Hassel JC, Winnemöller D, Schartl M
… +1 more, Wellbrock C
Melanoma Res
· 2008 Dec · PMID 19011510
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Malignant melanoma is a cancer whose incidence is rising rapidly. Extensive studies of primary tumors and tumor-derived cell lines revealed that inappropriate activation of signal transducer and activator of transcriptio...Malignant melanoma is a cancer whose incidence is rising rapidly. Extensive studies of primary tumors and tumor-derived cell lines revealed that inappropriate activation of signal transducer and activator of transcription (STAT) proteins, particularly of STAT3 and 5, occurs with high frequency in various human cancers. We reported that in the Xiphophorus fish melanoma model, constitutive activation of STAT5 correlates with the aggressiveness of melanoma. Investigations in human melanoma mainly focussed on the function of STAT1, but we have shown recently that STAT5 is also activated in human melanoma. The objectives of this investigation were to get more information about the function of STAT5 in melanoma. Here we demonstrate that in murine melanocytes activation of STAT5 measured by its tyrosine phosphorylation and translocation to the nucleus parallels upregulation with its target gene bcl-XL. This indicates a role for STAT5 in antiapoptotic signaling in pigment cells. In human melanoma cell lines, we found that constitutive activation of STAT5 correlates with expression of bcl-XL. Expression of dominant negative STAT5 in the human melanoma cell line A375 leads to a reduced bcl-XL expression and a dramatic increase of apoptotic cells. In contrast to STAT1, which is known to transduce antiproliferative effects of interferons, our data support a significant role for STAT5 in melanoma cell proliferation and survival via the activation of the antiapoptotic protein bcl-XL. Keeping in mind that interferons activate both STAT proteins, STAT5 activation could be of importance in interferon resistance of melanoma.
Melanoma Res
· 2008 Dec · PMID 18971788
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Breast is an uncommon site for metastasis from other malignancies especially melanomas. A 40-year-old lady presented with a rapidly growing, painless, solitary breast lump for 3 months. Past history was unremarkable for...Breast is an uncommon site for metastasis from other malignancies especially melanomas. A 40-year-old lady presented with a rapidly growing, painless, solitary breast lump for 3 months. Past history was unremarkable for skin lesions, biopsy or any surgery. The lump was hard and freely mobile with normal overlying skin, nipple, and areola. Careful examination of the skin did not reveal any lesion. Grossly the tumor was partially circumscribed and gray white. Microscopically, a highly cellular lesion was seen showing nests and sheets of large anaplastic cells with atypical mitotic figures without any evidence of cytoplasmic pigment. Immunoreactivity for S-100 and HMB-45, confirmed the diagnosis of amelanotic melanoma. It is important to be aware of this atypical presentation of amelanotic melanoma in the breast and to utilize immunohistochemistry to differentiate from other commoner high-grade malignant tumors.
Muchemwa FC, Nakatsura T, Fukushima S
… +3 more, Nishimura Y, Kageshita T, Ihn H
Melanoma Res
· 2008 Jun · PMID 18477890
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The objective of this study is to assess the expression of heat shock protein 105 (HSP105) in melanoma and benign melanocytic lesions. The expression of HSP105 in 62 human melanoma samples--46 primary and 16 metastatic l...The objective of this study is to assess the expression of heat shock protein 105 (HSP105) in melanoma and benign melanocytic lesions. The expression of HSP105 in 62 human melanoma samples--46 primary and 16 metastatic lesions--and 42 melanocytic naevi samples, was assessed by immunohistochemistry. Western blotting was performed on melanoma cell lines, melanoma tissues with matched normal skin and melanocytic naevi. The Mann-Whitney test was used for statistical analysis and significance was considered to be P less than 0.05. Seventy-four per cent of the primary melanoma lesions and 88% of the metastatic lesions overexpressed HSP105 by immunohistochemistry. The majority of melanocytic lesions (95%) were negative (P<0.05). Western blotting detected high expression of HSP105 in melanoma cell lines and tissues. The expression of HSP105 was related to the invasiveness of the lesions. Melanocytic naevi expressed HSP105 at a level that was similar to that of normal skin. Our results show that high expression of HSP105 is associated with malignant melanoma especially advanced and metastatic lesions. The results suggest that HSP105 analysis may be a helpful tool as a poor prognostic indicator and as a diagnostic aid in problematic lesions; in addition, melanoma can be included in the growing list of tumours overexpressing HSP105 to be targeted for potential HSP105-based therapeutic strategies.
