Neurocutaneous melanosis presenting with intracranial amelanotic melanoma.
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We describe imaging findings in a 2-year-old girl with neurocutaneous melanosis and malignant cerebral melanoma. Because the cerebral melanoma in this child was of the amelanotic type, high-signal intensity on unenhanced T1-weighted images was not present. The cutaneous lesions played a crucial role in establishing a correct (presumed) histopathologic diagnosis on the basis of the imaging findings. To our knowledge this is the first report describing an intracranial amelanotic malignant melanoma in association with neurocutaneous melanosis. (+info)
Active and higher intracellular uptake of 5-aminolevulinic acid in tumors may be inhibited by glycine.
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Topical 5-aminolevulinic acid is used for the fluorescence-based diagnosis and photodynamic treatment of superficial precancerous and cancerous lesions of the skin. Thus, we investigated the kinetics of 5-aminolevulinic acid-induced fluorescence and the mechanisms responsible for the selective formation of porphyrins in tumors in vivo. Using amelanotic melanomas (A-Mel-3) grown in dorsal skinfold chambers of Syrian golden hamsters fluorescence kinetics were measured up to 24 h after topical application of 5-aminolevulinic acid (1%, 3%, or 10%) for 1 h, 4 h, or 8 h by intravital microscopy (n = 54). Maximal fluorescence intensity in tumors after 1 h application (3% 5-aminolevulinic acid) occurred 150 min and after 4 h application (3% 5-aminolevulinic acid) directly thereafter. Increasing either concentration of 5-aminolevulinic acid or application time did not yield a higher fluorescence intensity. The selectivity of the fluorescence in tumors decreased with increasing application time. Fluorescence spectra indicated the formation of protoporphyrin IX (3% 5-aminolevulinic acid, 4 h; n = 3). The simultaneous application of 5-aminolevulinic acid (3%, 4 h) and glycine (20 microM or 200 microM; n = 10) reduced fluorescence in tumor and surrounding host tissue significantly. In contrast, neither decreasing iron concentration by desferrioxamine (1% and 3%; n = 10) nor inducing tetrapyrrole accumulation using 1, 10-phenanthroline (7.5 mM; n = 5) increased fluorescence in tumors. The saturation and faster increase of fluorescence in the tumor together with a reduction of fluorescence by the application of glycine suggests an active and higher intracellular uptake of 5-aminolevulinic acid in tumor as compared with the surrounding tissue. Shorter application (1 h) yields a better contrast between tumor and surrounding tissue for fluorescence diagnosis. The additional topical application of modifiers of the heme biosynthesis, desferrioxamine or 1,10-phenanthroline, however, is unlikely to enhance the efficacy of topical 5-aminolevulinic acid-photodynamic therapy at least in our model. (+info)
Expression and regulation of parathyroid hormone-related peptide in normal and malignant melanocytes.
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We examined parathyroid hormone-related peptide (PTHrP) production and regulation in both normal human melanocytes and in a human amelanotic melanoma cell line (A375). Northern blot and immunocytochemical analysis demonstrated that both cultured A375 cells and normal human melanocytes express PTHrP, but A375 cells expressed much higher levels of the peptide. PTHrP secretory rate increased at least 10-fold after treatment with 10% fetal bovine serum (100.2 +/- 2.8 pmol/10(6) cells vs. basal <15 pmol/10(6) cells) in proliferating A375 cells but only twofold in confluent cells. Treatment of A375 cells with increasing concentrations of 1, 25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] or its low-calcemic analog EB-1089 revealed that EB-1089 was 10-fold more potent than 1, 25-(OH)(2)D(3) on inhibition of both cell proliferation and PTHrP expression. Furthermore, inoculation of A375 cells into the mammary fat pad of female severe combined immunodeficiency mice resulted in the development of hypercalcemia and elevated concentrations of plasma immunoreactive PTHrP in the absence of detectable skeletal metastases. Our study, therefore, demonstrates a stepwise increase in PTHrP expression when cells progress from normal to malignant phenotype and suggests that EB-1089 should be further evaluated as a therapeutic agent in human melanoma. (+info)
Quantitative imaging of tumour blood flow by contrast-enhanced magnetic resonance imaging.
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Tumour blood flow plays a key role in tumour growth, formation of metastasis, and detection and treatment of malignant tumours. Recent investigations provided increasing evidence that quantitative analysis of tumour blood flow is an indispensable prerequisite for developing novel treatment strategies and individualizing cancer therapy. Currently, however, methods for noninvasive, quantitative and high spatial resolution imaging of tumour blood flow are rare. We apply here a novel approach combining a recently established ultrafast MRI technique, that is T(1)-relaxation time mapping, with a tracer kinetic model. For validation of this approach, we compared the results obtained in vivo with data provided by iodoantipyrine autoradiography as a reference technique for the measurement of tumour blood flow at a high resolution in an experimental tumour model. The MRI protocol allowed quantitative mapping of tumour blood flow at spatial resolution of 250 x 250 microm(2). Correlation of data from the MRI method with the iodantipyrine autoradiography revealed Spearman's correlation coefficients of Rs = 0.851 (r = 0.775, P < 0.0001) and Rs = 0.821 (r = 0.72, P = 0.014) for local and global tumour blood flow, respectively. The presented approach enables noninvasive, repeated and quantitative assessment of microvascular perfusion at high spatial resolution encompassing the entire tumour. Knowledge about the specific vascular microenvironment of tumours will form the basis for selective antivascular cancer treatment in the future. (+info)
2-aroylindoles, a novel class of potent, orally active small molecule tubulin inhibitors.
