Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Temozolomide (Temodar) has demonstrated clinical activity against melanoma equivalent to that of intravenous dacarbazine (DTIC). Phase I clinical studies have shown that low dose chronic administration of temozolomide permits the delivery of higher dose intensities than a 5 day dose schedule. Temozolomide is hydrolysed to its active metabolite monomethyltriazenoimidazole carboxamide (MTIC) upon absorption from the gastrointestinal tract, while DTIC is inactive until it is metabolized in the liver to MTIC. In view of this, a higher concentration of MTIC will pass through the liver during the first pass when its source is temozolomide rather than DTIC. To determine if these characteristics of temozolomide will translate into a higher response rate than that achieved with DTIC, we conducted a phase II clinical trial of temozolomide in patients with uveal melanoma metastatic to the liver. Temozolomide was administered orally at a starting dose of 75 mg/m2 per day for 21 days every 4 weeks. Fourteen patients were enrolled in the trial. No complete or partial responses were observed. Stabilization of disease was achieved in two patients. The treatments were well tolerated. We conclude that, like DTIC, temozolomide at the dose and schedule studied in this trial is not effective for the control of metastatic melanoma of uveal origin.
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PMID:Phase II evaluation of temozolomide in metastatic choroidal melanoma. 1277 87

The incidence of cutaneous malignant melanoma in the United States has increased more than any other cancer in recent years. Chemotherapy for metastatic melanoma is disappointing, there being anecdotal cases of complete remission. Dacarbazine (DTIC) is considered the gold standard for treatment, having a response rate of 15-20%, but most responses are not sustained. The mechanisms for the increased chemotherapeutic resistance of melanoma are unclear. The objective of this study was to determine the mechanisms by which melanoma cells escape the cytotoxic effect of DTIC. Here, we show that DTIC induced interleukin (IL)-8 and vascular endothelial growth factor (VEGF) protein overexpression and secretion via transcriptional up-regulation in the two melanoma cell lines SB-2 and MeWo. Luciferase activity driven by the IL-8 and VEGF promoters was up-regulated by 1.5-2- and 1.6-3.5-fold, respectively, in the SB2 and MeWo melanoma cell lines. The mitogen-activated protein kinase signal transduction pathway seemed to regulate at least partially the activation of IL-8, whereas it was not involved in VEGF promoter regulation. Electrophoretic mobility shift analysis analyses have revealed an increase in binding activity of activator protein 1 (c-Jun) and nuclear factor-kappaB after DTIC treatment for both melanoma cell lines. Metastatic melanoma cell lines secreting high levels of IL-8 and VEGF were more resistant to DTIC than early primary melanomas secreting low levels of the cytokines. In addition, transfection of the primary cutaneous melanoma SB-2 cells with the IL-8 gene rendered them resistant to the cytotoxic effect of the drug, whereas the addition of IL-8-neutralizing antibody to metastatic melanoma cells lowered their sensitivity to DTIC. Taken together, our data demonstrate that DTIC can cause melanoma cells to secrete IL-8 and VEGF, which might render them resistant to the cytotoxic effects of the drug. We propose that combination treatment with anti-VEGF/IL-8 agents may potentiate the therapeutic effects of DTIC.
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PMID:Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. 1502 59

In a retrospective study, O(6)-methylguanine-DNA-methyltransferase (MGMT) expression was analysed by immunohistochemistry using monoclonal human anti-MGMT antibody in melanoma metastases in patients receiving dacarbazine (DTIC) as single-drug therapy or as part of combination chemotherapy with DTIC-vindesine or DTIC-vindesine-cisplatin. The correlation of MGMT expression levels with clinical response to chemotherapy was investigated in 79 patients with metastatic melanoma. There was an inverse relationship between MGMT expression and clinical response to DTIC-based chemotherapy (P=0.05). Polymorphisms in the coding region of the MGMT gene were also investigated in tumours from 52 melanoma patients by PCR/SSCP and nucleotide sequence analyses. Single-nucleotide polymorphisms (SNPs) in exon 3 (L53L and L84F) and in exon 5 (I143V/K178R) were identified. There were no differences in the frequencies of these polymorphisms between these melanoma patients and patients with familial melanoma or healthy Swedish individuals. Functional analysis of variants MGMT-I143V and -I143V/K178R was performed by in vitro mutagenesis in Escherichia coli. There was no evidence that these variants decreased the MGMT DNA repair activity compared to the wild-type protein. All melanoma patients with the MGMT 53/84 polymorphism except one had tumours with high MGMT expression. There was no significant correlation between any of the MGMT polymorphisms and clinical response to chemotherapy, although an indication of a lower response rate in patients with SNPs in exon 5 was obtained. Thus, MGMT expression appears to be more related to response to chemotherapy than MGMT polymorphisms in patients with metastatic melanoma.
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PMID:O6-methylguanine-DNA-methyltransferase expression and gene polymorphisms in relation to chemotherapeutic response in metastatic melanoma. 1456 26