Melanoma Res
· 2008 Feb · PMID 18227706
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A 23-year-old woman was presented with a prolonged history of a small lump in the buccal mucosa. A local excision was performed. The morphology diagnosed a Spitz nevus and she underwent supplementary excision of scar tis...A 23-year-old woman was presented with a prolonged history of a small lump in the buccal mucosa. A local excision was performed. The morphology diagnosed a Spitz nevus and she underwent supplementary excision of scar tissue. Two years later a submandibular lump appeared on the ipsilateral side of the neck. Cytology from fine needle aspiration indicated spread of a melanocytic tumor and she underwent a modified supraomohyiod neck dissection. One of the lymph nodes showed an inclusion of cells in the deep layers with epitheloid and spindle cells in a pattern similar to that of the primary oral lesion. The finding suggests a mechanical spread of melanocytes from the Spitz nevus to the regional lymph node. After more than 3 years of follow-up there is no further manifestation of disease. It is believed that this may be an example of how a Spitz tumor, although inherently benign, can spread along lymphatics in a pseudometastatic fashion. To our knowledge this is the first report of an oral Spitz melanoma with metastatic behavior.
Garbe C, Hauschild A, Volkenandt M
… +13 more, Schadendorf D, Stolz W, Reinhold U, Kortmann RD, Kettelhack C, Frerich B, Keilholz U, Dummer R, Sebastian G, Tilgen W, Schuler G, Mackensen A, Kaufmann R
Melanoma Res
· 2007 Dec · PMID 17992123
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Melanoma is a malignant tumor that arises from melanocytic cells and primarily involves the skin. The most important exogenous etiological factor is exposure to ultraviolet irradiation. Diagnosis of melanoma is based pri...Melanoma is a malignant tumor that arises from melanocytic cells and primarily involves the skin. The most important exogenous etiological factor is exposure to ultraviolet irradiation. Diagnosis of melanoma is based primarily on its clinical features, and the A-B-C-D rule is useful in identifying pigmented lesions, which are suspicious for melanoma (Asymmetry, Border irregular, Color inhomogeneous and Diameter more than 5 mm). Dermoscopy is very helpful in clarifying the differential diagnosis of pigmented lesions. About 90% of melanomas are diagnosed as primary tumors without any evidence for metastasis. The tumor-specific 10-year survival for all such tumors is about 75-85%. The most important prognostic factors for primary melanoma without metastases are vertical tumor thickness (Breslow depth) as measured on the histological specimen, presence of histopathologically recognized ulceration, invasion level (Clark level) and identification of micrometastases in the regional lymph nodes via sentinel lymph node biopsy. The current tumor node metastasis classification for the staging of primary melanoma is based on these factors. Melanomas can metastasize either by the lymphatic or by the hematogenous route. About two-thirds of metastases are originally confined to the drainage area of regional lymph nodes. A regional metastasis can appear as satellite metastases up to 2 cm from the primary tumor, as intransit metastases in the skin between the site of the primary tumor and the first lymph node and as regional lymph node metastases. In the stage of regional metastasis, the differentiation between micrometastasis and macrometastasis and the number of lymph nodes involved are crucial. As soon as distant metastasis develops, prognosis depends on the site of the metastasis and on the lactate dehydrogenase levels in the blood. The frequency and extent of follow-up examinations is based on the initial tumor parameters. In thin primary melanomas up to 1-mm tumor thickness, clinical examinations at 6-month intervals are sufficient and in thicker primary melanomas, at 3-month intervals. Lymph node sonography as well as determination of the tumor marker protein S100beta are recommended. Additionally, in the stage of regional metastasis, whole body imaging should be performed every 6 months; in the stage of distant metastasis, surveillance has to be scheduled individually.
