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)

The aim of this study was to examine antitumorigenic Cis DDP properties in metastatic brain tumors. Thirty-four untreated patients with brain metastases recorded by CAT scans or radionuclide scans plus neurological examinations underwent the treatment. Pathohistology of primary tumors mainly showed breast [8] and lung [8] carcinomas and melanomas [10]. Other localizations of primary tumors were infrequent. Cis DDP was administered in doses of 30 mg/m2 body surface daily over 4 days. All the patients received at least two cycles and 33 have been evaluated. No corticosteroids were administered concurrently. An objective response (seven complete and seven partial remissions) was observed in 14 out of 33 patients (42%). Six stable disease cases were also noted. A complete response (5-14 months) was observed in breast cancer [4], lung cancer [1], and melanoma [2]. Seven partial responses lasted 2-5 months. Antitumorigenic activity of Cis DDP was also noted in extracerebral tumor lesions, especially in breast cancer patients. Toxicity was moderate but tolerable. The results of this study have shown Cis DDP to possess antitumorigenic properties also in patients with metastatic brain tumors, a point that has not been proved so far.
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PMID:Phase II clinical trial of cis dichlorodiammine platinum (Cis DDP) in metastatic brain tumors. 676 44

Tyrosinase in a melanosome is known to be inactivated during melanin formation in vivo, and a similar inactivation was observed in vitro when melanosomes isolated from Harding Passey mouse melanoma were incubated with dopa. Tyrosinase, whether particle bound or in soluble form, was inactivated during the dopa-tyrosinase reaction and the reduction rate of its activity was proportional to the reaction time. Tyrosinase inactivation also occurred when ascorbic acid was added to the reaction system; in which dopaquinone, an oxidation product of dopa which is immediately converted back to dopa by ascorbic acid thus preventing melanin formation. When 14C-dopa or 14C-ascorbic acid were added to the reaction mixture, these radioactive substances were not recovered from the inactivated enzyme protein fraction after incubation. In addition this inactivation of tyrosinase by dopa was not inhibited by any of: 1.4-diazabicyclo[2.2.2]octane, scavenger for singlet oxygen; D-mannitol, that for hydroxyl radical; superoxide dismutase, that for superoxide anion; and catalase, cleavaging enzyme for hydrogen peroxide. Thus the inactivation of tyrosinase appears to be due to neither these radicals, nor reaction products from dopa or ascorbic acid, but to changes in the enzyme itself.
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PMID:Inactivation of tyrosinase by dopa. 677 5

Six of eight human melanoma lines showed increased sensitivity to killing by dopa and by ascorbate:copper compared with two fibroblast strains and four other human cell lines of nonmelanoma origin. Catechol, epinephrine, and alpha-methyldopa, but not 5,6-dihydroxyindole, exhibited a similar degree of selectivity. Toxicity was greatly reduced when brief exposure times or high cell densities were used. Depending upon culture conditions, melanoma cells accumulated more [3H]dopa- and [14C]ascorbate-derived isotopic label within the first five min than fibroblasts, but after one hr this difference was less marked. The catalase activity in melanoma cells was not less than that in fibroblasts. Using two independent methods to determine each type of damage, dopa and ascorbate:copper were found to induce DNA breaks in both cell types but not DNA repair synthesis or DNA interstrand cross-links. More DNA breaks were found in melanoma cells (two lines) than in fibroblasts. Semiconservative DNA synthesis was inhibited immediately, recovered within six hr, and in melanoma cells, was again inhibited after 24 hr. RNA synthesis was inhibited less than DNA synthesis. Human cell lines with differential sensitivity to gamma-radiation, ultraviolet light, cross-linking agents, or monofunctional alkylating agents, exhibited normal survival levels when treated with dopa or ascorbate:copper.
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PMID:DNA damage and selective toxicity of dopa and ascorbate:copper in human melanoma cells. 680 13

Advanced human malignant melanoma continues to be an intractable tumor unresponsive to most forms of therapy. We have been engaged in the design of selective agents for the chemotherapy of malignant melanoma based on the unique biochemical features within this tumor. Several analogues have been prepared with significant antitumor activity against experimental melanoma models, and these include levodopa, dopamine, and the nonneurotoxic analogue 3,4-dihydroxybenzylamine. Pending the clinical availability of the improved analogues, we have investigated the effects of levodopa and dopamine on advanced human malignant melanoma. Dopamine has been shown to cause a significant biochemical inhibition of tumor in 4 patients treated, but cardiovascular effects have precluded its repetitive use. The combination of levodopa/carbidopa has been used in an attempt to circumvent these toxicities as well as deliver drug to the central nervous system (CNS). Of 12 patients treated to date, 8 are evaluable, and there have been 4 significant clinical responses. Importantly, the plasma levels achievable with levodopa are in tumoricidal range as predicted by in vivo assays (10(-5) M). One patient had a complete resolution of a CNS lesion as measured by CAT scan and a corresponding improvement in symptoms. Pending the availability of improved analogues, further study of the use of levodopa/carbidopa as therapy for malignant melanoma in humans appears warranted, and different methods of delivery, either alone or in combination with conventional agents, will be explored.
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PMID:The chemotherapy of malignant melanoma. 685 56

