoma tumour progression.
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PMID:Identification by differential display of a protein phosphatase-2A regulatory subunit preferentially expressed in malignant melanoma cells. 1041 69

The overexpression of the Xmrk oncogene (ONC-Xmrk) in pigment cells of certain Xiphophorus hybrids has been found to be the primary change that results in the formation of malignant melanoma. Spontaneous mutant stocks have been isolated that have lost the ability to induce tumor formation when crossed with Xiphophorus helleri. Two of these loss-of-function mutants were analyzed for genetic defects in ONC-Xmrk's. In the lof-1 mutant a novel transposable element, TX-1, has jumped into ONC-Xmrk, leading to a disruption of the gene and a truncated protein product lacking the carboxyterminal domain of the receptor tyrosine kinase. TX-1 is obviously an active LTR-containing retrotransposon in Xiphophorus that was not found in other fish species outside the family Poeciliidae. Surprisingly, it does not encode any protein, suggesting the existence of a helper function for this retroelement. In the lof-2 mutant the entire ONC-Xmrk gene was found to be deleted. These data show that ONC-Xmrk is indeed the tumor-inducing gene of Xiphophorus and thus the critical constituent of the tumor (Tu) locus.
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PMID:Melanoma loss-of-function mutants in Xiphophorus caused by Xmrk-oncogene deletion and gene disruption by a transposable element. 1054 66

Oral vitamin E (alpha-tocopherol) supplementation has been reported to improve facial hyperpigmentation. The compound of alpha-tocopherol and ferulic acid, also an antioxidant connected with an ester bond, alpha-tocopheryl ferulate (alpha-TF) can absorb ultraviolet (UV) radiation and thus maintain tocopherol in a stable state. Our aim was to determine whether alpha-TF can be applied to improve and prevent facial hyperpigmentation induced by UV as a whitening agent as well as an antioxidant. In this study, the effects of alpha-TF on melanogenesis were examined using cultured human melanoma cells and normal human melanocytes in vitro. alpha-TF solubilized in 0.5% lecithin inhibited melanization significantly at the concentration of 30 micrograms/ml compared with arbutin (100 micrograms/ml), kojic acid (100 micrograms/ml), ascorbic acid (600 micrograms/ml), and tranexamic acid (600 micrograms/ml). alpha-TF had no effect on the protein amounts of tyrosinase, TRP (tyrosinase related protein)-1, and TRP-2 of human melanoma cells exposed to UV radiation, but inhibited tyrosine hydroxylase activity. alpha-TF neither directly inhibited tyrosinase activity of the large granule fraction extracted from melanoma cells, nor modulated glycosylation of tyrosinase. These results suggest that alpha-TF may be a candidate for whitening agent which suppresses melanogenesis, possibly by inhibiting tyrosine hydroxylase activity in an indirect manner. Further, alpha-TF decreased the amount of 8-hydroxydeoxyguanosine produced indirectly through active oxygen species (AOS) in guinea pig skin exposed to 2 times the minimal erythema dose of UVB radiation, but did not suppress the direct formation of cyclobutane pyrimidine dimers and (6-4) photoproducts. Thus alpha-TF may reduce AOS-induced DNA damage and thereby contribute at least in part to suppressing or retarding skin cancer development.
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PMID:The inhibitory effect of DL-alpha-tocopheryl ferulate in lecithin on melanogenesis. 1062 56

Many preclinical studies of cancer immunotherapy are based on the testing of a single vaccination strategy in several tumor models. Moreover, most of those studies used xenogeneic Ags, which, owing to their high immunogenicity, may not represent realistic models for the validation of cancer immunotherapies. To address these issues, we compared the vaccination efficacy of three well established strategies (i.e., naked DNA; peptide-pulsed dendritic cells (DC), or a mixture of peptide and the Escherichia coli toxin LTR72) using the xenogeneic OVA or the naturally expressed tyrosinase-related protein 2 (TRP-2) tumor Ag in the B16 melanoma model. C57BL/6 mice received one to three s.c. injections of peptide-pulsed DC or DNA, or one to four mucosal administrations of peptide-toxin mixture. One to 2 wk later, the animals were challenged s.c. with B16 or B16 cells expressing OVA (B16-OVA). Vaccination of mice with OVA induced in all cases melanoma-specific CTL and protection against B16-OVA. When TRP-2 was used, all three vaccines elicited B16-specific CTL, but only DC pulsed with the immunodominant T cell epitope TRP-2181-188 allowed protection against B16. Even more importantly, a vaccination regimen with TRP-2-pulsed DC, started 24 h after the injection of a lethal number of B16 cells, caused a therapeutic effect in 60% of the challenged animals. Our results strongly emphasize the relevance of the tumor Ag in the definition of immunotherapeutic strategies for cancer, and support the use of peptide-pulsed DC as cancer vaccine in humans.
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PMID:Relevance of the tumor antigen in the validation of three vaccination strategies for melanoma. 1094 94

