Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

7-Aminocephalosporin doxorubicin (AC-Dox) was condensed with monomethoxypoly(ethylene glycol)-propionic acid N-hydroxysuccinimide ester (5 kDa) or with a branched form of poly(ethylene glycol)-propionic acid N-hydroxysuccinimide ester (10 kDa), forming M-PEG-AC-Dox and B-PEG-AC-Dox, respectively. These polymer drug derivatives were designed such that doxorubicin would be released upon Enterobacter cloacae beta-lactamase (bL)-catalyzed hydrolysis. Both M-PEG-AC-Dox (IC50 = 80 microM) and B-PEG-AC-Dox (IC50 = 8 microM) were less toxic to H2981 human lung adenocarcinoma cells than doxorubicin (IC50 = 0.1-0.2 microM) and could be activated in an immunologically specific manner by L6-bL, a monoclonal antibody-bL conjugate that bound to H2981 cell surface antigens. In addition, the polymers were relatively stable in mouse plasma (< 26% hydrolysis after 24 h at 37 degrees C) and were less toxic to mice (maximum tolerated dose > 52 mumol/kg) than doxorubicin (maximum tolerated dose = 13.8 mumol/kg). Pharmacokientic studies were performed in mice bearing subcutaneous 3677 melanoma tumors. B-PEG-AC-Dox cleared from the blood more slowly than M-PEG-AC-Dox and was retained to a 2.1-fold greater extent in human 3677 melanoma tumor xenografts over a 4 h period. The intratumoral concentrations of both polymers far exceeded that of doxorubicin. Thus, the PEG-AC-Dox polymers offer the possibility of generating large intratumoral doxorubicin concentrations owing to their reduced toxicities, the amounts that accumulate in tumors, and the fact that doxorubicin is released upon beta-lactam ring hydrolysis.
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PMID:Poly(ethylene glycol)-doxorubicin conjugates containing beta-lactamase-sensitive linkers. 757 58

The antimetastatic activities of synthetic peptides corresponding to fragments of the adhesion-related molecules, such as fibronectin and laminin, were examined. We prepared three peptides derived from the type III connecting segment domain (IIICS) of fibronectin: Glu-Ile-Leu-Asp-Val (EILDV), Glu-Ile-Leu-Asp-Val-Pro-Ser-Thr (EILDVPST), Arg-Glu-Asp-Val (REDV), and a laminin-related peptide, Tyr-Ile-Gly-Ser-Arg (YIGSR). Each peptide inhibited the experimental tumor metastasis of B16-BL6 melanoma, while EILDV had the strongest effect. The peptides conjugated with poly(ethylene glycol) (PEG) were more effective than the unmodified peptides in molar ratio terms. A mixture composed of PEG hybrids with EILDV, REDV and YIGSR significantly inhibited tumor metastasis.
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PMID:Antimetastatic effects of synthetic peptides containing the core sequence of the type III connecting segment domain (IIICS) of fibronectin. 794 46

Fusion of mouse melanoma cells grown in monolayers has been directly monitored by fluorescence resonance energy transfer between fluorescein and rhodamine probes attached to octadecanoic acid. Various poly(ethylene glycol)s (PEG), either alone or in combination with amphipathic molecules, have been used as fusogens. Fusion starts at a maximum rate as soon as PEG is removed from the medium and reaches a plateau after 20-30 min. Both the initial rate and extent of fusion have been recorded for each experiment. The extent of fusion shows in general a positive correlation with the initial rate, although PEGs with different molar masses appear to induce fusion at different rates, but to a similar extent. A good correlation has been found between the extent of fusion, as measured by fluorescence, and the 'fusion index' computed from cell and nucleus counting; a calibration curve is provided for the interconversion of both parameters. Optimum fusion values are obtained with 50% (w/v) PEG 1500. The effect of pre-treatments with surfactants (Triton X-100, sodium dodecylsulphate) on PEG-induced fusion has also been tested. Sodium dodecylsulphate, but not Triton, enhances considerably both the rate and extent of cell fusion. The in situ generation of the amphipathic molecule diacylglycerol, through the catalytic activity of a phospholipase C, also enhances significantly the fusion parameters. These results are in good agreement with previous studies based on syncytia counting.
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PMID:Real-time measurements of chemically-induced membrane fusion in cell monolayers, using a resonance energy transfer method. 829 22

