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

The effect of sodium butyrate on mouse and human melanoma cell lines was evaluated. Sodium butyrate (0.1-2mM) is shown to reduce the clonogenic potential of several melanoma cell lines. The antiproliferative effect of sodium butyrate is accompanied by a marked increase in the activity of the plasma-membrane bound enzyme gamma-glutamyl transpeptidase. Sodium butyrate treated cells acquire a well developed rough endoplasmic reticulum and accumulate fat droplets. The development of the endoplasmic reticulum is associated with a marked increase in the activity of the enzyme marker NADPH cytochrome c reductase. It is suggested that the phenotypic alterations induced by sodium butyrate may serve as markers for the action of this agent on melanoma cells and other tumours.
 ...
PMID:Biochemical and ultrastructural alterations accompany the anti-proliferative effect of butyrate on melanoma cells. 288 47

A method for synthesis of the phaeomelanin pigment intermediate compound 5-S-L-cysteinyl-glycine-L-dopa is presented. This thioether has been suggested as a precursor to 5-S-L-cysteinyl-L-dopa, the key intermediate compound in phaeomelanin pigment formation. 5-S-Glutathione-L-dopa is first synthesized by the tyrosinase-catalyzed reaction between L-dopa and glutathione. The 5-S-glutathione-L-dopa is then converted to 5-S-L-cysteinyl-glycine-L-dopa using the enzyme gamma-glutamyl transpeptidase. The compound thus obtained was suitable as a substrate for melanoma cell and serum dipeptidase which converts the compound into 5-S-L-cysteinyl-L-dopa and glycine. The optimum pH for the dipeptidase from melanoma cells was 7.5 and the Km was 1.2 mM.
 ...
PMID:Synthesis of 5-S-L-cysteinyl-glycine-L-dopa, a natural substrate for serum and melanocyte dipeptidase. 312 Jun 20

Transglutaminase (TGase; R-glutaminyl-peptide:amine gamma-glutamyltransferase, EC 2.3.2.13) and ornithine decarboxylase (ODCase; L-ornithine carboxy-lyase, EC 4.1.1.17) activities were measured after the addition of retinoid analogs to Chinese hamster ovary (CHO) cells released from quiescence and Cloudman S91 (CCL 53.1) mouse melanoma cells stimulated to differentiate with alpha-melanocyte-stimulating hormone (MSH, melanotropin). In both cell culture lines, we detected a biphasic increase in TGase activity and a single peak of ODCase activity within 7 hr after release or stimulation. Retinoid analogs altered the expression of the initial TGase peak in both CHO and melanoma cells. Retinol increased the activity of TGase 1 hr after release in CHO cells, and the activity remained elevated until hr 4. A broad peak of TGase activity also occurred after the addition of alpha-difluoromethylornithine, an irreversible inhibitor of ODCase, and after addition of alpha-difluoromethylornithine plus retinol. In mouse melanoma cells, retinoic acid plus MSH markedly enhanced the activity of the initial TGase peak compared to MSH alone. Retinoic acid alone also increased TGase activity biphasically in these cells without the addition of MSH. These studies suggest that retinoid effects that increase TGase activity may alter the ODCase expression in proliferation and differentiation.
 ...
PMID:Retinoids increase transglutaminase activity and inhibit ornithine decarboxylase activity in Chinese hamster ovary cells and in melanoma cells stimulated to differentiate. 612 41

A study of 116 patients with histologically proven uveal malignant melanoma suggested that hepatic metastases were present at the same time that the ocular tumor was diagnosed in 15 patients (13%) by serum gamma-glutamyl transpeptidase assay. The average pretherapy gamma-glutamyl transpeptidase levels were statistically higher (P less than .01) in the 28 patients who developed metastases compared with those in 88 patients who have remained clinically free of metastases for a follow-up period of at least two years. The predictive value test indicated that pretherapy gamma-glutamyl transpeptidase levels greater than or equal to 22 IU/ml were increased in patients developing metastasis. With this upper-normal limit, 15 (54%) of the 28 patients who later developed clinical evidence of metastasis had increased pretherapy levels. In comparison, only 12 (14%) of the 88 patients who remained tumor-free for at least two years had increased pretherapy levels. Although not all patients who developed metastases had increased pretherapy levels, most developed increases at some time during the course of their disease. Because the gamma-glutamyl transpeptidase assay can detect hepatic metastases before other liver function assays, it should be included as a routine liver function study for patients with uveal malignant melanoma.
 ...
PMID:Gamma-glutamyl transpeptidase in the prognosis of patients with uveal malignant melanoma. 613 55

