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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In view of the rising melanoma incidence and the absence of effective treatments for metastatic disease, there is an urgent need for new methods that allow the early detection of melanoma. To this end, in vivo detection by patient imaging with single-chain Fv (scFv) antibody fragments is an attractive diagnostic approach. However, high non-specific accumulation of scFvs in the kidney reduces image quality in this body area and prevents the use of scFvs for melanoma radioimmunotherapy. We have tested the effect of coadministration of L-lysine with (125)I-labelled scFvs against melanoma-associated proteoglycan on kidney accumulation in a nude mouse xenograft model. Coadministration of L-lysine had no significant effect on tumour accumulation of scFvs or blood clearance, but decreased kidney accumulation by factors of 2.25, 2.3, 6.3 and 5.8, respectively, at 1, 3, 6 and 18 h post-injection, and improved tumour to muscle contrast. The reduction in kidney accumulation was maximal at time points that can be extrapolated to patient studies. The time dependence of the effect suggests that further improvements could be achieved with an optimized dosing regimen. When combined with other strategies to reduce kidney accumulation of scFvs, coadministration of L-lysine has the potential to significantly improve tumour to kidney contrast.
Melanoma Res 2002 Aug
PMID:Reducing renal accumulation of single-chain Fv against melanoma-associated proteoglycan by coadministration of L-lysine. 1217 Jan 87

The purpose of our study was to optimize melanoma tumor uptake of 188Re-CCMSH and reduce its nonspecific kidney retention. Nephrotoxicity is often a serious problem associated with targeted radiotherapy, therefore, increasing the tumor/kidney uptake ratio of 188Re-CCMSH is crucial for optimizing its therapeutic efficacy. Structural modification of the peptide and amino acid co-infusion were investigated as strategies to improve the tumor/kidney uptake ratio of 188Re-CCMSH. The substitution of Lys11 with Arg11 was examined to determine if removal of lysine from the peptide would improve kidney clearance without sacrificing tumor uptake. The pharmacokinetics of 188Re-CCMSH and 188Re-(Arg(11))CCMSH were determined in B16/F1 murine melanoma-bearing C57 mice. Tumor uptake values of (188)Re-CCMSH and 188Re-(Arg(11))CCMSH were 15.03 +/- 5.20% ID/g and 20.44 +/- 1.91% ID/g at 1 hr postinjection and 1.94 +/- 0.47% ID/g and 3.50 +/- 2.32% ID/g at 24 hr postinjection. Renal retention of 188Re-(Arg(11))CCMSH was 11.79 +/- 1.29 ID/g and 3.67 +/- 0.51 ID/g at 1 hr and 4 hr postinjection, which was a greater than 50% reduction compared to 188Re-CCMSH. The Arg for Lys substitution in 188Re-(Arg(11))CCMSH resulted in improved tumor uptake and reduced kidney retention. Renal retention of both 188Re-CCMSH and 188Re-(Arg(11))CCMSH were significantly reduced by co-injection of 20 mg of L-lysine, L-arginine and a combination of L-lysine:L-arginine. Tumor/kidney uptake values for 188Re-CCMSH and 188Re-(Arg(11))CCMSH were maximally reduced by 52.9% and 46.3%, respectively. However, even with amino acid co-injection, the tumor/kidney ratio of 188Re-CCMSH was lower than that of 188Re-(Arg(11))CCMSH. Improved tumor uptake and reduced kidney retention of 188Re-(Arg(11))CCMSH will facilitate targeted irradiation of melanoma tumors while minimizing the dose to the kidneys.
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PMID:In vivo evaluation of 188Re-labeled alpha-melanocyte stimulating hormone peptide analogs for melanoma therapy. 1221 78

