摘要:

During the past few years significant progress has been made in the treatment of cutaneous melanoma. These developments often involve the use of interferon-α (IFNα). Promising results have been reported in high risk patients using adjuvant treatment with high dose IFNα. A confirmatory trial of high dose IFNαand several adjuvant trials using low or intermediate dose IFNαare ongoing, and currently a standard regimen cannot be defined. High response rates have been reported in patients with metastatic disease with combination chemoimmunotherapy schedules. Randomized trials have to be performed in order to demonstrate a survival benefit over less toxic regimens. In this paper the current status of IFNαin the treatment of cutaneous melanoma is reviewed.

ISSN:0960-8931    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

4-S-Cysteaminylphenol (4-S-CAP), a phenolic thioether, has been evaluated for melanocytotoxicity. We have recently shown that dihydro-1,4-benzothiazine-6,7-dione (benzothiazine BQ) is the ultimate toxic metabolite produced by tyrosinase oxidation of 4-S-CAP. In this study we compared the antimelanoma effects of 4-S-CAP and its two homologues, α-methyl-4-S-cysteaminylphenol (α-Me-4-S-CAP) and 4-S-homocysteaminylphenol (4-S-Homo-CAP). Biochemical experiments showed that upon tyrosinase oxidation α-Me-4-S-CAP and 4-S-Homo-CAP also produced homologues of BQ which reacted rapidly with reduced glutathione (GSH) and also inhibited alcohol dehydrogenase, an SH enzyme.In vitroexperiments showed that 4-S-CAP and its two homologues were taken up into B16-F1 melanoma cells at comparable rates but that 4-S-Homo-CAP was least effective in GSH deprivation, which was reflected in the low cytotoxicity of this phenol, and that the cytotoxicity of the phenols was tyrosinase dependent, as proved by the negligible effects on B16-G4F cells which have a much lower tyrosinase activity.In vivoexperiments showed that direct intratumoral administration of these phenols inhibited the subcutaneous growth of B16 melanoma, with 4-S-Homo-CAP being the least effective, and that indirect intraperitoneal administration of 4-S-CAP inhibited melanoma growth much more effectively than the two homologues. These results indicate that 4-S-CAP is the most promising antimelanoma agent among the three phenols examined.

ISSN:0960-8931    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The purpose of this study was to investigate the effects of retinoid analogues with different retinoid receptor specifity on the growth of human D10 and Cloudman S91 mouse melanoma cells. We compared the growth inhibitory effects with the ability of retinoids to downregulate cell surface expression of the melanocortin receptor (MC1-R). Retinoic acid receptor (RAR)-γ-selective retinoids exerted the most prominent growth effects, with up to 68% and 69% inhibition in D10 and S91 cells, respectively. A retinoid X receptor (RXR)-selective compound inhibited cell growth by only 14% and 23% in D10 and S91 cells, respectively. Growth inhibition by RARα- and RARβ-selective compounds was below 10% in both cells. In D10 cells, MC1-R downregulation was also induced most effectively by an RARγ-selective retinoid (84% relative to controls). RARα-, RARβ-and RXR-selective agonists induced only 16–24% MC1-R downregulation in these cells. The pattern for MC1-R downregulation was completely different in S91 cells. The RXR-selective compound was the most active (85%), followed by the RARα-selective agonist (58%), the RARγ-selective compound (47%), and finally by the RARβ-selective agonist (29%). We conclude that RARγ-selective retinolds may have potential as therapeutic agents in melanoma. Different selectivity profiles for growth inhibition and MC1-R downregulation in S91 cells suggest that these two retinoid effects are not directly dependent on each other.