Topical application of 4-tertiary butyl catechol (TBC) causes vitiligo in the skin of man and animals, and previous electron microscopic studies showed pheomelanin formation in the affected areas. In the present study, we investigated changes of enzyme activities, eumelanin content and amount of sulfur in tissue cultured human melanoma cells exposed to the depigmenting chemical. TBC enhanced glutathione reductase activity without changing the eumelanin content by 24 hr after exposure and subsequently (by 42 hr) increased gamma-glutamyl transpeptidase activity and sulfur content in the cells with a decrease in eumelanin content. It is suggested that this chemical alters the types of melanin formed by modulation of these enzyme activities.
 ...
PMID:Reduction in eumelanin by the activation of glutathione reductase and gamma-glutamyl transpeptidase after exposure to a depigmenting chemical. 613 32

The distribution of gamma-glutamyl transpeptidase (gamma-GTP), tyrosinase, and 5-S-cysteinyldopa (5-S-CD) within melanoma cells has been studied in vitro as well as in vivo. Sodium periodate treatment of intact B-16 melanoma cells has been found to inhibit gamma-GTP present as an ectoenzyme. However, these periodate-treated cells in the presence of 10(-5) M dopa and glutathione have been found to continue to secrete large quantities of 5-S-CD in their medium. The large-granule fraction of Greene's melanotic melanoma contains substantial amounts of both tyrosinase and gamma-GTP. However, further separation of the large-granule fraction into sub-fractions indicates that tyrosinase and gamma-GTP seem to co-exist with premelanosome. It is suggested that glutathione-dependent t-S-CD genesis proceeds within premelanosomes through the formation of glutathione-dopa. The excess of glutathione-dopa and 5-S-CD, unutilized for pheomelanin formation overglow into the cytoplasm.
 ...
PMID:gamma-Glutamyl transpeptidase, tyrosinase, and 5-S-cysteinyldopa production in melanoma cells. 613 33

4-Tertiary butyl catechol (TBC) causes depigmentation in humans and animals and stimulates formation of pheomelanosomes. In this study, we investigated the effects of noncytotoxic doses of TBC on glutathione S-transferase (GST) activity in the skin of Uscd strain mice and B16 murine melanoma cells in culture, in relation to changes in activities of glutathione reductase (GR) and gamma-glutamyl transpeptidase (GGT) reported to be involved in pheomelanogenesis. Occurrence of pheomelanosomes in skin melanocytes was demonstrated by electron microscopy and reduction (25%) of eumelanin content in melanoma cells was shown by spectrophotometry. Topical application of 1 M TBC-DMSO-acetone solution on the ear skin elevated GST activity about 27%, and activities of GGT and GR to 35% and 19%, respectively, within 1 week. Melanoma cells cultured in 10(-4) M TBC-containing medium for 2 h showed no changes in GST and GGT activities, but 12% increase of GR activity during the first 12 h. Activities of all 3 enzymes was elevated (11-17%) 24 h later. The elevation detected by 48 h was 25% for GST, 26% for GGT, and 14% for GR. The findings were interpreted to show that depigmentation produced by the antioxidant results from stimulated pheomelanogenesis through activation of glutathione-metabolizing enzymes and suppressed oxidation of eumelanin intermediates.
 ...
PMID:Effects of 4-tertiary butyl catechol on glutathione-metabolizing enzymes in vivo and in vitro. 614 Feb 89

In a total of 1,828 determinations, urinary excretion of 5-S-Cysteinyldopa was studied over a period of three years in 384 patients treated for melanoma or with metastases of malignant melanoma. By serial investigations the excretion of 5-S-Cysteinyldopa was compared to the course of the disease. In the case of small and circumscribed metastases which could be eliminated by surgical treatment, the excretion of 5-S-Cysteinyldopa remained normal. When the disease became generalized, an increase of the urinary excretion of 5-S-Cysteinyldopa prior to the clinical manifestation of the metastases was observed in only four out of 26 cases. In the remaining cases, the increase of 5-S-Cysteinyldopa coincided with the manifestation of metastases, or the excretion of the substance became pathological when the metastases were already conspicuous. In five patients, the urinary excretion of 5-S-Cysteinyldopa remained normal inspite of widespread disease. Therefore, its diagnostic value seems to be similar to that of the "common" laboratory investigations the results of which are only pathological when the disease has already become generalized. Our investigations demonstrate that serial investigations of the urinary excretion of 5-S-Cysteinyldopa only rarely indicate melanoma metastases prior to their clinical manifestation. In cases of early metastasing melanoma, all common laboratory investigations are of limited value. BSR and GGT levels which become pathological very early in the course of the disease are so sensitive that slightly pathological levels may be ambiguous. In these cases, however, pathological levels of 5-S-Cysteinyldopa most probably will indicate a widespread disease.
 ...
PMID:[5-S-cysteinyldopa in the urine - a "tumor test" for malignant melanoma? Comparison with the usual laboratory examinations]. 678 80