A polypeptide with 33 amino acid residues was designed and synthesized. Its C terminal was composed of multiple lysine residues, which played as a DNA condensing agent, whereas the N terminal was the receptor binding domain of Epidermal Growth Factor(N32-K48). Through a spontaneous self-assembly process with electrostatic interaction, the synthetic peptide combined with a luciferase expression vector, pEBluc, to form an EGF receptor targeting nucleic acid complex. Significant luciferase activity was detected 48 hours after adding this complex directly to the culture medium of the A431 cells. This synthetic peptide could be used to construct a gene transfer system mediated by the endocytosis via EGF receptor. It promoted a very possibility of the gene therapy for the cancers such as glioma, melanoma and squamous carcinoma which are known of epidermal growth factor receptor overexpression.
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PMID:[A novel gene delivery system targeting to epidermal growth factor receptor overexpressing cancer cells]. 1251 70

BRAF mutations have recently been detected with a high frequency (66%) in cutaneous melanoma. All those mutations are activating, with a single substitution (T1796A) at codon 599 (V599E) accounting for over 90%. To investigate the stage in which those mutations occur in the currently proposed sequential malignant transformation of melanocytes, 22 benign melanocytic nevi, 23 melanocytic atypical nevi, and 25 primary cutaneous melanoma from 63 different patients were examined for BRAF mutations using DNA extracted from microdissected formalin-fixed and paraffin-embedded tissues, and a two-round PCR-RFLP-based strategy. A subset of samples was sequenced for mutation confirmation. Sixteen benign (73%) and eleven atypical (52%) melanocytic nevi, and thirteen melanoma (56%) demonstrated BRAF mutations at codon 599, and no statistically significant differences were detected among all three types of lesions. No mutations were demonstrated in microdissected epidermal keratinocytes adjacent to melanocytic lesions having BRAF mutations. No correlation was detected between BRAF mutational status and age, sun exposure, and Clark's level in malignant melanoma. However, comparing only atypical nevi and melanoma lesions the frequency of BRAF mutation is significantly greater in male (78%) than female (35%) patients (P = 0.0194). The previously described T1796A point mutation was detected in 17 of 18 mutated samples, and a novel mutation consisting of a substitution of valine for lysine (GT1795-96AA) was detected in one melanoma case. Our findings of a high frequency of BRAF mutations at codon 599 in benign melanocytic lesions of the skin indicate that this mutation is not sufficient by itself for malignant transformation.
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PMID:BRAF mutation: a frequent event in benign, atypical, and malignant melanocytic lesions of the skin. 1450 Dec 84

On exposure to an acidic pH, linear poly(amidoamine)s (PAAs) cause membrane perturbation and consequently have potential as endosomolytic polymers for the intracellular delivery of genes and toxins. Previous studies used PAAs in the hydrochloride form only. The aim of this study was to investigate systematically the effect of the PAA counterion on pH-dependent membrane activity, general cytotoxicity, and PAA solution properties to help guide optimization of PAA structure for further development of PAA-protein conjugates. PAAs (ISA 1, 4, 22, and 23; M(w) 10000-50000 g/mol) were synthesized to provide a library of PAAs having different counterions including the acetate, citrate, hydrochloride, lactate, phosphate, and sulfate salts. pH-Dependent membrane activity was assessed using a rat red blood cell haemolysis assay (conducted at a starting pH of 7.4, 6.5, or 5.5; 1 mg/mL; 1 h), and general cytotoxicity was investigated using a murine melanoma cell line (B16F10) and a human bladder endothelial-like cell line (ECV-304). Whereas poly(ethyleneimine) was haemolytic at the starting pH of 7.4 at 1 h [ approximately 50% haemoglobin (Hb) release], none of the PAA salts were haemolytic at a starting pH of 7.4 or 6.5. Although PAA acetate, citrate, and lactate were also non-haemolytic at the starting pH of 5.5, the sulfate and hydrochloride forms caused significant haemolysis (up to 80% Hb release) and ISA 22 and 23 phosphate were also markedly haemolytic ( approximately 70% Hb release). These counterion-specific differences were also clearly visible using scanning electron microscopy, which was used to visualize the red blood cell morphology. All PAAs were relatively nontoxic (IC(50) >or= 300-5000 microg/mL) compared to poly-l-lysine (IC(50) = 2-10 microg/mL), the PAA hydrochloride salts produced the greatest cytotoxicity, and the B16F10 cells were more sensitive than the ECV-304 cells. Small-angle neutron scattering suggested that ISA 23 hydrochloride had a larger hydrodynamic radius (5.1 +/- 0.2 nm) than the citrate salt (3.1 +/- 0.2 nm). These results provide indirect evidence for the salt- and pH-dependent changes in the conformation of the polymer coil. This study clearly demonstrates the importance of optimization of the counterion form when developing endosomolytic polymers designed to mediate pH-dependent membrane permeabilization.
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PMID:Poly(amidoamine) salt form: effect on pH-dependent membrane activity and polymer conformation in solution. 1513 5