Dendritic cells (DCs) are potent antigen-presenting cells and are capable of activating naive T cells. Gene transfer of tumor antigen and cytokine genes into DCs could be an important strategy for immunotherapeutic applications. Dendritic cells derived from peripheral blood monocytes do not divide and are therefore poor candidates for gene transfer by Moloney murine leukemia virus (Mo-MuLV)-based retroviral vectors. Lentiviral vectors are emerging as a powerful tool for gene delivery into dividing and nondividing cells. A three-plasmid expression system pseudotyped with the envelope from vesicular stomatitis virus (VSV-G) was used to generate lentiviral vector particles expressing enhanced green fluorescent protein (EGFP). Peripheral blood monocyte-derived DCs were cultured in the presence of GM-CSF and IL-4 and transduced with lentiviral or Mo-MuLV-based vectors expressing EGFP. FACS analysis of lentiviral vector-transduced DCs derived either from normal healthy volunteers or from melanoma patients demonstrated transduction efficiency ranging from 70 to 90% compared with 2-8% using Mo-MuLV-based vectors pseudotyped with VSV-G. Comparison of lentiviral vectors expressing EGFP driven by CMV or human PGK promoters showed similar levels of transgene expression. Lentiviral vector preparations produced in the absence of HIV accessory proteins transduced DCs at efficiencies equal to vectors produced with accessory proteins. Alu-HIV-1 LTR PCR demonstrated the genomic integration of the lentiviral vector in the transduced DCs. Transduced cells showed characteristic dendritic cell phenotype and strong allostimulatory capacity and maintained the ability to respond to activation signals such as CD40 ligand and lipopolysaccharide. These results provide evidence that lentiviral vectors are efficient tools for gene transfer and expression in monocyte-derived DCs that could be useful for immunotherapeutic applications.
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PMID:Efficient gene transfer to human peripheral blood monocyte-derived dendritic cells using human immunodeficiency virus type 1-based lentiviral vectors. 1098 62

To increase the antitumor effects of cytosine deaminase (AdCD) gene therapy and induce more potent antitumor immunity, Th1 cytokine interleukin-18 encoded adenovirus (AdIL18) was combined with adenovirus encoding CD (AdCD) for the therapy of established murine B16 melanoma. Combination therapy of the tumor-bearing mice with AdIL 18 and AdCD/5FC inhibited the growth of the subcutaneous B16 tumors more significantly, compared with AdIL 18 or AdCD/5FC alone. In vivo depletion analysis with anti-CD4, anti-CD8 or anti-NK 1.1 McAb illustrated that both CD8+ T cells and CD4+ T cells played key roles in the augmented antitumor response of the combined therapy. Peptide/MHC tetramer represents a powerful and general tool for rapid, highly sensitive, and direct analysis of antigen-specific T cells. In this study, we prepared H-2Kb/TRP-2180-188 tetramer, which was demonstrated to bind H-2Kb-restricted, B16 melanoma-specific CD8+ T cells. B16 specific H-2Kb/TRP2180-188 tetramer was used to stain the tumor-specific CD8+ T cells and the results showed that CD8+ tetramer+ T cells were about 3-5% of the splenic CD8+ T cells derived from tumor-bearing mice after combined therapy. The CTL cytotoxicity was markedly induced in mice after combined therapy, suggesting efficient induction of tumor-specific CD8+ T cells after combined gene therapy with AdCD/5FC/AdIL18. IL-18 gene transfer could significantly augment the cytotoxicity of NK cells and macrophages, and increase the production of interleukin-2 and interferon-gamma, as compared with treatments with AdCD/5FC, AdlacZ/5FC or PBS. These data suggested that in vivo IL-18 gene transfer could augment the antitumor effects of CD suicide gene therapy through efficient induction of antitumor immunity.
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PMID:Interleukin-18 gene transfer increases antitumor effects of suicide gene therapy through efficient induction of antitumor immunity. 1108 76

