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)

The purpose of this study was to develop oil-in-water emulsions (100-120 nm in diameter) and to correlate the surface properties of the emulsions with blood residence time and accumulation into neoplastic tissues by passive targeting. We investigated the effect of phospholipid and sphingolipid emulsifiers, hydrogenated soybean phosphatidylcholine (HSPC) and egg sphingomyelin (ESM), in combination with polysorbate 80 (PS-80) and 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE)-PEG lipids of various PEG chain lengths and structures in prolonging circulation time and enhancing accumulation into B16 melanoma or C26 colon adenocarcinoma. The relationship between amphiphile molecular packing at the air/water interface on emulsion stability upon dilution in albumin and circulation longevity in vivo was also explored for non-PEGylated emulsions. PEGylation of the droplet surface with 10-15 mol% of DSPE-PEG 2000 or 5000 enhanced the circulation time of the emulsions, however, accumulation was only observed in the C26 tumor model. The tighter molecular packing observed with ESM/PS-80 monolayers at the air/water interface compared to HSPC/PS-80 correlated with improved emulsion stability in vitro, however, enhanced circulation time in vivo was not observed. A better understanding of the relationships between composition and performance will result in improved emulsion-based drug delivery vehicles for cancer therapy.
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PMID:Long-circulating poly(ethylene glycol)-coated emulsions to target solid tumors. 1749 Aug 68

Terminal prostate cancer is refractory to conventional anticancer treatments because of frequent overexpression of antiapoptotic proteins Bcl-2 and/or Bcl-x(L). Adenovirus-mediated delivery of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), a secreted cytokine having cancer-selective apoptosis-inducing properties, profoundly inhibits prostate cancer cell growth. However, forced overexpression of Bcl-2 or Bcl-x(L) renders prostate cancer cells resistant to Ad.mda-7. We constructed a conditionally replication-competent adenovirus in which expression of the adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of progression elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the adenovirus (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV). This CTV generates large quantities of MDA-7/IL-24 as a function of adenovirus replication uniquely in cancer cells. Infection of Ad.PEG-E1A-mda-7 (CTV) in normal prostate epithelial cells and parental and Bcl-2- or Bcl-x(L)-overexpressing prostate cancer cells confirmed cancer cell-selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 (CTV) into xenografts derived from DU-145-Bcl-x(L) cells in athymic nude mice completely eradicated not only primary tumors but also distant tumors (established in the opposite flank), thereby implementing a cure. These provocative findings advocate potential therapeutic applications of this novel virus for advanced prostate cancer patients with metastatic disease.
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PMID:Eradication of therapy-resistant human prostate tumors using a cancer terminator virus. 1754 25

Poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) and newly developed poly(ethylene oxide)-block-poly(alpha-benzyl carboxylate epsilon-caprolactone) (PEO-b-PBCL) micelles were evaluated for the solubilization and delivery of cucurbitacin I and B, poorly water soluble inhibitors of signal transducer and activator of transcription 3 (STAT3). Encapsulation of cucurbitacins in PEO-b-PCL and PEO-b-PBCL by co-solvent evaporation technique resulted in polymeric micelles <90 nm in diameter. The aqueous solubility of both derivatives increased from less than 0.05 mg/mL in the absence of the copolymer to around 0.30-0.44 and 0.65-0.68 mg/mL in the presence of 5000-5000 and 5000-24,000 PEO-b-PCL micelles, respectively. Maximum cucurbitacin solubilization was achieved with PEO-b-PBCL micelles for both derivatives. PEO-b-PCL micelles having longer PCL block were found to be more efficient in sustaining the rate of release for cucurbitacins. The anti-cancer and STAT3 inhibitory activity of polymeric micellar cucurbitacins were comparable with free drugs in B16.F10 melanoma cell line in vitro. Intratumoral injection of 1 mg/kg/day cucurbitacin I resulted in the regression of established B16.F10 mouse melanoma tumors in vivo. In comparison to free cucurbitacin I, PEO-b-PBCL micellar cucurbitacin I was found to provide comparable anti-cancer effects against B16.F10 tumors and limit drug levels in animal serum while maintaining high drug levels in tumor following intratumoral administration. The results indicate the potential of polymeric micelles as suitable vehicles for the delivery of cucurbitacin- I and B.
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PMID:Polymeric micelles for the solubilization and delivery of STAT3 inhibitor cucurbitacins in solid tumors. 1768 40