Melanoma Res
· 2007 Jun · PMID 17505259
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We have reported recently that changes in expression level of COX-2 are correlated with development and progression of human melanoma. In this study, we investigated whether the COX-2 expression level might be a useful i...We have reported recently that changes in expression level of COX-2 are correlated with development and progression of human melanoma. In this study, we investigated whether the COX-2 expression level might be a useful immunohistochemical marker for distinguishing cutaneous melanomas from benign melanocytic lesions. Up to now, immunohistochemical markers have not ensured satisfactory sensitivity and specificity of differential pathologic diagnosis of melanoma. The expression of COX-2 was determined immunohistochemically in formalin-fixed, paraffin-embedded specimens of 33 early Clark I/II melanomas and 58 naevi. Mean COX-2 expression in melanomas was significantly stronger than in naevi (P approximately 10(-13)). A simple diagnostic algorithm using threshold values of the COX-2 expression level allows for differentiation between early melanomas and naevi with high sensitivity (Se) and specificity (Sp) (for Se between 91 and 100%, Sp values change between 96.5 and 51.7%). Areas under the receiver operating characteristic curves were, respectively, 0.97+/-0.02 and 0.86+/-0.04 for the COX-2 expression in central and border regions of the lesions. For all the melanomas (not only the early ones),the respective areas under the ROC curve values were 0.98+/-0.01 and 0.97+/-0.02. In conclusion, COX-2 is the first immunohistochemical marker that allows the distinguishing of early melanomas from benign melanocytic lesions with both high sensitivity and specificity.
Melanoma Res
· 2006 Oct · PMID 17013096
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We describe a case of pseudomelanoma after Solcoderm treatment. Pseudomelanoma is a pathological entity describing the histological findings in cases of recurrences of a partially excised melanocytic nevus, resembling me...We describe a case of pseudomelanoma after Solcoderm treatment. Pseudomelanoma is a pathological entity describing the histological findings in cases of recurrences of a partially excised melanocytic nevus, resembling melanoma. Solcoderm is an aqueous solution containing organic and inorganic acids that destroys a lesion by tissue mummification. It has been used for the treatment of benign skin lesions. Appearance of pseudomelanoma after Solcoderm treatment stressed the controversy of the use of Solcoderm in pigmentary lesions, and that surgical removal is preferred in cases of pigmented nevi.
Melanoma Res
· 2006 Oct · PMID 17013093
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Cyclin-dependent kinase 2 (CDK-2) is strongly involved in regulating the progression of the cell cycle through G1/S checkpoint and S phase. Numerous studies demonstrated increased levels of CDK-2 (and also of its regulat...Cyclin-dependent kinase 2 (CDK-2) is strongly involved in regulating the progression of the cell cycle through G1/S checkpoint and S phase. Numerous studies demonstrated increased levels of CDK-2 (and also of its regulatory cyclins E and/or A) in different types of human tumours. Correlations found between the expression of those cell cycle regulators and progression and/or invasiveness of some tumours indicated the importance of CDK-2 as a potential prognostic marker. At the same time, in vitro studies of melanoma cell lines revealed melanocyte-specific regulation of CDK-2. The present study was aimed at examining levels of CDK-2 in human melanomas and benign pigmented lesions to evaluate whether it might be considered a potential molecular marker of melanoma progression. Expression of CDK-2 was determined immunohistochemically in formalin-fixed paraffin-embedded specimens comprising 76 lesions including 41 primary cutaneous melanomas, 15 lymph node melanoma metastases (in eight cases correlated with primary tumours), three melanoma recurrences (two cases correlated with both primary and metastatic melanomas) and 17 nevi. Our results demonstrate that development and progression of melanoma are associated with changes in CDK-2 expression level. Statistical significance of the observed correlations indicates that CDK-2 may be a suitable prognostic marker for melanoma and perhaps also a target for chemotherapeutic drugs.