Health-related quality of life (HRQL) is a crucial endpoint in the evaluation of treatments that have limited survival benefits. The HRQL evaluations help ensure that patients are not sacrificing life quality for quantity. Current treatments for metastatic melanoma are primarily palliative, because cure is unattainable. The purpose of this article is to report detailed HRQL results of a phase III clinical trial comparing temozolomide to dacarbazine (DTIC) in patients with metastatic melanoma. Patients were randomized to receive either oral temozolomide for 5 days every 4 weeks or intravenous DTIC for 5 days every 3 weeks. The HRQL was evaluated on day 1 cycle 1 and after each subsequent treatment cycle using the EORTC QLQ-C-30. The HRQL was compared between groups at weeks 12 and 24. Patients treated with temozolomide reported significantly better physical functioning and less fatigue and sleep disturbances than patients treated with DTIC at week 12. For all but two function and symptom subscales, EORTC QLQ-C30 subscale scores were numerically better for patients treated with temozolomide at week 12. All subscales except diarrhea were better for temozolomide at week 24. Analyses of change scores revealed that patients treated with temozolomide reported statistically significant improvements in emotional well-being and sleep disturbance. Patients also reported near significant change in cognitive functioning (3.9, p = 0.06). Patients treated with DTIC deteriorated on most function subscales and many symptom subscales at week 12. Deterioration in physical functioning approached significance (-6.8, p = 0.06). At week 24, patients treated with DTIC improved on the emotional functioning subscale and deteriorated on the physical, role, and global HRQL subscales, although many of the symptom scores improved. The results of this study suggest that treatment with temozolomide leads to important functional improvements and decreased symptoms compared to treatment with DTIC in patients being treated for metastatic melanoma.
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PMID:Health-related quality of life in patients with advanced metastatic melanoma: results of a randomized phase III study comparing temozolomide with dacarbazine. 1473 85

The management of patients with metastatic malignant melanoma remains difficult. Conventional chemotherapy has been disappointingly ineffective. Dacarbazine (DTIC) is considered to be one of the most active single agents with a response rate of approximately 15-20%. Many patients who initially respond to treatment subsequently relapse. Clearly, there is a need for improvement, and the evaluation of new agents is warranted. This article reviews current phase II studies of single-agent taxanes and their combinations in patients with metastatic melanoma, and examines the likely impact of taxanes on treatment strategies. Response rates from phase II trials with single-agent taxanes vary from 3.3% to 17%. Prolonged durations of disease control are observed. Combinations of taxanes with DTIC, temozolomide, cisplatin, carboplatin and tamoxifen have demonstrated response rates from 12% to 41%, suggesting that they are at least as effective as various other combination regimens. Encouraging results have been produced in the second-line metastatic setting. Taxanes, both as single agents and in combinations, may be a treatment option for some patients with metastatic melanoma, especially in the second-line setting.
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PMID:The role of taxanes in the treatment of metastatic melanoma. 1545 99

This study was conducted to investigate the serum levels of bcl-2 and survivin in patients with melanoma and the relationship with tumour progression and known prognostic parameters. Forty-four patients with cutaneous melanoma were investigated. Serum samples were obtained on first admission before adjuvant and metastatic treatment were given and at follow-up. Serum bcl-2 and survivin levels were determined using enzyme immunometric assay (EIA) and enzyme-linked immunosorbent assay (ELISA). The baseline serum bcl-2 levels were significantly higher in patients with melanoma than in the control group (P=0.01). For the serum survivin levels, no difference was found (P=0.6). No significant correlations were found between the prognostic parameters analysed and the serum survivin concentrations. The same was true of the serum bcl-2 values, except for the age of the patient (P=0.025) and nodal involvement (P=0.003). No significant relationship was found between the serum levels of bcl-2 and survivin (r=-0.13, P=0.4). In node-positive patients (n=8) both of these anti-apoptotic substances were unchanged after interferon-alpha-2b therapy. However, serum survivin concentrations were significantly increased in 10 patients with metastatic melanoma who underwent dacarbazine (DTIC)-based cytotoxic chemotherapy (P=0.047). A similar finding was not determined for the serum bcl-2 levels. In conclusion, the results of this study suggest that decreased apoptosis is associated partly with an increase in serum bcl-2. However, much research continues in this field, and exciting new knowledge will ultimately emerge.
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PMID:Serum bcl-2 and survivin levels in melanoma. 1557 28

Except for high-dose interferon as adjuvant therapy in stage III disease, little success has emerged over the last 20 years for metastatic melanoma. Recent advances in melanoma biology suggest that disarming oncogenic mechanisms in melanoma may be an attractive approach to therapy. For instance, sustained expression of Bcl2 has been associated with an increased resistance to apoptosis, and recently, anti-sense-mediated reduction of Bcl2 levels was shown to chemosensitize patients to dacarbazine, dimethyl triazino imidazole carboxomide, or DTIC. Likewise, the identification of activating mutations in the RAS signaling pathway, including the NRAS and BRAF genes, opens up new therapeutic options for RAS and RAF inhibitors. A more thorough understanding of melanoma biology and tumor immunology will undoubtedly yield new promise for patients with advanced disease.
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PMID:Melanoma treatment update. 1583 58