Camptothecin (CPT) is an alkaloid that displays considerable antitumour activity, but clinical use has been limited by its poor water solubility and the instability of the lactone moiety (active form) in physiological media. We have therefore formulated the drug into nanocarrier systems in an attempt to improve its therapeutic properties. This study evaluates the effect of intraperitoneally administered stealth and non-stealth nanocapsules containing CPT on lung metastatic spread in mice inoculated with B16-F10 melanoma cells, and on the cytotoxic activity against B16-F10 melanoma cells in-vitro. Poly (D,L-lactide) PLA (non-stealth) and methoxy polyethylene glycol-(D,L-lactide) (PLA-PEG) (stealth) nanocapsules (49 and 66.6 kDa) were prepared by interfacial deposition of preformed polymer. CPT, as free drug or as drug-loaded nanocapsules, was administrated at a dose of 0.5 mg kg(-1) at 3-day intervals for 17 days. Free drug and CPT-loaded nanocapsules reduced the number of metastatic nodules by 45.09-91.76% (P < 0.05 vs positive control). However, only CPT-loaded PLA-PEG 49 kD nanocapsules significantly decreased the number of lung metastases when compared with free drug (P < 0.05). The administration of CPT-loaded nanocapsules and free drug did not result in neutropenia at the administered dose. The improved effectiveness of pegylated nanocapsules was attributed to protection of the drug by nanoencapsulation and to reduced uptake of particles by macrophages located in the lymph nodes. This assumption was supported by the in-vitro study, in which both PLA and 49 kDa PLA-PEG nanocapsules containing CPT were more cytotoxic than the free drug against B16-F10 melanoma cells.
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PMID:Stealth and non-stealth nanocapsules containing camptothecin: in-vitro and in-vivo activity on B16-F10 melanoma. 1791 Aug 10

Arginine deiminase (ADI; EC 3.5.3.6), an arginine-degrading enzyme, has been studied as a potential anti-tumor drug for the treatment of arginine-auxotrophic tumors, such as hepatocellular carcinomas (HCCs) and melanomas. Studies with human lymphatic leukemia cell lines further suggest that ADI is a potential anti-angiogenic agent and is effective in the treatment of leukemia. For instance ADI-PEG-20, patented by Pheonix Pharmacologic Inc., is currently in clinical trials for the treatment of HCC (Phase II/III) and melanoma (Phase I/II). This review summarizes results on recombinant expression, structural analysis, PEG (polyethylene glycerol) modification, in vivo anti-cancer activities, and clinical studies of ADI. Discussions on heterogeneous expression of ADI, directed evolution for improving enzymatic properties, and HSA-fusion for increased in vivo activity conclude this review.
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PMID:Arginine deiminase, a potential anti-tumor drug. 1817 62

The prognosis and response to conventional therapies of malignant melanoma inversely correlate with disease progression. With increasing thickness, melanomas acquire metastatic potential and become inherently resistant to radiotherapy and chemotherapy. These harsh realities mandate the design of improved therapeutic modalities, especially those targeting metastases. To develop an approach to effectively treat this aggressive disease, we constructed a conditionally replication-competent adenovirus in which expression of the adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of progression-elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the adenovirus (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV). This CTV produces large quantities of MDA-7/IL-24 protein as a function of adenovirus replication uniquely in cancer cells. Infection of Ad.PEG-E1A-mda-7 (CTV) in normal human immortal melanocytes and human melanoma cells demonstrates cancer cell-selective adenoviral replication, mda-7/IL-24 expression, growth inhibition and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 CTV into xenografts derived from MeWo human metastatic melanoma cells in athymic nude mice completely eliminated not only primary treated tumors but also distant non-treated tumors (established in the opposite flank), thereby implementing a cure. These provocative findings advocate potential therapeutic applications of this novel virus for treating patients with advanced melanomas with metastases.
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PMID:A cancer terminator virus eradicates both primary and distant human melanomas. 1832 53

A new series of poly(ethylene glycol)(PEG)-paclitaxel conjugates that increases water solubility of paclitaxel was synthesized. We developed well-designed self-immolating linkers between a drug and a water-soluble polymer moiety which gave an extremely rapid hydrolysis rate to convert a pro-drug into a parent drug without any reduction in drug efficacy. The self-immolating spacer groups were introduced between the solubilizing PEG and C7-OH of paclitaxel in order to control the rate of enzymatic hydrolysis. All these pro-drugs had a water-solubility of 400 mg/ml or more compared with a solubility of about 0.01 mg/ml. The rate of hydrolysis for the pro-drugs in rat plasma showed considerable variation of t((1/2)) ranging from 0.94 min to 42.7 min. To evaluate the anti-tumor efficacy of the pro-drug which had the fastest enzymatic hydrolysis rate, the growth inhibitory effect (IC(50)), the anti-tumor activity and the anti-metastatic potential of the pro-drug were examined. The pro-drug was potent to inhibit the growth of various cancer cell lines, such as human lung, ovarian, colon and melanoma cancer cells. On the development of melanoma lung colonies in C57B/6 mice following intravenous administration of metastatic murine B16/F10 melanoma cells, the pro-drug seems to be more efficacious than paclitaxel. The reduction of the number of melanoma lung colonies was 46.9% (dose: 5 mg/kg) with pure paclitaxel, and 24.5%, and 40.0% with the pro-drug in the dose of 0.71 mg paclitaxel equivalent/kg and 1.42 mg paclitaxel equivalent/kg, respectively.
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PMID:Synthesis and anti-cancer efficacy of rapid hydrolysed water-soluble paclitaxel pro-drugs. 1832 33