In spite of pharmacokinetic studies, which have shown that only cis-DDP traces are found in brain tissue, cytotoxic activity of this drug in primary brain tumors has recently been reported. The purpose of our study was to examine whether cis-DDP aslo has antitumor properties in metastatic brain tumors. Twelve consecutive untreated patients with brain metastases recorded by CAT scans or radionuclide scans plus neurologic examinations underwent the treatment. Histology of primaries revealed 4 bronchial, 3 breast, 1 gastric, 2 colorectal carcinoma, 2 melanomas, and 1 soft tissue sarcoma. Cis-DDP was administered at the doses of 30 mg/m2 body surface daily for 4 days. All the patients were evaluated. Objective response (3 complete and 2 partial remissions) was observed in 5 of 12 patients (response rate 42%). Three stable disease cases were also noted; however, in the remaining 4 patients the disease in the brain progressed. Complete response (5 months) was observed in a breast cancer patient, in a melanoma (4+ months), and in a microcellular bronchial cancer (2+ months). Two partial responses (lung, breast) lasted 2+ and 2+ months. Toxicity was moderate but tolerable for the patients. The preliminary results of this study show that cis-DDP possesses antitumorigenic properties also in patients with metastatic brain tumors, which has not been proved till now.
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PMID:Preliminary report on antitumorigenic activity of cis-dichlorodiamine platinum in metastatic brain tumors. 719 35

Cachexia is rare in nude mice bearing human malignant tumors even when the transplanted tumors become as large as the body size of the host. In our series on heterotransplantation of a variety of human malignant tumors into nude mice, a malignant melanoma (SEKI) was found to induce severe body weight loss in the host at the early stage of transplantation. There was no electrolyte disturbance, hyper- or hypoadrenocorticism, hyperthyroidism, or destruction of cells of vital organs to account for the weight loss. Moreover, no evidence was obtained for concomitant infection with bacteria, Mycoplasma or fungi. These cachectic mice revealed remarkably increased levels of serum sialyltransferase and decreased liver catalase activity. The removal of tumor tissues from these mice resulted in prompt recovery of body weight, serum sialyltransferase, and liver catalase activity within 1 to 2 weeks. On the basis of the results obtained, the SEKI melanoma was thought to have produced a pathophysiological state in host nude mice which was very similar to that of cachexia in cancer patients. Nude mice bearing transplants of SEKI melanoma may provide a useful system for the study of cancer cachexia in humans.
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PMID:Serum sialyltransferase and liver catalase activity in cachectic nude mice bearing a human malignant melanoma. 724 51

Recent studies have demonstrated that preincubation of SK-Mel-28 melanoma cells with ferric ammonium citrate (FAC) resulted in marked stimulation of 59Fe uptake from 59Fe-125I-transferrin (Tf), but only at Tf concentrations above that required for saturation of the Tf receptor (Richardson and Baker (1992) J. Biol. Chem. 267, 13972-13979). The mechanism responsible for this stimulation was unknown and is the subject of the present report. Preincubation of cells with FAC (25 micrograms/ml), followed by a 2 h incubation with 59Fe-125I-Tf (0.1 mg/ml; 1.25 microM), resulted in temperature-dependent 59Fe uptake to approx. 200% of the control value. Furthermore, the effect was not specific for melanoma cells and was also observed in other normal and neoplastic cells. Preincubation of melanoma cells with FAC also stimulated 59Fe uptake from 59Fe-citrate, but to a far greater extent than that observed with 59Fe-125I-Tf (viz., > 20-fold that seen for the control). Interestingly, neither receptor-mediated endocytosis nor the postulated diferric Tf reductase were involved in the FAC-activated Fe uptake process from Tf. However, the addition of free radical scavengers to FAC such as catalase, superoxide dismutase, ceruloplasmin, Hepes, mannitol and high concentrations of BSA or ascorbate, markedly depressed FAC-activated 59Fe uptake from 59Fe-125I-Tf and 59Fe-citrate. These agents when added to control cells had no effect on 59Fe uptake. The addition of superoxide generating agents and hydrogen peroxide to minimum essential medium (MEM) containing FAC but not to MEM alone, also stimulated 59Fe uptake. These data suggest that the initial activation of the FAC-stimulated Fe uptake system was caused by the production of hydroxyl radicals via the Fe-catalysed Haber-Weiss reaction. We propose that this Fe uptake process represents an important cellular defense mechanism against oxidant stress generated in the presence of low-molecular-weight Fe complexes.
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PMID:Identification of a mechanism of iron uptake by cells which is stimulated by hydroxyl radicals generated via the iron-catalysed Haber-Weiss reaction. 748 42