ISSN:0960-8931    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Cystemustine (N‘-(2-chloroethyl)-N-(2-(methylsulphonyl)-ethyl)-N’-nitrosourea) is a new chloroethylnitrosourea (CENU) being used in phase II clinical trials of disseminated melanoma. Clinical results show that tumour regression has only been observed in 25% of melanomas treated by CENUs. Tumour resistance to CENU is known to be mainly due to a DNA repair protein,O6-methylguanine-DNA methyltransferase (MGMT). The poor remission rate of melanoma with CENUs is attributed to the fact that metastases contain high MGMT levels. Previously, we have shown thatO6-benzyl-N2-acetylguanosine (BNAG), an MGMT inhibitor, can be combined with cystemustine by intravenous administration, and increases the antitumour effect of cystemustine in resistant human melanoma. In the work presented here, we investigated thein vitropharmacological effect of this combination on the DNA of human melanoma cells (M3Dau cells). A quantitative polymerase chain reaction (QPCR) assay was used to measure DNA damage in a fragment (2.7 kb) of thehprtgene. The results show that treatment with BNAG enhances the number of lesions in the DNA of cystemustine-treated resistant malignant melanocytes, which may account for the high tumour-cell toxicity of the combination of cystemustine and BNAG.

ISSN:0960-8931    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Theophylline- and caffeine-treated B16-F10 cells exhibited low adhesion to laminin/collagen type IV and reduced invasion through Matrigel in anin vitroassay. In contrast, theobromine appeared ineffective. When young adult C57BL/6 mice were injected intravenously with theophyl-line-treated B16-F10 cells, the number of surface lung tumours was markedly reduced. Densitometric analyses performed on digitalized microscopic images of histological sections of lung were used to estimate the frequency (number of lung foci; NLF) and the size (average area of metastatic foci; AMF) of the resulting tumour foci. These parameters were correlated to the proliferation (AMF) and invasion (NLF) of melanoma cellsin vivo. The data showed a similar theophylline-induced decrease in the AMF and NLF values (71%,P< 0.01). Caffeine treatment produced a more pronounced decrease in the AMF (61%,P< 0.01) than in the NLF (25%,P< 0.01). To our knowledge, this is the first demonstration that theophylline and caffeine possess the capacity to inhibit not only cell proliferation, but also the metastatic behaviour of melanoma cancer cells.

ISSN:0960-8931    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The role of thec-myconcogene has been little investigated in uveal melanoma. In this study an analysis ofc-myconcoprotein expression was undertaken using flow cytometry in 71 patients with posterior uveal melanoma. Nuclearc-myconcoprotein was detected in all of the tumours, and survival analysis revealed a significant association between high oncoprotein positivity and improved survival (log rank test: χ2= 6.47,P= 0.01). Multifactorial analysis using Cox's proportional hazards model revealed nuclearc-myconcoprotein to be an independent prognostic marker more accurate than other clinicopathological parameters (log rank test: χ2= 6.61,P= 0.01). However, this result of high oncoprotein expression correlating with improved outcome is surprising and in contrast to our previous studies using the same method on cutaneous melanoma, where high levels of nuclearc-mycexpression have been found to correlate with poor outcome both in primary and secondary disease. This study suggests that the pattern of oncogene expression in uveal melanoma is distinct from cutaneous melanoma and that the underlying biology of these tumours is different.

ISSN:0960-8931    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The combination of cisplatin-based chemotherapy with interleukin-2 (IL-2) and interferon, referred to as biochemotherapy, has shown encouraging results in patients with advanced melanoma. Toxicity is high, however and no objective parameters exist to distinguish between patients who are likely to respond and those who are not. The purpose of this pilot study was to determine whetherin vitrocisplatin-induced damage to the glutathione S-transferase-π (GST-π) gene in peripheral blood mononuclear cells (PBMCs) before therapy correlated with the histological response in melanoma patients with local-regional metastases who received concurrent biochemotherapy before definitive surgery. Before therapy, PBMCs from 16 patients were exposed to cisplatin at concentrations of 25, 50 or 100 μM for 3 h and the extent of damage to the GST-π gene was quantitated by polymerase chain reaction (PCR). Patients were subsequently treated on a biochemotherapy regimen consisting of cisplatin 20 mg/m2intravenously (i.v.) on days 1–4, vinblastine 1.5 mg/m2i.v. on days 1–4, dacarbazine 800 mg/m2i.v. on day 1, IL-2 9 MIU/m2per day i.v. by continuous infusion on days 1–4 (total of 96 h), and interferon α2a 5 MU/m2subcutaneously on days 1–5. The 16 patients were categorized into two groups: major responders (n= 7) and non-major responders (n= 9). Although we observed a wide interpatient variation, a statistically significant correlation existed between the histological response and the degree of DNA damage caused in the PBMCs at all three cisplatin concentrations tested (P= 0.024 for 25 μM;P= 0.036 for 50 μM;P= 0.007 for 100 μM). Our pilot study suggests that determination ofin vitrocisplatin-induced DNA damage using a gene-specific PCR assay may be useful in predicting the histological response to biochemotherapy.