Carboxyamido-triazole (CAI) is a synthetic inhibitor of non-excitable calcium channels that reversibly inhibits angiogenesis, tumor cell proliferation, and metastatic potential. Inhibition of calcium influx and calcium-dependent events is a potential common mechanism underlying these effects of CAI. The cytostatic and antiangiogenic properties of CAI led to its development for clinical investigation. In a Phase I clinical trial open to patients with refractory solid tumors, 49 patients received p.o. administered CAI daily or every other day. Two oral formulations, PEG-400 CAI solution and a gelatin capsule containing CAI in PEG-400, were tested. All administered dosages of CAI yielded plasma concentration at or above the range demonstrated to be effective in inhibiting signaling and cancer progression in vitro and in preclinical models (1 microgram/ml, 2.3 microM). Toxicity of p.o. administered CAI most commonly consisted of dose-related grade 1-2 nausea, vomiting, and occasional anorexia. CAI administration at bedtime ameliorated gastrointestinal complaints in many patients; others required addition of simple antiemetic regimens, usually consisting of metoclopropamide or prochlorperazine. Gastrointestinal complaints were the cause for compliance-limiting toxicity at 175 mg/m2/day of the liquid formulation and 125 mg/m2/day of the gelatin capsule formation. Reversible and rare sensory axonal neuropathy (grade 3, 1 patient) and neutropenia (grade 4, 1 patient) were dose-limiting toxicities observed at the 330 mg/m2 every-other-day liquid CAI dose level. No evidence of cumulative end organ damage or central nervous system injury was observed. Disease stabilization and improvement in performance status was observed. Disease stabilization and improvement in performance status was observed in 49% of evaluable patients who had disease progression before CAI. Disease stabilization and associated improvement in performance status was seen in patients with renal cell carcinoma (7 months), pancreaticobiliary carcinomas (3, 5, and 5 months), melanoma (7 months), ovarian cancer (7 months), and non-small cell lung cancer (3 months). The recommended Phase II doses from this trial are 150 mg/m2/day in the liquid formation and 100 mg/m2/day in the gelatin capsule formation.
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PMID:Clinical investigation of a cytostatic calcium influx inhibitor in patients with refractory cancers. 856 73

Water-soluble paclitaxel may cause less side effects and be less costly to administer in comparison to a taxol formulation using a cremophor EL/alcohol vehicle. In this study, polyethylene glycol (PEG; MW 5000) was conjugated to the 2' position of paclitaxel through a spacer succinyl group. PEG-paclitaxel as a non-ionic paclitaxel prodrug was highly water soluble (> 20 mg equiv. paclitaxel/ml). The release of paclitaxel from phosphate-buffered solution was pH dependent. The half-life of PEG-paclitaxel was 7.6, 54 and 311 min at pH 9.0, 7.4 and 6.0, respectively. PEG-paclitaxel inhibited the growth of B16 melanoma cells to an extent similar to that of paclitaxel. In MCA-4 mammary tumor-bearing mice, a single dose of PEG-paclitaxel (40 mg equiv. paclitaxel/kg body weight) significantly delayed tumor growth. The average number of days for the tumor to reach 12 from 8 mm in diameter increased from 6.5 days for control animals to 8.5 days for PEG-paclitaxel-treated animals and 9.4 days for paclitaxel-treated animals. These studies demonstrated that PEG may be used as an effective solubilizing carrier for paclitaxel.
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PMID:Synthesis and evaluation of water-soluble polyethylene glycol-paclitaxel conjugate as a paclitaxel prodrug. 891 32