Paradisi A, Capizzi R, De Simone C
… +3 more, Fossati B, Proietti I, Amerio PL
Melanoma Res
· 2006 Aug · PMID 16845335
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Tattooing is a fairly widespread practice worldwide, despite the trauma it entails and the potentially toxic pigments it employs. Several benign and malignant lesions have been described in relation to tattoos, including...Tattooing is a fairly widespread practice worldwide, despite the trauma it entails and the potentially toxic pigments it employs. Several benign and malignant lesions have been described in relation to tattoos, including verrucae, granulomas, basal cell and squamous cell carcinoma. Overall, only 10 cases of malignant melanoma in tattoos are reported in the English literature. We describe a malignant melanoma that developed on a nevus on which a tattoo had been made. The possible pathogenetic relationship between malignant melanoma and tattoos is also discussed.
Melanoma Res
· 2006 Jun · PMID 16718270
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Lysosome-associated membrane protein-1 is a protein with a significant content of beta1,6-branched N-glycans. It is thought that enhanced expression of lysosome-associated membrane protein-1 in tumour cells may promote i...Lysosome-associated membrane protein-1 is a protein with a significant content of beta1,6-branched N-glycans. It is thought that enhanced expression of lysosome-associated membrane protein-1 in tumour cells may promote invasion by influencing both adhesion to extracellular matrix and perhaps also binding to endothelial cells. The present study was aimed at examining levels of lysosome-associated membrane protein-1 in human melanomas and benign pigmented lesions to evaluate whether this protein might be considered a potential molecular marker of melanoma progression. The expression of lysosome-associated membrane protein-1 was for the first time determined immunohistochemically in formalin-fixed paraffin-embedded specimens comprising 42 primary cutaneous melanomas, 15 lymph node melanoma metastases (11 correlated with primary tumours), three melanoma recurrences (correlated with both primary and metastatic melanomas), 27 nevi and four epithelial tumours (two seborrhoeic keratoses and two basal cell carcinomas). Our results demonstrate that development and progression of melanoma are associated with changes of the lysosome-associated membrane protein-1 level. The expression was strongest in melanoma recurrences and lymph node metastases, weaker in primary cutaneous melanomas and not detectable in melanocytes of pigmented nevi. Nodular melanomas expressed lysosome-associated membrane protein-1 at higher level than superficially spreading melanomas.
Spontaneous or therapy-induced depigmentation in patients with melanoma has long been considered a favourable prognostic indicator. In this report, we isolated T cells infiltrating the depigmented skin of an HLA-A2+/DR4+...Spontaneous or therapy-induced depigmentation in patients with melanoma has long been considered a favourable prognostic indicator. In this report, we isolated T cells infiltrating the depigmented skin of an HLA-A2+/DR4+ patient with melanoma, and detected a very high frequency of CD8+ T cells specific for melanocortin receptor 1 (MC1R), a hormone receptor involved in cutaneous pigmentation. In particular, tissue-infiltrating CD8+ T cells dominantly recognized the novel MC1R52-60 peptide epitope in an HLA-A2-restricted manner, and peptide-reactive CD8+ T cells were also detected in freshly isolated peripheral blood from this patient. Although type 1 CD4+ T-cell responses against MC1R were not detected in fresh tissue isolates, short-term in-vitro stimulation of peripheral blood lymphocytes resulted in the rapid expansion of CD4+ T cells reactive against novel HLA-DR4-presented epitopes derived from the MC1R protein (i.e. MC1R82-95, MC1R105-118 and MC1R149-161). MC1R peptide-specific CD8+ T-cell clones isolated from the depigmented skin of this patient were characterized by comparatively low functional avidity for specific major histocompatibility complex-peptide complexes and were poorly lytic; however, these effector cells were capable of secreting both interferon-gamma and granzyme B against relevant target cells in vitro, and may have played an important role in the induction of leucoderma in situ in this patient.