Polymer-protein conjugation, particularly PEGylation, is well-established as a means of increasing circulation time, reducing antigenicity, and improving the stability of protein therapeutics. However, PEG has limitations including lack of polymer biodegradability, and conjugation can diminish or modify protein activity. The aim of this study was to explore a novel approach for polymer-protein modification called polymer-masking-unmasking-protein therapy (PUMPT), the hypothesis being that conjugation of a biodegradable polymer to a protein would protect it and mask activity in transit, while enabling controlled reinstatement of activity at the target site by triggered degradation of the polymeric component. To test this hypothesis, dextrin (alpha-1,4 polyglucose, a natural polymer degraded by alpha-amylase) was conjugated to trypsin as a model enzyme or to melanocyte stimulating hormone (MSH) as a model receptor-binding ligand. The effect of dextrin molecular weight (7700, and 47200 g/mol) and degree of succinoylation (9-32 mol %) on its ability to mask/unmask trypsin activity was assessed using N-benzoyl-L-arginine-p-nitroanilide (L-BAPNA). Dextrin conjugation reduced enzyme activity by 34-69% depending on the molecular weight and degree of succinoylation of dextrin. However, incubation with alpha-amylase led to reinstatement of activity to a maximum of 92-115%. The highest molecular dextrin (26 mol % succinoylation) gave optimum trypsin masking-unmasking. This intermediate was used to synthesize a dextrin-MSH conjugate (dextrin Mw = 47200 g/mol; MSH content 37 wt %), and its biological activity (+/-alpha-amylase) was assessed by measuring melanin production by murine melanoma (B16F10) cells. Conjugation reduced melanin production to 11%, but addition of alpha-amylase was able to restore activity to 33% of the control value. These were the first studies to confirm the potential of PUMPT for further application to clinically important protein therapeutics. The choice of masking polymer, activation mechanism, and the rate of unmasking can be tailored to therapeutic application.
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PMID:Polymer masked-unmasked protein therapy. 1. Bioresponsive dextrin-trypsin and -melanocyte stimulating hormone conjugates designed for alpha-amylase activation. 1834 31

Reducible heparin nanogels cross-linked with disulfide linkages were developed for efficient cellular uptake of therapeutic heparin to induce apoptotic cell death. The heparin nanogels were synthesized by forming nanocomplexes between thiolated heparin and poly(ethylene glycol) in a selected organic solvent, and subsequently producing intermolecular disulfide bonds between thiolated heparin molecules by ultrasonication. The resultant heparin nanogels had a stable structure with an average diameter of 248.7+/-26.8nm in aqueous solution. However, they rapidly disintegrated and released free heparin molecules under reductive environments, such as intracellular cytosol, through the cleavage of disulfide cross-links within their network structure. Confocal laser scanning microscopy and flow cytometric analysis revealed that these heparin nanogels significantly inhibited proliferation of mouse melanoma cells by inducing caspase-mediated apoptotic cell death. The present study suggested that the reducible heparin nanogels exhibiting a remarkable apoptotic activity could be potentially applied for cancer cell targeted delivery when combined with various therapeutic and diagnostic agents.
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PMID:Synthesis, characterization, and intracellular delivery of reducible heparin nanogels for apoptotic cell death. 1847 96

To develop a new potent anti-melanogenic agent, we have conjugated lipoic acid (LA) to poly (ethylene) glycol (PEG) of molecular weight 2000 and examined the effects on inhibition of tyrosinase activity and melanin synthesis in B16F10 melanoma cells. The water-soluble LA-PEG 2000 was synthesized from LA and methylated PEG by an esterification reaction in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide. Synthetic LA-PEG 2000 was confirmed by IR and (1)H-NMR spectroscopy. The new conjugate is a highly water-soluble molecule, which has lower cell cytotoxicity than LA. Treatment with LA-PEG 2000 significantly suppressed the biosynthesis of melanin by up to 63% at 0.25 mM and reduced tyrosinase activity by up to 80% at 0.50 mM in B16F10 melanoma cells. Furthermore, Western blot and RT-PCR studies indicated that treatment with LA-PEG 2000 decreased the level of tyrosinase, which is a melanogenic enzyme. Taken together, these results suggest that LA-PEG 2000 may inhibit melanin biosynthesis by down-regulating levels and expression of tyrosinase activity. Therefore, LA-PEG 2000 can be used effectively as a new agent to inhibit melanogenesis, with lower cytotoxicity than LA (parent molecule) in B16F10 melanoma cells.
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PMID:Synthesis and anti-melanogenic effects of lipoic acid-polyethylene glycol ester. 1854 72


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