Peptides (H-Glu-Ile-Leu-Asp-Val-NH2, H-Glu-Ile-Leu-Asp-Val-Pro-Ser-Thr-NH2, H-Arg-Glu-Asp-Val-NH2) and their poly(ethylene glycol) (PEG) hybrids related to the core sequence of the type III connecting segment domain of fibronectin A chain were prepared by the solution method or the solid phase method. Their inhibitory effects on the adhesion and migration of B16-BL6 melanoma cells to fibronectin were assessed in vitro, and their therapeutic potency against tumor metastasis were also examined. Anti-adhesive and anti-migrative effects of the synthetic fibronectin-related peptids were superior to those of their PEG hybrids, so we found that the in vitro bioactivity of peptides decreased by PEGylation. In the in vivo assay, we found that the synthetic peptides containing Glu-Ile-Leu-Asp-Val and Arg-Glu-Asp-Val sequences exhibited an inhibitory effect on the experimental metastasis of B16-BL6 melanoma. Of the synthetic peptides, H-Glu-Ile-Leu-Asp-Val-NH2 exhibited the most potent inhibitory effect. Hybrid formation of Arg-Glu-Asp-Val with poly(ethylene glycol) resulted in potentiation of the inhibitory effect of the parent peptides. A mixture composed of PEG hybrids of Glu-Ile-Leu-Asp-Val, Arg-Glu-Asp-Val and Tyr-Ile-Gly-Ser-Arg dramatically inhibited tumor metastasis.
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PMID:Amino acids and peptides. XXIX. Synthesis and antimetastatic effects of peptides and peptide-poly(ethylene glycol) hybrids related to the core sequence of the type III connecting segment domain of fibronectin. 899 42

An analogue of human melanin-concentrating hormone (MCH) suitable for radioiodination was designed in which Tyr13 and Val19 of the natural peptide were replaced by phenylalanyl and tyrosyl residues: [Phe13, Tyr19]-MCH. The peptide was synthesized by the continuous-flow solid-phase methodology using Fmoc-strategy and polyhipe PA 500 and PEG-PS resins. The linear MCH peptides with either acetamidomethyl-protected or free cysteinyl residues were purified to homogeneity and cyclized by iodine oxidation, yielding the final product with the correct molecular weight of 2434.61. Radioiodination of the C-terminal tyrosine was carried out enzymatically using solid-phase bound glucose oxidase/lactoperoxidase, followed by purification on a reversed-phase mini-column and by high-pressure liquid chromatography. The resulting [125I]-[Phe13, Tyr19]-MCH tracer was the first radiolabelled MCH peptide suitable for radioreceptor assay: saturation binding analysis using mouse G4F-7 melanoma cells demonstrated the presence of 1090 MCH receptors per cell. The dissociation constant (KD) was 1.18 x 10(-10) M, indicating high-affinity MCH receptors on these cells. MCH receptors were also found in other cell lines such as mouse B16-F1 and G4F and human RE melanoma cells as well as in PC12 and COS-7 cells. Competition binding analyses with a number of other peptides such as alpha-MSH, neuropeptide Y, substance P and pituitary adenylate cyclase activating peptide, demonstrated that the binding to the MCH receptor is specific. Atrial natriuretic factor was found to be a weak competitor of MCH, indicating topological similarities between MCH and ANF when interacting with MCH receptors.
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PMID:Synthesis and iodination of human (phenylalanine 13, tyrosine 19) melanin-concentrating hormone for radioreceptor assay. 922 84

A photoreactive analogue of human melanin-concentrating hormone was designed, [D-Bpa13,Tyr19-MCH, containing the D-enantiomer of photolabile p-benzoylphenylalanine (Bpa) in position 13 and tyrosine for radioiodination in position 19. The linear peptide was synthesized by the continuous-flow solid-phase methodology using Fmoc-strategy and PEG-PS resins, purified to homogeneity and cyclized by iodine oxidation. Radioiodination of [D-Bpa13,Tyr19]-MCH at its Tyr19 residue was carried out enzymatically using solid-phase bound glucose oxidase/lactoperoxidase, followed by purification on a reversed-phase mini-column and HPLC. Saturation binding analysis of [125I]-[D-Bpa13,Tyr19]-MCH with G4F-7 mouse melanoma cells gave a K(D) of 2.2+/-0.2 x 10(-10) mol/l and a B(max) of 1047+/-50 receptors/cell. Competition binding analysis showed that MCH and rANF(1-28) displace [125I]-[D-Bpa13,Tyr19]-MCH from the MCH binding sites on G4F-7 cells whereas alpha-MSH has no effect. Receptor crosslinking by UV-irradiation of G4F-7 cells in the presence of [125I]-[D-Bpa13,Tyr19]-MCH followed by SDS-polyacrylamide gel electrophoresis and autoradiography yielded a band of 45-50 kDa. Identical crosslinked bands were also detected in B16-F1 and G4F mouse melanoma cells, in RE and D10 human melanoma cells as well as in COS-7 cells. Weak staining was found in rat PC12 phaeochromocytoma and Chinese hamster ovary cells. No crosslinking was detected in human MP fibroblasts. These data demonstrate that [125I]-[D-Bpa13,Tyr19]-MCH is a versatile photocrosslinking analogue of MCH suitable to identify MCH receptors in different cells and tissues; the MCH receptor in these cells appears to have the size of a G protein-coupled receptor, most likely with a varying degree of glycosylation.
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PMID:(D-(p-benzoylphenylalanine)13, tyrosine19)-melanin-concentrating hormone, a potent analogue for MCH receptor crosslinking. 1036 6

Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, approved by the FDA for the treatment of ovarian and breast cancers. Due to its low solubility in water, it is clinically administered dissolved in Cremophor EL, (polyethoxylated castor oil) and ethanol, which cause serious side effects. Inclusion of paclitaxel in liposomal formulations has proved to be a good approach to eliminating this vehicle and improving the drug's antitumor efficacy. We prepared different conventional and PEGylated liposomes containing paclitaxel and determined encapsulation efficiency, physical stability and drug leakage in human plasma. The best conventional liposome formulation was composed of ePC/PG 9:1, while for PEGylated liposomes the best composition was ePC/PG/CHOL/PEG(5000)-DPPE 9:1:2:0.7. PEGylated liposomes were found to be less stable during storage than the corresponding conventional liposomes and to have lower drug release in human plasma at 37 degrees C. In vitro cytotoxic activities were evaluated on HT-29 human colon adenocarcinoma and MeWo melanoma cell lines. After 2 and 48 h, conventional liposomes had the same cytotoxicity as free paclitaxel, while PEGylated liposomes were as active as free drug, only after 48 h. Pharmacokinetics and biodistribution were evaluated in Balb/c mice after i.v. injection of paclitaxel, formulated in Cremophor EL or in conventional or in PEGylated liposomes. Encapsulation of paclitaxel in conventional liposomes produced marked differences over the free drug pharmacokinetics. PEGylated liposomes were long-circulating liposomes, with an increased t(1/2) beta 48.6 h, against t(1/2) beta 9.27 h of conventional liposomes. Biodistribution studies showed a considerable decrease in drug uptake in MPS-containing organs (liver and spleen) at 0.5 and 3 h after injection with PEGylated compared to conventional liposomes.
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PMID:Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes. 1064 May 77

We evaluated the use of poly(ethylene glycol) (PEG)-modified lipids to control the surface properties of a lipid-based gene transfer system. The lipid-DNA particles (LDPs) used form spontaneously when plasmid DNA is added to mixed detergent lipid micelles consisting of the non-ionic detergent n-octyl-D-glucopyranoside, the cationic lipid dioleyldimethylammonium chloride (DODAC), the zwitterionic lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and selected PEG-modified phosphatidylethanolamines. The inclusion of DODAC is required to form the hydrophobic lipid-DNA complex. DOPE is included to facilitate dissociation of DNA from the cationic lipid and the PEG-modified lipids are added in an effort to stabilize the surface attributes of the resulting lipid-DNA particles. We used PEG-lipids that varied in acyl chain composition because of recent results demonstrating acyl chain dependent transfer of PEG-lipids from lipid vesicles, providing the potential to allow a transformation of the surface properties due to loss of surface grafted PEG. The addition of PEG-modified lipids does not interfere in LDP formation and its presence favors formation of smaller particles (75 nm in contrast to 130 nm in the absence of the PEG-modified lipid). PEG-lipid incorporation causes a concentration dependent reduction in LDP-mediated transfection of B16/BL6 melanoma cells, a result that can be partially attributed to a reduction in particle binding to cells. However, significant LDP binding to B16/BL6 cells was still observed under conditions where LDP transfection activity was reduced by more than 85%. The potential for PEG to interfere with LDP processing following cell binding is discussed.
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PMID:Use of poly(ethylene glycol)-lipid conjugates to regulate the surface attributes and transfection activity of lipid-DNA particles. 1075 31


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