BRAF somatic mutations are frequently found in primary and metastatic melanomas and melanocytic naevi. Commonly found BRAF mutants stimulate constitutive RAF/MEK (mitogen-activated ERK-activating kinase)/ERK (extracellul...BRAF somatic mutations are frequently found in primary and metastatic melanomas and melanocytic naevi. Commonly found BRAF mutants stimulate constitutive RAF/MEK (mitogen-activated ERK-activating kinase)/ERK (extracellular signal-regulated kinase) pathway activation and act as transforming oncogenes in NIH-3T3 cells and immortalized murine melanocytes. The most common BRAF mutation is the V600E alteration, but over 30 distinct BRAF mutations, varying in biological activity, have been found and may be predictive of clinically relevant tumour differences. The origin of these acquired mutations remains unknown, but melanomas have a different BRAF mutational spectrum from other tumours, possibly resulting from unique environmental exposures. In melanoma cases, BRAF mutations are frequently found in superficial spreading or nodular histological subtypes, in tumours on intermittently sun-exposed sites and in younger patients. Although evidence indicates that the activation of the RAF/MEK/ERK pathway influences the proliferation, invasion and survival of melanoma cells in vitro, the exact role of BRAF mutation in melanoma tumour progression, maintenance and outcome remains controversial. In addition, although BRAF and NRAS mutations are mutually exclusive in melanomas, other genetic events may complement BRAF mutation to produce biological activity similar to NRAS mutation. Nonetheless, preclinical and early clinical studies predict that RAF/MEK/ERK pathway inhibitors will have therapeutic activity towards melanoma, but that tumour subclassification by BRAF/NRAS mutational status may be necessary to evaluate their efficacy.
Papp T, Schipper H, Kumar K
… +2 more, Schiffmann D, Zimmermann R
Melanoma Res
· 2005 Oct · PMID 16179867
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Eighteen congenital melanocytic naevi (CMN) from 17 patients and 18 dysplastic melanocytic naevi (DMN) from 18 patients were screened for mutations in the BRAF oncogene (present study) and the N-ras oncogene (in the cour...Eighteen congenital melanocytic naevi (CMN) from 17 patients and 18 dysplastic melanocytic naevi (DMN) from 18 patients were screened for mutations in the BRAF oncogene (present study) and the N-ras oncogene (in the course of two foregoing studies) by single-strand conformational polymorphism (SSCP)/sequencing analysis. BRAF mutations were demonstrated in both types of lesion. As a whole, 17 of 18 CMN (94.4%) and five of 18 DMN (27.7%) harboured either BRAF or N-ras mutations. As the BRAF oncogene is frequently found to be mutated in human cutaneous melanomas, it may constitute a risk factor for melanoma formation within CMN and DMN.
Melanoma Res
· 2005 Jun · PMID 15917697
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BACKGROUND: Cells of melanocytic naevi and cutaneous malignant melanomas (MM) are surrounded by a basement membrane (BM). AIM: To scrutinize any difference between the deposits of alpha1 (IV) and alpha5 (IV) collagen cha...BACKGROUND: Cells of melanocytic naevi and cutaneous malignant melanomas (MM) are surrounded by a basement membrane (BM). AIM: To scrutinize any difference between the deposits of alpha1 (IV) and alpha5 (IV) collagen chains in melanocytic naevi and MM. METHODS: A total of 27 common melanocytic naevi, 11 dysplastic naevi, 21 atypical naevi (melanocytomas) including Spitz and non-Spitz types, as well as 24 MM were studied. Their phenotypic and functional characteristics defined by immunohistochemistry using a panel of antibodies, including those directed to the alpha1 (IV), alpha3 (IV) and alpha5 (IV) collagen chains. RESULTS: Almost all naevi and half the melanocytomas exhibited a strong positivity for the alpha1 (IV) collagen chain. By contrast, the remaining melanocytomas and MM presented a heterogeneous staining pattern for the alpha1 (IV) collagen chain. One third of the naevi, 23% of the MM without cutaneous micrometastasis and 83% of MM with cutaneous micrometastasis showed discrete cytoplasmic positivity for the alpha5 (IV) collagen chain. All other melanocytic tumours were negative for this antibody. Rare MM cells in transepidermal migration were stained with the anti-alpha1 (IV) or alpha5 (IV) collagen chain antibodies. No immunoreactivity for the alpha3 (IV) collagen chain was disclosed in any of the samples. CONCLUSION: We report the expression of alpha1 (IV) and alpha5 (IV) collagen chains in naevi and MM. The inconsistent staining pattern for alpha1 (IV) collagen chain in phenotypically atypical melanocytomas and in MM highlight the heterogeneity in both cell differentiation and stroma-tumour interactions. This biological aspect may be related to neoplastic progression and influence metastatic potential.
