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

We aimed to evaluate a concurrent chemobiotherapy (CBT) regimen consisting of cisplatin (CDDP), dacarbazine (DTIC), decrescendo interleukin-2 (IL-2), and interferon alpha2b (INF-alpha2b), in metastatic melanoma patients. A total of 60 patients with biopsy proven, metastatic melanoma were treated between October 2000 and November 2005 at the Oncology Institutes of RMC and CSMC. Patients received concurrent CBT for 5 days, consisting of CDDP, DTIC, decrescendo IL-2, and subcutaneous INF-alpha2b. GM-CSF was given subcutaneously on days 8 to 12 of each cycle, to the first 26 patients. Treatment was administered q21d for a total of six cycles or until severe toxicity or progression; 57 patients who received at least two cycles, followed for at least 24 months, were included in response analysis. The overall response rate (RR) reached 44% (28/57 patients); 14 patients had a complete response (CR, 25%); 11 (19%) reached a partial response. The median progression-free survival was 7 months. Median overall survival (OS) was 11.7 months. At a median follow-up of 29 months, 8 of 14 complete responders remain alive for more than two years, with no clinical evidence of disease. Median OS of patients with CR has not been reached; 17% of the courses were modified due to toxicity, and 20% of the patients were removed from the protocol due to toxicity or refusal to continue. The data from this study indicate that this protocol of concomitant CBT is feasible with a fraction of the patients achieving a durable CR.
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PMID:Concurrent chemobiotherapy with cisplatin, dacarbazine, decrescendo interleukin-2 and interferon alpha2b in patients with metastatic melanoma. 1902 Jul 38

Delimotecan (MEN 4901/T-0128) is a new cytotoxic prodrug constituted by a camptothecin analog (T-2513) bound to carboxymethyl dextran through a triglycine linker. A significant antitumor activity of delimotecan against human metastatic melanoma xenograft model Me15392 is reported. Dacarbazine, the drug approved for the treatment of metastatic melanoma, was ineffective in this melanoma model. Pharmacokinetic studies, together with the expression analysis of mRNA for enzymes involved in delimotecan metabolism, showed that T-2513 and other cytotoxic metabolites of delimotecan (SN 38 and T-0055) are generated in greater quantities in the tumor tissue than in toxicity target tissues, such as liver, thus accounting for the antitumoral activity. Moreover, we demonstrated that human metastatic melanoma cells are able to phagocytose delimotecan and cleave it to release the cytotoxic moieties T-2513 in the tumoral environment. Further flow cytometric analysis showed a higher recruitment of macrophages in xenografted human metastatic melanoma, when compared with other human tumors. Thus, the antitumoral activity of delimotecan exerted on metastatic melanoma is due to several factors: (i) the ability of melanoma cells to phagocytose and metabolise delimotecan; (ii) the accumulation of delimotecan in tumoral mass; (iii) the recruitment of macrophage cells to the melanoma nodule and (iv) the expression in melanoma cells of a pattern of enzymes that converts delimotecan into cytotoxic metabolites. Based on these results, delimotecan might be exploited as a new anticancer agent for the therapy of metastatic melanoma because of its high efficacy and good selectivity, and therefore clinical trials for this indication are warranted.
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PMID:Antitumor activity of delimotecan against human metastatic melanoma: pharmacokinetics and molecular determinants. 1953 74

The successful management of advanced melanoma remains an unmet need because of a resolutely poor prognosis and therapeutic options with limited effectiveness. Dacarbazine and fotemustine are the only approved chemotherapeutic agents for advanced melanoma, yet neither alone or in combination regimens has been shown to extend survival in randomized clinical trials. The only agent to be approved for advanced melanoma in the US in more than 30 years is high-dose bolus interleukin-2, but its use is associated with high toxicity and cost, and it has also failed to show a survival benefit. Our expanding knowledge of the complex factors and pathways regulating immune function has led to the advent of novel immunotherapeutic agents. Among these are ipilimumab and tremelimumab - fully human, monoclonal antibodies directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4). The pivotal role of CTLA-4 in regulating T-cell function is established, and a series of preclinical studies provided proof-of-concept evidence of the antitumor activity of anti-CLTA-4 antibodies in combination with vaccines or chemotherapy. Subsequently, anti-CTLA-4 antibodies have shown encouraging results in clinical trials in advanced melanoma. Recent progress in the understanding of melanoma genetics and tumorigenesis has led to potential new therapeutic targets. Molecular targeted agents that inhibit the proliferation and survival of metastatic melanoma cells offer potential partners for anti-CTLA-4 antibodies in combined modality regimens. Novel combinations are reviewed in the context of creating an immunosupportive environment in the host.
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PMID:Novel immunotherapies as potential therapeutic partners for traditional or targeted agents: cytotoxic T-lymphocyte antigen-4 blockade in advanced melanoma. 1995 52

