ISSN:0960-8931    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Melanoma research has made great advances in recent years. Particularly in the field of immunology, melanoma researchers have opened new avenues for basic and translational cancer research overall. Emerging research areas such as molecular epidemiology promise to develop a similar leadership role. On the other hand, research in biology, genetics or experimental therapy of melanoma has remained confined to few laboratories and entire research areas are not covered due to lack of researchers and resources. New developments in defining stem cells in skin and bone marrow enable us to develop new concepts for melanoma development and progression. New technologies allow rapid progress but they require close cooperation between laboratories. The field has to better bridge experimental with clinical research and increase communication. Corroboration with advocacy groups should activate the public for increased awareness and funding.

ISSN:0960-8931    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

CD43, the major transmembrane sialoglycoprotein of neutrophils, monocytes, T lymphocytes and platelets, is highly glycosylated and its high sialic acid content contributes to the strongly negative charge of cells. In this study the role of CD43 in melanoma development was addressed using CD43−/− mice (nullmutated for the corresponding gene or knockout [KO]). Growth of B16F10 melanoma was retarded in the KO mice compared with the wild-type CD43+/+ control (WT). A marked difference in lung colonization and other metastatic foci was observed in the KO and WT mice up to 15 days after intravenous injection of tumour cells. The initial resistance of KO mice was reversed with time, and in the long term there was no difference in the survival rate of the two animal groups. Transient resistance was attributed to increased adhesion of thrombin-activated platelets and leukocytes to melanoma and endothelial cells in KO mice. In the KO mice tumour emboli were found in the central portion of the lung more than at the lung periphery immediately after intravenous injection, in contrast to the WT mice. Activation of melanoma adhesion receptors by thrombin or TRAP stimulated lung colonization in WT but not KO mice. Therefore, the correlation of tumour embolism and metastasis in short-term experiments depends on the nature and stability of interactions between the tumour and the blood/endothelial cells of the host.

ISSN:0960-8931    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The efficacy of sequential chemoimmunotherapy involving interleukin-2 (IL2) in metastatic melanoma is limited, in part, by the severe toxicity associated with most therapeutic regimens. Glutathione (GSH), the most prevalent intracellular non-protein thiol, plays an important role in protecting against cellular injury caused by various anticancer agents. GSH is also involved in the IL2-induced proliferative activity of immune system cells and some melanoma cells expressing IL2 receptors, such as B16 melanoma cells. The present study investigated the effect of selective manipulation of GSH using the cysteine prodrug l-2-oxothiazolidine-4-carboxylate (OTZ) on the response of B16 melanoma to sequential biochemotherapy with cyclophosphamide (CY) and IL2. We found that OTZ, by depressing GSH levels, abrogates thein vitrogrowth-promoting effects of IL2 on B16 melanoma cells. The combination of OTZ plus IL2in vivoalso showed antitumour activity in mice bearing B16 melanoma liver metastases, significantly increasing their life span. Schedule dependency between both compounds was found; OTZ given intermittently in combination with daily IL2 administration was found to be the best therapeutic schedule. We also observed that whereas IL2 or OTZ alone added to CY resulted in a lower or non-significant improvement in the life span of the mice compared with tolerated doses of CY alone, the addition of both OTZ and IL2 to CY produced a significantly greater increase in survival than CY alone, and markedly protected mice against CY-induced toxicity, which allowed the administration of otherwise lethal doses of CY, with the CY activity/toxicity ratio being increased by four-fold.

ISSN:0960-8931    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The incidence of melanoma is estimated to be growing at the second fastest rate among all cancers in the United States. The progression of the melanocyte to a malignant melanoma involves various sequential steps: development of benign naevocellular naevus, preneoplastic dysplastic naevus, primary melanoma, and metastatic melanoma. Despite these clearly defined stages, very little is known about the molecular events leading to melanoma progression. We established a human congenital naevus cell line (UISO-CMN-1). UISO-CMN-1 cells were confirmed to have melanocytic origin by S100 immunoreactivity and the presence of melanin granules and melanosomes. UISO-CMN-1 cells, even though they showed structural and numerical abnormalities in karyotype, were non-tumorigenic when transplanted into athymic mice. However, following frequent exposure to ultraviolet C radiation, UISO-CMN-1 cells acquired tumorigenic potential. Transformation of UISO-CMN-1 cells into tumorigenic cells was accompanied by induction of ganglioside-2 expression without any significant changes in cellular ganglioside-3. These transformed and non-transformed UISO-CMN-1 cell lines can serve as excellent research tools for studying the molecular changes associated with melanoma development and progression, and for identifying agents that might prevent development of malignant melanoma.

ISSN:0960-8931    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Melanoma exhibits heterogeneous growth patterns and widely varying sensitivities to multiple treatment modalities. This variability may reflect intrinsic genetic differences in factors giving rise to altered metabolism. Glucose is the primary energy source of tumours, including melanoma, and glucose transporter isoform 1 (Glut-1) and hexokinase are key rate-limiting factors in glucose metabolism. The levels of Glut-1 and total hexokinase activity were measured in 31 melanoma biopsies to determine the extent of tumour-to-tumour variability in these parameters. Relative Glut-1 levels were determined by Western immunoblot analysis using human anti-Glut-1 rabbit polyclonal antibody, and hexokinase activity was measured in the same samples by an enzymatic assay monitoring the reduction in the oxidized form of nicotinamide adenine dinucleotide phosphate (NADP+) (in nmol NADP+reduced/min per mg protein). All melanomas were from patients who had received no therapy prior to surgery. Immediately after excision, tumour biopsies were disaggregated to single cells by collagenase and DNase and frozen in liquid nitrogen. Thirty human melanomas exhibited a 22-fold variation in levels of Glut-1 and 29 exhibited a nine-fold variation in total cellular hexokinase activity. Glut-1 levels and hexokinase activity were not correlated with one another. The broad range in Glut-1 levels and hexokinase activity observed between melanomas suggests that these glycolytic rate-limiting parameters that influence the rate of glucose metabolism may contribute to the variability in melanoma response to treatment modalities.