Angiogenesis, the formation of new capillaries from preexisting blood vessels, is involved in many pathological conditions, for example, tumorigenesis, diabetic retinopathy, and rheumatoid arthritis. Angiostatin, which contains the kringle 1-4 domains of plasminogen, is known to be a potent inhibitor of angiogenesis and a strong suppressor of various solid tumors. In this study, we expressed recombinant protein containing the kringle 1-3 domains of human plasminogen in Escherichia coli and investigated its biological activities. The protein was successfully refolded from inclusion bodies and purified at a 30% overall yield, as a single peak by HPLC. The purified recombinant protein had biochemical properties that were similar to those of the native form, which included molecular size, lysine-binding capacity, and immunoreactivity with a specific antibody. The recombinant protein was also found to strongly inhibit the proliferation of bovine capillary endothelial cells in vitro, and the formation of new capillaries on chick embryos. In addition, it suppressed the growth of primary Lewis lung carcinoma and B16 melanoma in an in vivo mouse model. Our findings suggest that the recombinant kringle 1-3 domains in a prokaryote expression system have anti-angiogenic activities, which may be useful in clinical and basic research in the field of angiogenesis.
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PMID:Characterization and biological activities of recombinant human plasminogen kringle 1-3 produced in Escherichia coli. 1517 78

Utilizing three biocompatible components, a series of novel cationic lipids has been chemically synthesized and tested for their gene-transferring capabilities in 293 transformed kidney cells and B16BL6 mouse melanoma cells. The synthesized cationic lipids consisting of a core of lysine and aspartic acid with hydrocarbon chains of varied length were assigned the acronyms DLKD (O,O'-dilauryl N-lysylaspartate), DMKD (O,O'-dimyristyl N-lysylaspartate), DPKD (O,O'-dipalmityl N-lysylaspartate), and DSKD (O,O'-distearyl N-lysylaspartate). The gene-transferring capabilities of these cationic lipids were found to be dependent on the hydrocarbon chain length. Under similar experimental conditions, the order of gene transfection efficiency was DMKD > DLKD > DPKD > DSKD. Addition of cholesterol or dioleoyl phosphatidylethanolamine (DOPE) as a colipid did not change this order. Colipid addition affected the transfection efficiency positively or negatively depending on the length of the cationic lipid acyl chain. On the whole, the length of the hydrophobic carbon chain was a major factor governing the gene-transferring capabilities of this series of cationic lipids. The observed differences in transfection efficiency may be due to differing binding affinities to DNA molecules as well as differences in the surface charge potential of the liposome-DNA complexes (lipoplexes) in the aqueous environment.
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PMID:Gene-transferring efficiencies of novel diamino cationic lipids with varied hydrocarbon chains. 1536 65