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2-Aroylindoles with 5-methoxy-1H-2-indolyl-phenylmethanone (D-64131) as the lead structure were discovered as a new class of synthetic, small molecule tubulin inhibitors. By competitively binding with [(3)H]colchicine to alphabeta-tubulin and inhibiting microtubule formation, cycling cells were arrested in the G(2)-M phase of the cell division cycle. The proliferation of tumor cells from 12 of 14 different organs and tissues was inhibited with mean IC(50)s of 62 nM and 24 nM by D-64131 and D-68144, respectively, comparable with the potency of paclitaxel with mean IC(50) of 10 nM. By measuring the cytotoxicity in a human colon carcinoma cell model with ectopic ecdysone-inducible expression of the cyclin-dependent kinase inhibitor p21(WAF1), specificity toward cycling cells was demonstrated. In contrast to microtubule inhibitors from natural sources, 2-aroylindoles did not alter the polymerization-dependent GTPase activity of beta-tubulin and are not substrates of the multidrug resistance/multidrug resistance protein efflux pump. No cross-resistance toward cell lines with multidrug resistance/multidrug resistance protein independent resistance phenotypes became evident. In animal studies, no signs of systemic toxicity were observed after p.o. dosages of up to 400 mg/kg of D-64131. In xenograft experiments with the human amelanoic melanoma MEXF 989, D-64131 was highly active with treatment resulting in a growth delay of 23.4 days at 400 mg/kg. Therefore, D-64131 and analogues have the potential to be developed for cancer therapy, replacing or supplementing standard therapy regimens with tubulin-targeting drugs from natural sources. (+info)
Tyrosinase and tyrosinase-related protein 1 require Rab7 for their intracellular transport.
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We have recently identified the association of Rab7 in melanosome biogenesis and proposed that Rab7 is involved in the transport of tyrosinase-related protein 1 from the trans-Golgi network to melanosomes, possibly passing through late-endosome-delineated compartments. In order to further investigate the requirement of Rab7-containing compartments for vesicular transport of tyrosinase family proteins, we expressed tyrosinase and tyrosinase-related protein by recombinant adenovirus and analyzed their localization in human amelanotic melanoma cells (SK-mel-24) in the presence or absence of a dominant-negative mutant of Rab7 (Rab7N125I). Co-infection of the recombinant adenoviruses carrying tyrosinase (Ad-HT) and TRP-1 (Ad-TRP-1) resulted in the enhancement of tyrosinase activity and melanin production compared to a single infection of Ad-HT. In the Ad-HT-infected SK-mel-24 cells many of the newly synthesized tyrosinase proteins were colocalized in lysosomal lgp85-positive granules of the entire cytoplasm, whereas in the presence of Rab7N125I the colocalization of tyrosinase and lgp85 proteins was decreased markedly in the distal area of the cytoplasm. In the Ad-TRP-1-infected SK-mel-24 cells, TRP-1, which is reported to be present exclusively in melanosomes, was detected throughout the cytoplasm, but not colocalized in prelysosomal (early endosomal) EEA-1 granules. In the presence of Rab7N125I, however, TRP-1 was retained in the EEA-1-positive granules. Our findings indicate that the dominant-negative mutant of Rab7 impairs vesicular transport of tyrosinase and TRP-1, suggesting that the transport of these melanogenic proteins from the trans-Golgi network to maturing melanosomes requires passage through endosome-delineated compartments. (+info)
A rare case of intracranial metastatic amelanotic melanoma with cyst.
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A rare case of intracranial metastatic amelanotic melanoma with cyst is presented. The patient was a 51 year old woman with a malignant melanoma arising on her right chest. Two years after a wide excision, skin and brain metastasis occurred. Brain magnetic resonance images demonstrated a tumour with a cyst in the left occipital lobe. Because the tumour showed low intensity on T1 weighted images and high intensity on T2 weighted images, the metastatic melanoma was identified as an amelanotic melanoma. Intracranial amelanotic melanoma is very rare, and there have been few reports of melanoma with cyst. (+info)
Comparison of tyrosinase-related protein-2, S-100, and Melan A immunoreactivity in canine amelanotic melanomas.
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Tyrosinase-related protein-2 (TRP-2) is a highly conserved melanogenic enzyme expressed in both pigmented and unpigmented melanomas of the mouse. To determine whether TRP-2 would be a good diagnostic marker for amelanotic melanomas of the dog, we performed immunohistochemistry for TRP-2, S-100, and Melan A on 21 canine tumors identified as amelanotic melanomas based on routine histopathologic examination. Thirteen of the tumors were TRP-2 positive, 10 were Melan A positive, and 19 were S-100 positive. TRP-2 was expressed in the cytoplasm of tumor cells in both primary and metastatic melanomas. S-100 staining was positive in all of three schwannomas and two of three gastrointestinal stromal tumors (one fibrosarcoma and one leiomyosarcoma) tested. Neither Melan A nor TRP-2 antibodies reacted with these tumors. Our findings indicate that staining for TRP-2 is a sensitive and specific method for confirming the diagnosis of amelanotic melanoma in dogs. (+info)