ISSN:0960-8931    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

During recent years it has become evident that protein kinase B (PKB)/Akt plays an important role in oncogenic transformation. The gene for PKB/Akt has been found to be overexpressed in certain human tumours and a viral fusion protein gains transforming capacity. Recruitment to the plasma membrane is mandatory for the physiological activation of PKB/Akt; this shift from cytoplasm to the membrane is achieved by the N-terminal pleckstrin homology (PH) domain. We attempted to find out whether mutations of this domain were present in human malignant melanoma. RNA from 18 primary melanoma lesions of different sizes and histological subtypes and two melanoma metastases from 20 Caucasian patients were used for reverse transcription and subsequent polymerase chain reaction (PCR) amplification of the PH domain of PKB/Akt α. Cycle sequencing of the purified PCR products showed that mutations of the PH domain of PKB/Akt were absent in all 20 melanoma specimens. In virtual Northern hybridizations PKB/Akt showed a low expression in both melanomas and acquired melanocytic naevi; however, no overexpression of PKB/Akt was detected. Thus in human melanoma PH domain mutations of PKB/Akt do not play a major role in melanoma carcinogenesis.

ISSN:0960-8931    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

To date, two genes have been implicated in melanoma pathogenesis. The first,CDKN2A, is a tumour suppressor gene with germline mutations detected in 20% of melanoma-prone families. The second,CDK4, is an oncogene with co-segregating germline mutations detected in only three kindreds worldwide. We examined 16 American melanoma-prone families for mutations in all coding exons ofCDK4and screened additional members of two previously reported families with the Arg24Cys germlineCDK4mutation to evaluate the penetrance of the mutation. No newCDK4mutations were identified. In the two Arg24Cys families, the penetrance was estimated to be 63%. Overall, 12 out of 12 invasive melanoma patients, none out of onein situmelanoma patient, five out of 13 dysplastic naevi patients, two out of 15 unaffected family members, and none out of 10 spouses carried the Arg24Cys mutation. Dysplastic naevi did not strongly co-segregate with the Arg24Cys mutation. Thus the phenotype observed in melanoma-proneCDK4families appears to be more complex than just theCDK4mutation. Both genetic and environmental factors are likely to contribute to the occurrence of melanoma and dysplastic naevi in these families. In summary, althoughCDK4is a melanoma susceptibility gene, it plays a minor role in hereditary melanoma.

ISSN:0960-8931    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The increasing incidence of melanoma and the lack of effective treatment, with the exception of tumour excision before the onset of the metastatic phase, make it important to identify genes that may function as new molecular markers for diagnosis and/or prognosis or as new targets for therapy. Recently, a new technique using high density oligonucleotide arrays has been developed to simultaneously screen for the expression of thousands of genes. We used this technique to compare the mRNA expression patterns of two human melanoma cell lines with different metastatic behaviour. Eight differentially expressed genes, namely apolipoprotein CII, tyrosinase-related protein 1, transforming growth factor-β superfamily, subtilisin-like protein, elongation factor 1 α2, α2-macroglobulin, human cell division cycle 10 and serine/threonine protein kinase (DYRK1A), were selected to validate the array results by Northern blotting and reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, a reliable correlation between differential expression of these genes in the melanoma cell lines and in fresh lesions of melanocytic tumour progression was demonstrated by RT-PCR analysis. Altogether, our data indicate that high density oligonucleotide arrays are a valuable and reliable tool to screen for differentially expressed genes, and that our study may be considered a basic step in the characterization of genes that are involved in the (malignant) progression of melanoma.

ISSN:0960-8931    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

In tissue counter analysis, a novel image analysis tool in the evaluation of dermatoscopic images, a lattice of elementary measuring masks (elements) of equal size is randomly placed over the image and the contents of each element is evaluated by a set of colour and texture features. In this study, we tested the efficiency of tissue counter analysis on the diagnostic discrimination of benign and malignant melanocytic skin lesions. In order to assess the amount of benign and malignant tumour elements in each case, 20 cases each of naevus and malignant melanoma were sampled. Analysis was performed by the Classification and Regression Tree (CART), which provided a subclassification into 32 terminal nodes in the learning sets, 16 of them suggestive for the class ‘malignant elements', the remaining 16 for ‘benign elements'. For diagnostic assessment, only the percentage of the elements suggestive for malignancy in each lesion was used. ROC analysis showed that a threshold level of 36.45% classified all melanomas and 18 out of 20 naevi correctly (sensitivity 100%, specificity 90%, positive predictive value 90.9%). Prospective studies with larger series of cases will have to be performed for clinical relevance.

ISSN:0960-8931    

出版商:OVID    

年代:2002

数据来源: OVID