Transcriptional targeting of cytotoxic genes is an important way to control toxicity associated with gene transfer therapies, but supposedly, tissue-specific promoters are often either very weak and/or leaky. In addition, the phenotypic leakiness of such tissue-specific promoters is dependent upon the toxicity of the gene being used. Therefore, we devised a transcriptional feedback loop to restrict gene expression of very potent genes to melanoma cells. We screened different elements of the human tyrosinase promoter to find one which gave no detectable expression in non-melanoma cells but was active in melanoma cell lines. This weak, but highly tissue specific, element (Tyr-300) was then used as the basis for a transcriptional amplification feedback loop in which a consensus heat shock element (HSE) was cloned upstream of Tyr-300. The cytotoxic gene was cloned downstream of the HSE-Tyr-300 element along with a mutated form of the heat shock factor-1 (HSF-1) transcription factor, which no longer requires cellular stress to activate its trimerisation, nuclear localisation and transcriptional activation properties. Low levels of expression from Tyr-300 initiated expression of both the cytotoxic and the HSF-1 genes in melanoma cells. Gradual build up of HSF-1 amplified expression through binding to the HSE to give levels of cytotoxicity similar to that provided by a CMV promoter. However, no leakiness was observed in multiple non-melanoma cell lines tested. In addition to amplifying low levels of weak tissue-specific expression, the use of HSF-1 also leads to activation of endogenous stress-related genes such as hsp70. Induction of these genes, in the presence of cell killing by the cytotoxic gene, is a highly immunostimulatory event which enhances the antitumour vaccination effects of direct tumour cell destruction. Having demonstrated the compatibility of the component elements in plasmid form, we incorporated the feedback loop into a hybrid LTR-modified retroviral vector and confirmed that the system can be effective in the form of a viral vector. The format of the feedback loop described here could be exploited for any tissue type in which a highly tissue-specific element can be identified but which is itself too weak to be effective therapeutically.
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PMID:A transcriptional feedback loop for tissue-specific expression of highly cytotoxic genes which incorporates an immunostimulatory component. 1143 33

Cellular translocation into a human Bowes melanoma cell line was investigated and compared for penetratin and pIsl, two peptides that correspond to the third helices of the related homeodomains, from the Antennapedia transcription factor of Drosophila and the rat insulin-1 gene enhancer protein, respectively. Both biotinylated peptides internalized into the cells with similar efficacy, yielding an analogous intracellular distribution. When a large cargo protein, 63 kDa avidin, was coupled to either peptide, efficient cellular uptake for both the peptide-protein complexes was observed. The interactions between each peptide and SDS micelles were studied by fluorescence spectroscopy and acrylamide quenching of the intrinsic tryptophan (Trp) fluorescence. Both peptides interacted strongly and almost identically with the membrane mimicking environment. Compared to penetratin, the new transport peptide pIsl has only one Trp residue, which simplifies the interpretation of the fluorescence spectra and in addition has a native Cys residue, which may be used for alternative coupling reactions of cargoes of different character.
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PMID:Cellular internalization of a cargo complex with a novel peptide derived from the third helix of the islet-1 homeodomain. Comparison with the penetratin peptide. 1171 81

We showed in human melanoma cells tryptophan hydroxylase (TPH) and hydroxyindole methyltransferase genes expression with the sequential enzymatic activities of TPH, serotonin (Ser) N-acetyltransferase and hydroxyindole methyltransferase. The presence of the products Ser, 5OH-tryptophan, N-acetylserotonin, melatonin (Mel), 5-methoxytryptamine and 5-methoxytryptophol was documented by liquid chromatography-mass spectrometry. Thus, human melanoma cells can synthesize and metabolize Ser and Mel.
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PMID:Conversion of L-tryptophan to serotonin and melatonin in human melanoma cells. 1182 Oct 57


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