This study compares the antineoplastic potential of a novel treatment strategy combining cell cycle inhibitor-779 (CCI-779) plus dacarbazine (DTIC) versus DTIC monotreatment, the current chemotherapeutic mainstay in combating metastatic melanoma. A controlled four-group parallel study design comprising 24-40 mice per tumor cell line was used in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model. SCID mice were injected with 518A2, Mel-JUSO, or 607B human melanoma cells. After they developed tumors, mice received daily CCI-779 or solvent over 14 days. From treatment day 4-8 mice were additionally injected with DTIC or saline. Treatment with CCI-779 plus DTIC was superior to single agent DTIC in two out of three cell lines (P<0.05). The tumor weight reduction was 44+/-17 and 61+/-6% compared with DTIC monotreatment in Mel-JUSO and 607B melanomas, respectively (P<0.05). In contrast, in 518A2 xenotransplants, CCI-779 plus DTIC treatment was as effective as DTIC monotreatment. CCI-779 monotherapy exerted no statistically significant antitumor effect. Collectively, these data indicate that CCI-779 has the potential to increase the chemotherapeutic efficacy, as the combination of CCI-779 plus DTIC proved to be more efficacious compared to DTIC monotherapy in two out of three melanoma cell lines in vivo.
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PMID:Comparison of a treatment strategy combining CCI-779 plus DTIC versus DTIC monotreatment in human melanoma in SCID mice. 1750 24

Numerous preclinical and clinical studies have shown that interleukin-2 (IL-2) induces regression of metastatic tumors. We have conducted a phase I/II, multicenter, open-label, dose-escalating study to evaluate the safety, efficacy, and biological effects of repeated intratumoral injections of adenovirus-IL-2 (TG1024) in patients with advanced solid tumors and melanoma. Thirty five patients (twenty-five with metastatic melanoma and ten with other solid tumors) were treated in eight successive cohorts at dose levels ranging from 3 x 10(8) to 3 x 10(11) viral particles (vp). Intratumoral TG1024 injections in combination with dacarbazine (DTIC) were tested in metastatic melanoma in one cohort. No clinical responses were observed at doses below 3 x 10(11) vp. Six local objective responses were recorded in patients receiving 3 x 10(11) vp per treatment [five in metastatic melanoma and one in metastatic squamous cell carcinoma (SCC) of the skin], of which two were complete responses (CRs). Most of the common side effects were injection site reactions and flu-like syndrome. TG1024 dose intensification across cohorts resulted in increased serum IL-2 levels after the injection. Intratumoral TG1024 injection induced pronounced inflammation of the treated lesion, with predominant CD8(+), TIA+ lymphocytic infiltrate. Our results show that intratumoral injections of TG1024 are safe and well tolerated. The clinical activity of TG1024 observed in this study warrants further investigations.
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PMID:Intralesional adenovirus-mediated interleukin-2 gene transfer for advanced solid cancers and melanoma. 1838 30

In advanced metastatic melanoma (AJCC stage IV), the prognosis is still poor, and views differ on the appropriate systemic treatment for these patients. Therefore, new approaches in therapeutic regimens are mandatory. Sorafenib is an oral multikinase inhibitor that targets 2 classes of kinases which are known to be involved in both tumor proliferation and angiogenesis. These kinases include Raf kinases and the vascular endothelial growth factor (VEGF) receptor. Sorafenib has been evaluated as a single therapy agent as well as in combination with various chemotherapeutical drugs in a number of clinical trials. The vast majority of clinical data exists for patients with advanced renal cell cancer for which sorafenib has been approved by the FDA and EMEA. Very recently, sorafenib was approved for advanced hepatocellular cancers due to its overall survival improvement. Since B-raf gene mutations have been found in 69% of melanoma cell lines, sorafenib was brought into various phase I/II and phase III trials in metastatic melanoma. However, as a single-agent therapy, sorafenib seems to be of limited use. Also, the combination of sorafenib with the chemotherapeutic agents carboplatin and paclitaxel has failed to show superiority in progression-free and overall survival compared to the same chemoregimen plus an oral placebo in a phase III trial (PRISM study). More promising data were observed in large-sized phase II studies on dacarbazine (DTIC) plus sorafenib and temozolomide plus sorafenib. However, these data need to be confirmed in prospective randomized phase III trials. Till then, sorafenib remains an interesting but still experimental new agent for melanoma.
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PMID:Metastatic melanoma: scientific rationale for sorafenib treatment and clinical results. 1859 89


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