We have shown previously that overexpression of p-170 glycoprotein-mediated multidrug resistance plays only a minor role in conferring chemoresistance to human melanoma cells. In addition to membrane transporters like p-170, metabolizing enzyme systems have been implicated in altered drug sensitivity. Recently, glutathione and associated enzymes have been associated with resistance to alkylating substances, particularly in gastrointestinal and gynecologic cancers. In this study, we investigated whether increased levels of glutathione and related enzymes may play a role in chemoresistance in melanoma. Levels of glutathione, glutathione S-transferase (GST), glutathione reductase, and gamma-glutamyl transpeptidase were analyzed in melanoma and non-melanoma cell lines. In addition, 18 melanoma metastases derived from skin and lymph nodes were examined. Levels of gamma-glutamyl transpeptidase were statistically different in cells derived from melanocytic tumors compared with non-melanoma cell lines and normal cells. In addition, GST levels in metastases derived from skin or lymph nodes were significantly lower than those in permanent cell lines. However, levels of glutathione and related enzymes in metastases and cell lines fluctuated over a wide range, up to 40-fold, regardless of treatment status or origin of metastases. In a second part of the study, the expression of GST isoenzymes alpha, mu, and pi was studied by immunohistology in 10 benign nevi, 29 primary melanomas, and 39 melanoma metastases before and during chemotherapy. Expression of GST isoenzymes was increased with tumor progression, and GST pi was the strongest isoform expressed. However, no correlation was found between GST levels by immunohistochemistry and the course of tumor progression, between GST levels in metastases obtained before or during chemotherapy, or between GST levels and clinical response. These data suggest that alterations in glutathione metabolism and the expression of GST do not play a major role in resistance to chemotherapeutic drugs in melanoma.
 ...
PMID:Glutathione and related enzymes in tumor progression and metastases of human melanoma. 761 63

gamma-L-glutaminyl-4-hydroxy-3-iodobenzene (I-GHB), a novel iodinated analog of gamma-L-glutaminyl-4-hydroxybenzene (GHB), demonstrates greater anti-tumor activity in human and in murine melanoma cell lines. These phenolic amides are substrates for gamma-glutamyltranspeptidase (GGTP; E.C. 2.3.2.2), a cell-membrane-associated ecto-enzyme which is elevated in a number of tumor systems. We now present data to show that the growth-inhibitory activity of I-GHB and GHB may be mediated via GGTP-catalyzed reactions. The growth-inhibitory activity of I-GHB and GHB in pigmented B16-BL6 melanoma cells was blocked significantly by rabbit anti-rat GGTP polyclonal antibodies. The combination of L-serine and sodium borate, a specific transition-state inhibitor of GGTP, as well as acivicin, a glutamine antagonist and irreversible GGTP inhibitor, inhibited the killing of BL6 cells by GHB and I-GHB. To further define the role of GGTP expression in the regulation of phenolic amide cytotoxicity, GGTP-negative Chinese hamster ovary cells (CHO-K1) were transfected with a functional rat renal cDNA representing the full-length GGTP transcript. I-GHB and GHB were significantly more cytotoxic in GGTP cDNA transfected Chinese hamster ovary (CHO-K1-GGTP) cells than in non-transfected CHO-K1 cells. The combination of L-serine and sodium borate blocked the cytotoxic activity of these pro-drugs and also inhibited GGTP-catalyzed formation of polymerized products from these phenolic amides in intact BL6 melanoma and CHO-K1-GGTP cells. Furthermore, melanin formation from GHB was not observed in non-transfected CHO-K1 cells lacking GGTP expression. The combined data strongly suggest that GGTP-catalyzed hydrolysis of the anti-tumor pro-drugs I-GHB and GHB to 4-aminophenols mediates the expression of antitumor activity.
 ...
PMID:Gamma-glutamyltranspeptidase expression regulates the growth-inhibitory activity of the anti-tumor prodrug gamma-L-glutaminyl-4-hydroxy-3-iodobenzene. 790 80


<< Previous 1 2 3 4 5 6 7 Next >>