Casorzo L, Luzzi C, Nardacchione A
… +3 more, Picciotto F, Pisacane A, Risio M
Melanoma Res
· 2005 Jun · PMID 15917696
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Loss of the 9p21 region, 6q and 10q and gain of chromosome 7 are the most frequent chromosomal abnormalities found in human melanomas, but very few cytogenetic data are available regarding dysplastic and common naevi. To...Loss of the 9p21 region, 6q and 10q and gain of chromosome 7 are the most frequent chromosomal abnormalities found in human melanomas, but very few cytogenetic data are available regarding dysplastic and common naevi. To study the occurrence of the most consistent chromosomal changes during melanocytic tumorigenesis, archival samples from 30 common naevi and 30 naevus-associated melanomas were analysed by interphase fluorescence in situ hybridization (FISH) using centromeric probes for chromosomes 9 and 7 and locus-specific probes for 9p21, 6q11.1, 6q24.1, 10p15.3 and 10q23.1 regions. In naevus-associated melanomas, separate evaluations were made for sectors corresponding to residual naevus, dysplastic naevus, radial growth phase melanoma and vertical growth phase melanoma. No chromosomal aberrations were found in common naevi, but monosomy 7 was observed in one case. In naevus-associated melanomas, loss of the entire chromosome 9 or of the 9p21 region was observed in 56% of common and 54% of dysplastic naevus sectors, in 64% of radial growth phase melanoma and in 82% of vertical growth phase melanoma. Loss of the long arm of chromosome 6, monosomy 10 and deletion 10q were exclusively confined to radial (18% for both chromosomes) and vertical (29 and 59%, respectively) growth phase melanomas. Polysomy of chromosome 7 was detected only in melanoma sectors (radial growth phase, 14%; vertical growth phase, 59%). The high incidence of 9p21 loss in melanoma-associated naevi, which is maintained in all evolutionary phases of melanocytic tumorigenesis, and the complete absence of chromosomal aberrations in common naevi, strongly suggest that 9p21 loss may be regarded as a cytogenetic marker of melanocytic naevi with a high potential for progression.
Melanoma Res
· 2005 Feb · PMID 15714119
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Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) play a key role in vasculogenesis and angiogenic sprouting, which are crucial for tumour development and metastasis. I...Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) play a key role in vasculogenesis and angiogenic sprouting, which are crucial for tumour development and metastasis. In order to determine their possible role in the acquisition of metastatic potential throughout melanocytic tumour progression, VEGF and VEGFR-2 immunohistochemical expression were evaluated in 36 human melanocytic tumours of the skin (24 malignant melanomas and 12 common naevi). Different VEGFR-2 immunostaining patterns were detected in the vast majority of melanomas (21/24; 88%). A nuclear membrane-like pattern was mainly associated with in situ and microinvasive melanomas, whereas a combined cytoplasmic membrane and nuclear membrane-like pattern was seen in invasive melanomas. A nuclear membrane-like pattern was also observed in 83% (10/12) of common naevi. Cytoplasmic immunostaining for VEGF was observed in 72% (8/11) of in situ/microinvasive melanomas, 84% (11/13) of invasive melanomas and 91% (11/12) of naevi. CD31 was also investigated as an immunohistochemical marker for microvessel density (MVD) evaluation. No associations were found between MVD and VEGF/VEGFR-2 expression. Taken together, these data indicate that VEGF production is a common event in benign melanocytic tumours, whereas VEGFR-2 expression, co-localized in the cytoplasmic and nuclear membrane, is associated with progression towards invasive melanoma. The role exerted by VEGF/VEGFR-2, however, seems to be independent of the development of a tumour-related capillary network.