Peptides of melanosomal proteins have recently been shown to be recognized in an HLA-restricted mode by specific cytolytic T lymphocytes in melanoma patients. Dendritic antigen-presenting cells (DC) are considered to be the most effective stimulators of T cell responses, and the use of these cells has therefore been proposed to generate therapeutic responses to tumor antigens in cancer patients. We, therefore, generated DC from peripheral blood of normal donors in the presence of granulocyte/macrophage colony-stimulating factor and interleukin-4. Flow cytometric analysis of the cells during a 2-week culture revealed a loss of CD14 and CD34 expression, a concomittent increase of CD1a, CD11a,b and c, CD44, CD45, CD54, HLA-class I and II, and intermediate levels of CD26, CD80 and CD86. Cultured DC stimulated proliferation of allogeneic T cells and induced a marked, up to 20-fold, stimulation of T cell proliferation after pulsing with tetanus toxoid. To achieve independence of already-identified antigenic peptides presented in HLA class I-restricted fashion, which limits the general applicability of such peptides for vaccination of melanoma patients, we tested whether DC are transfectable with eukaryotic expression plasmids. DC transfected with two reporter genes (CAT, beta-galactosidase) using a liposome-based transfection technique, exhibited only low levels of enzymatically active proteins, but were able to degrade rapidly intracellular proteins and to process peptides efficiently. Chloramphenicol acetyltransferase as well as tyrosinase mRNA were detectable after transfection by reverse-transcriptase-polymerase chain reaction, and enzyme activities became measurable. Furthermore, DC transfected with the tyrosinase gene were able to induce specific T cell activation in vitro, indicating appropriate peptide processing and presentation in DC after transfection. These data suggest new approaches to future tumor vaccination strategies.
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PMID:Dendritic cells generated from peripheral blood transfected with human tyrosinase induce specific T cell activation. 748 49

X-rays were used to induce melanin biosynthesis in brown and black guinea pigs in vivo. During the course of pigmentation, the expression of thioredoxin reductase was increased, whereas for the other antioxidant enzymes, superoxide dismutase (cytosol Cu/Zn-enzyme), catalase, and glutathione reductase, levels and activities decreased. Isobutylmethylxanthine induced eumelanin biosynthesis in murine melanoma cells (Cloudman S-91). In these cells, thioredoxin reductase levels coincided with melanogenesis. Our results suggest that both tyrosinase and thioredoxin reductase respond to oxidative stress in the epidermis as well as in melanoma cells and react with superoxide anion radicals to stimulate melanogenesis and to prevent peroxidative damage, respectively.
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PMID:Thioredoxin reductase induction coincides with melanin biosynthesis in brown and black guinea pigs and in murine melanoma cells. 752 41

To identify the so-called toxohormone, which is a tumor-derived factor with activity to induce cancer cachexia syndrome in tumor-bearing animals, 5 human cancer cell lines with this activity were studied for cytokine production. Tumor cell products with activity to inhibit lipoprotein lipase (LPL) were shown to play an important role in the development of the cancer cachexia syndrome. All culture media conditioned by the 5 cell lines possessed LPL-inhibitory activity. However, the activity differed with the cell line. In order to characterize the activity, we examined whether the cultured cells produced cytokines with activity to inhibit LPL. A melanoma cell line, SEKI, and a neuroepithelioma cell line, NAGAI, were found to express a large amount of leukemia inhibitory factor (LIF) mRNA. Furthermore, both of these cell lines were demonstrated to produce a large amount of LIF protein, and plasma levels of LIF were extremely elevated in SEKI- and NAGAI-bearing nude mice, indicating that LIF produced by the tumor cells induced cancer cachexia syndrome in the animals. Thus, LIF fulfills the requirements for a toxohormone, except for suppressive activity on liver catalase. In contrast, the mechanisms responsible for cachexia in the MKN-1-, LX-1- and LS180-bearing mice remain unknown. These findings suggest that various types of bioactive substances produced by cancer cells could be toxohormones.
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PMID:Cytokine production in five tumor cell lines with activity to induce cancer cachexia syndrome in nude mice. 762 21


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