In vivo magnetic resonance (MR) spectroscopy at 1.5T was performed on a large polypoid cutaneous melanoma, and two enlarged lymph nodes containing metastatic melanoma, from three patients. Spectra were acquired in vivo from voxels wholly within the primary tumour or secondary lymph node and were thus uncontaminated by signals from adjacent tissue. Tissue biopsies taken after resection of primary tumours and secondary lymph nodes were examined by 8.5T magnetic resonance spectroscopy (MRS) and the results compared with the in vivo spectra, and with spectra from normal skin and a benign skin lesion. There was good agreement between the dominant features of 1.5T spectra acquired in vivo and 8.5T spectra acquired from resected tissue. However, less intense resonances observed at 8.5T in malignant biopsy tissue were not consistently observed at 1.5T in vivo. In vivo spectra from primary and metastatic melanoma showed high levels of choline metabolites. An intense lactate resonance was also present in the in vivo spectrum of primary melanoma. All 8.5T spectra of biopsies from primary and secondary melanoma showed high levels of choline metabolites and lactate, and additional resonances consistent with elevated levels of taurine, alanine, lysine, and glutamate/glutamine relative to normal and benign tissue. Elevated levels of choline, lactate, taurine, and amino acids appear to be clinically useful markers for identifying the pathology of primary and metastatic melanoma.
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PMID:In vivo and ex vivo proton MR spectroscopy of primary and secondary melanoma. 1574 Oct 26

DEK is a mammalian protein that has been implicated in the pathogenesis of autoimmune diseases and cancer, including acute myeloid leukemia, melanoma, glioblastoma, hepatocellular carcinoma, and bladder cancer. In addition, DEK appears to participate in multiple cellular processes, including transcriptional repression, mRNA processing, and chromatin remodeling. Sub-nuclear distribution of this protein, with the attendant functional ramifications, has remained a controversial topic. Here we report that DEK undergoes acetylation in vivo at lysine residues within the first 70 N-terminal amino acids. Acetylation of DEK decreases its affinity for DNA elements within the promoter, which is consistent with the involvement of DEK in transcriptional repression. Furthermore, deacetylase inhibition results in accumulation of DEK within interchromatin granule clusters (IGCs), sub-nuclear structures that contain RNA processing factors. Overexpression of P/CAF acetylase drives DEK into IGCs, and addition of a newly developed, synthetic, cell-permeable P/CAF inhibitor blocks this movement. To our knowledge, this is the first reported example of acetylation playing a direct role in relocation of a protein to IGCs, and this may explain how DEK can function in multiple pathways that take place in distinct sub-nuclear compartments. These findings also suggest that DEK-associated malignancies and autoimmune diseases might be amenable to treatment with agents that alter acetylation.
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PMID:p300/CBP-associated factor drives DEK into interchromatin granule clusters. 1598 77

The microphthalmia transcription factor MITF plays important roles in several cell lineages including retinal and neural crest-derived pigment cells. Previous reports have shown that besides its regulation at the transcriptional level, MITF is also regulated post-translationally by phosphorylation and ubiquitination which affect the protein's activity and stability. Here we demonstrate that in addition, MITF is modified in melanoma cells by small ubiquitin-like modifier (SUMO). In vitro assays further show that sumoylation occurs at two lysine residues, K182 and K316, and depends on SUMO E1 activating enzyme (SAE I/SAE II) and E2 conjugating enzyme (Ubc9). Interestingly, MITF with double lysine 182/316 to arginine mutations, although displaying normal DNA binding, stability and nuclear localization, shows a substantial increase in the transcriptional stimulation of promoters containing multiple but not single MITF binding sites. MITF containing the double lysine-to-arginine substitution also shows enhanced cooperation with Sox10 on the Dct promoter. We conclude that SUMO modification of MITF regulates the protein's transcriptional activity especially with respect to synergistic activation. The results suggest that sumoylation plays a significant role among the multiple mechanisms that regulate MITF during development and in adulthood.
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PMID:Sumoylation modulates transcriptional activity of MITF in a promoter-specific manner. 1602 20


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