Metastatic melanomas are hypervascular tumours with poor prognosis. We hypothesized that treatment of metastatic melanoma with a combination of bevacizumab, a monoclonal antibody against vascular endothelial growth factor, dacarbazine (DTIC) and low-dose interferon alpha-2a (IFN-alpha2a) might lead to a synergistic inhibition of angiogenesis and regression of tumours. Patients with metastatic melanoma were treated with bevacizumab (5 mg/kg every 2 weeks), DTIC (200 mg/m days 1-5 every 4 weeks) and IFN-alpha2a (three MIU subcutaneously daily from day 15 onwards). Patients exhibiting response or stable disease after 6 months were treated with bevacizumab+/-IFN-alpha2a until disease progression. The primary study objectives were progression-free survival (PFS), overall survival and safety. Twenty-six patients were accrued. Response rate was 23% (two complete responses, four partial responses), and six patients showed stable disease. The median PFS for all patients was 2.3 months and for responders 8.1 months. The median overall survival for all patients was 11.5 months. Four life-threatening adverse events were seen: two pulmonary thromboembolisms, an intracerebral haemorrhage, and one grade 4 hypertension. One of the pulmonary emboli and the intracerebral haemorrhage were observed > or =3 months after the last bevacizumab-DTIC dose. Serum matrix metalloproteinase-9 and vascular endothelial growth factor levels changed during therapy. There was a trend towards favourable PFS among patients with only minimal or moderate change in these marker expression levels. The present regimen was active in this patient group but was also associated with remarkable vascular events.
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PMID:A phase II trial of bevacizumab with dacarbazine and daily low-dose interferon-alpha2a as first line treatment in metastatic melanoma. 2037 44

Metastatic melanoma responds poorly to systemic treatment. We report the results of a prospective single institution study evaluating O(6)-methylguanine-DNA methyltransferase (MGMT) status as a potential predictive and/or prognostic marker among patients treated with dacarbazine (DTIC) 800-1000 mg/m(2) monotherapy administered as a 3-weekly schedule for advanced malignant melanomas. The study was approved by the Regional Ethical Committee. Surgical biopsies from metastatic or loco-regional deposits obtained prior to DTIC treatment were snap-frozen immediately upon removal and stored in liquid nitrogen up to processing. Median time from enrolment to end of follow-up was 67 months. MGMT expression levels evaluated by qRT-PCR correlated significantly to DTIC benefit (CR/PR/SD; p=0.005), time to progression (TTP) (p=0.005) and overall survival (OS) (p=0.003). MGMT expression also correlated to Breslow thickness in the primary tumour (p=0.014). While MGMT promoter hypermethylation correlated to MGMT expression, MGMT promoter hypermethylation did not correlate to treatment benefit, TTP or OS, suggesting that other factors may be critical in determining MGMT expression levels in melanomas. In a Cox proportional regression analysis, serum lactate dehydrogenase (LDH, p<0.001), MGMT expression (p=0.022) and p16(INK4a) expression (p=0.037) independently predicted OS, while TTP correlated to DTIC benefit after 6 weeks only (p=0.001). Our data reveal MGMT expression levels to be associated with disease stabilisation and prognosis in patients receiving DTIC monotherapy for advanced melanoma. The role of MGMT expression as a predictor to DTIC sensitivity versus a general prognostic factor in advanced melanomas warrants further evaluation.
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PMID:MGMT expression levels predict disease stabilisation, progression-free and overall survival in patients with advanced melanomas treated with DTIC. 2054 96

Metastatic melanoma is an aggressive cancer with very low response rate against conventional chemotherapeutic agents such as dacarbazine (DTIC). Inhibitor of Rb-Raf-1 interaction RRD-251 was tested against the melanoma cell lines SK-MEL-28, SK-MEL-5, and SK-MEL-2. RRD-251 was found to be a potent inhibitor of melanoma cell proliferation, irrespective of V600E B-Raf mutation status of the cell lines. In a SK-MEL-28 xenograft experiment, RRD-251 exerted a significant suppression of tumor growth compared with vehicle (P = 0.003). Similar to in vitro effects, tumors from RRD-251-treated animals showed decreased Rb-Raf-1 interaction in vivo. Growth suppressive effects of RRD-251 were associated with induction of apoptosis as well as a G(1) arrest, with an accompanying decrease in S-phase cells. RRD-251 inhibited Rb phosphorylation and downregulated E2F1 protein levels in these cells. Real-time PCR analysis showed that RRD-251 caused downregulation of cell-cycle regulatory genes thymidylate synthase (TS) and cdc6 as well as the antiapoptotic gene Mcl-1. Combinatorial treatment of RRD-251 and DTIC resulted in a significantly higher apoptosis in DTIC resistant cell lines SK-MEL-28 and SK-MEL-5, as revealed by increased caspase-3 activity and PARP cleavage. Because aberrant Rb/E2F pathway is associated with melanoma progression and resistance to apoptosis, these results suggest that the Rb-Raf-1 inhibitor could be an effective agent for melanoma treatment, either alone or in combination with DTIC.
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PMID:Rb-Raf-1 interaction disruptor RRD-251 induces apoptosis in metastatic melanoma cells and synergizes with dacarbazine. 2113 44