ISSN:0960-8931    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The combination of cisplatin-based chemotherapy with interleukin-2 (IL-2) and interferon-α (IFN-α), referred to as biochemotherapy, has produced overall response rates of greater than 50% in advanced melanoma patients, with durable complete responses in the range of 5–10%. The mechanism of action of biochemotherapy is unknown. Preclinical work suggests synergistic interactions between the cytotoxic agents, especially cisplatin, and the biological agents in killing melanoma cells. Immune effector cells activated by the components of the biochemotherapy may also be involved, as direct cytotoxic effectors and/or as sources of secondary cytokines, which can induce nitric oxide (NO) production in a wide variety of cell types. In addition, high levels of neopterin, a marker of monocyte/macrophage activation, have been found in patients undergoing immunotherapy or biochemotherapy for melanoma. Based on these data, we hypothesized that the degree of elevation of serum NO metabolic products and neopterin during treatment would correlate with the response to biochemotherapy in melanoma patients. Blood samples were obtained before and during preoperative biochemotherapy with cisplatin, vinblastine, dacarbazine, IL-2 and IFN-α in 45 melanoma patients with locoregionally advanced disease. NO was measured as nitrite after enzymatic reduction, using the colorimetric assay of Griess, and neopterin was measured by radioimmunoassay. Our results demonstrate a higher day 5 nitrite level (of borderline statistical significance,P= 0.057) in major responders to the therapy than in those who did not achieve a major response, while there was no difference in the elevation in neopterin level during therapy between major and non-major responders. These results suggest that induction of NO during biochemotherapy may be playing a role in the mechanism of action of this therapy, while the role of monocyte/macrophage activation is still in question.

ISSN:0960-8931    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We report two patients with multiple agminate Spitz naevi (MASM), a rare disorder. In case 1, a 16-year-old girl, the results of chromosomal investigation of fibroblasts from the affected area (translocation 45, X, t(4; 7) (p14; p22) in a mosaic pattern) suggest that early during embryogenesis ade novoreciprocal translocation has occurred between chromosomes 4 and 7. This resulted in the skin lesions as described on the right shoulder, arm and hand. The melanoma risk in MASM is also discussed.

ISSN:0960-8931    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

In a previous qualitative study it has been shown that the incorporation of pre-existing collagen bundles from the reticular dermis into the bulk of melanoma lesions metastatic to the skin indicates rapid systemic spread. In the present study the amount of pre-existing dermal collagen in the bulk of the melanoma lesions in 267 cases of primary melanoma of the skin with a Clark level of at least III was quantitatively assessed using automated image analysis based on RGB (red, green and blue) colour images of sections stained with haematoxylin and eosin. There was a weak correlation between the amount of pre-existing collagen and the Clark level and the Breslow index. With regard to prognosis, a large amount of pre-existing collagen (> 0.13 mm2per index slide) was significantly associated with a particularly poor outcome (24-month survival rate: 71 ± 17% compared with 96 ± 2%; log rank test:P< 0.001). It is clear that a large amount of pre-existing collagen bundles occurring as a particular feature of tumour–stroma interaction indicates high metastatic capacity in primary malignant melanoma.

ISSN:0960-8931    

出版商:OVID    

年代:1998

数据来源: OVID