Melanoma Res
· 2004 Oct · PMID 15457100
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Violacein is the main pigment produced by Chromobacterium violaceum, a saprophytic gram-negative bacillus. Violacein is formed by the condensation of two modified tryptophan molecules and has potential anti-neoplastic ef...Violacein is the main pigment produced by Chromobacterium violaceum, a saprophytic gram-negative bacillus. Violacein is formed by the condensation of two modified tryptophan molecules and has potential anti-neoplastic effects. The purpose of this pilot study was to investigate the in vitro activity of violacein in human uveal melanoma cell lines. Human uveal melanoma cell lines 92.1 and OCM-1 were incubated with five different concentrations of violacein (10(-5)-10(-9) M), and the total cellular protein content was measured by means of the sulphorhodamine B assay. Dose-response curves were obtained and the concentration inhibiting cell growth by 50% (IC50) together with the concentration inhibiting the net cell growth by 50% (GI50) were calculated for both cell lines. Violacein IC50 and GI50 concentrations to cell line 92.1 were 2.78 x 10(-6) M and 1.69 x 10(-6) M, respectively. The IC50 and GI50 concentrations to cell line OCM-1 were 3.69 x 10(-6) M and 2.12 x 10(-6) M, respectively. Previous studies using the same methodology have revealed violacein to have a GI50 in the range (3-6) x 10(-8) M for MOLT-4 leukaemia, NCI-H460 large cell lung cancer and KM12 colon cancer cell lines. Violacein displayed borderline cytotoxic activity in human uveal melanoma cell lines 92.1 and OCM-1, as measured by the sulphorhodamine B assay, and further studies are necessary to define its suitability as a potential therapeutic agent for metastatic uveal melanoma.
Yoneta A, Yamashita T, Jin HY
… +2 more, Kondo S, Jimbow K
Melanoma Res
· 2004 Oct · PMID 15457095
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Patients with familial atypical multiple mole and melanoma (FAMMM) [so-called familial dysplastic naevus syndrome (FDNS)] have a high risk for the development of malignant melanoma. The underlying gene defect has an auto...Patients with familial atypical multiple mole and melanoma (FAMMM) [so-called familial dysplastic naevus syndrome (FDNS)] have a high risk for the development of malignant melanoma. The underlying gene defect has an autosomal dominant inheritance with variable expression and incomplete penetrance. Fibroblasts derived from FAMMM patients have high sensitivity to UVC and mutagens, e.g. 4-nitroquinoline-1-oxide. We were interested in identifying how the combination of inherent sensitivity to UV light and abnormal melanin synthesis interacts in the development of melanoma in FAMMM patients. Intermediates of melanin synthesis produce free radicals that are toxic to cells. Atypical moles (dysplastic naevi) are engaged in the biosynthesis of abnormal melanin pigments. This study examined whether there was any abnormal melanin pigmentation or cell damage after the ectopic expression of tyrosinase in fibroblasts from FAMMM patients when compared with fibroblasts from normal subjects. Fibroblasts from FAMMM patients (3012T and 3072T) were associated with a higher sensitivity than normal human fibroblasts to the toxicity of UVB. When cells were infected with tyrosinase-expressing adenovirus (Ad-HT) and irradiated with UVB, FAMMM fibroblasts showed higher tyrosinase activity, produced more melanin pigments and were degraded more significantly than normal human fibroblasts. Western blot analysis revealed that Ad-HT-infected 3072T produced a larger amount of tyrosinase protein than did Ad-HT-infected normal fibroblasts after UVB irradiation. Our findings suggest: (1) that FAMMM fibroblasts have an unknown machinery which enhances tyrosinase expression by UVB irradiation; and (2) that the resulting increase in melanin synthesis affects the cytotoxicity of UVB to FAMMM fibroblasts. All of these processes may be involved in the genomic instability and development of melanoma in FAMMM patients.