Metastatic melanoma is a very aggressive cancer. Dacarbazine has been considered as the standard therapy for decades. Due to a better understanding of melanoma cells signalling and immunological response, new targeted therapies are now proposed. The efficency of these new drugs needs to be confirmed by on larger clinical trials. Ipilimumab (anti-CTLA4 monoclonal antibody) and V600-E-B-raf inhibitor have shown encouraging results, while c-KIT and MEK inhibitors are currently under evaluation. These recently published data shed the light on melanoma management. We review here the latest development of these molecules and the current perspectives in the treatment of metastatic melanoma.
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PMID:Targeted therapies in metastatic melanoma: toward a clinical breakthrough? 2123 37

Dacarbazine (DTIC) is the treatment of choice for metastatic melanoma, but its response in patients remains very poor. Ceramide has been shown to be a death effector and to play an important role in regulating cancer cell growth upon chemotherapy. Among ceramidases, the enzymes that catabolize ceramide, acid ceramidase (aCDase) has been implicated in cancer progression. Here we show that DTIC elicits a time- and dose-dependent decrease of aCDase activity and an increase of intracellular ceramide levels in human A375 melanoma cells. The loss of enzyme activity occurred as a consequence of reactive oxygen species-dependent activation of cathepsin B-mediated degradation of aCDase. These events preceded autophagic features and loss of cell viability. Down-regulation of acid but not neutral or alkaline ceramidase 2 resulted in elevated levels of ceramide and sensitization to the toxic effects of DTIC. Conversely, inducible overexpression of acid but not neutral ceramidase reduced ceramide levels and conferred resistance to DTIC. In conclusion, we report that increased levels of ceramide, due to enhanced degradation of aCDase, are in part responsible for the cell death effects of DTIC. These results suggest that down-regulation of aCDase alone or in combination with DTIC may represent a useful tool in the treatment of metastatic melanoma.
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PMID:Acid ceramidase expression modulates the sensitivity of A375 melanoma cells to dacarbazine. 2170 Jul

Metastatic melanoma (MM) presents a treatment challenge to oncologists worldwide. Dacarbazine is the first line chemotherapy treatment for MM, though the overall response rates are very poor. Recently, the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation was found to play a main role in MM. This mutation is present in 40-60% of melanoma patients. Vemurafenib is a BRAF kinase inhibitor that showed impressive results in phase I-III trials and was thus recently approved for the treatment of MM. This paper will briefly focus on vemurafenib in the treatment of MM and highlight concerns.
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PMID:Metastatic melanoma and vemurafenib: novel approaches. 2282 88

In 2011, two therapies were approved for the treatment of metastatic melanoma: ipilimumab, an immunotherapeutic agent, and vemurafenib, a BRAF kinase inhibitor. These approvals were based on data from phase III trials, which showed that treatment with these agents produced substantial improvements in overall survival (OS). Ipilimumab has been investigated in two phase III trials: one as monotherapy in patients with pretreated metastatic melanoma at a dose of 3 mg/kg and the second in combination with dacarbazine (DTIC) chemotherapy in patients with previously untreated metastatic melanoma at a dose of 10 mg/kg. Among the pretreated patients, ipilimumab monotherapy significantly improved median OS (Hazard ratio (HR): 0.66, P = 0.003) from 6.4 months in gp100 vaccine controls to 10.1 months. The rates of OS in the ipilimumab-alone group and the gp100 group, respectively, were 45.6% and 25.3% at 12 months and 23.5% and 13.7% at 24 months. In the second trial, OS was significantly longer in previously untreated patients receiving ipilimumab plus DTIC than those receiving DTIC plus placebo (11.2 months versus 9.1 months; HR: 0.72, P < 0.001), with higher survival rates in the ipilimumab plus DTIC group at 1 year (47.3% versus 36.3%), 2 years (28.5% versus 17.9%) and 3 years (20.8% versus 12.2%). When using ipilimumab in the clinic, special consideration should be given to immune-related adverse events (irAEs) and assessment of response. Established guidelines can be used to manage the majority of irAEs effectively. Proposed modifications made to the existing response criteria mean that the clinician can accurately detect immune-related responses that would have been considered representative of progressive disease using conventional criteria. Further research is warranted to establish how immunotherapeutic agents can be combined with conventional agents, with each other or with molecularly targeted agents such as vemurafenib, to further optimise clinical outcomes.
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PMID:How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma. 2291 23


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