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)

Conventional and sterically stabilized liposomes derived from phosphatidylcholine or the antitumor agents, hexadecylphosphocholine and octadecyl-(1,1-dimethyl-4-piperidino-4-yl)-phosphate, as bilayer forming constituents, containing bleomycin, were developed and tested. Liposomal encapsulation of bleomycin enhanced strongly the antitumor activity against P388 leukemia and the Lewis lung carcinoma. This effect was clearly dependent on the size and lipid composition of the bleomycin-containing liposomes. The therapeutic effects were nearly equal for liposomal and free bleomycin in the B16 melanoma. The partial replacement of phosphatidylcholine by alkylphospholipids and the inclusion of polyethylene glycol modified lipids for sterical stabilization did not further improve the therapeutic efficacy but increased, in some cases, the toxicity of liposomes. Bleomycin-induced lung injury was not observed if liposomal bleomycin was administered.
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PMID:Liposomal bleomycin: increased therapeutic activity and decreased pulmonary toxicity in mice. 1128 Apr 37

Although the current clinical formulation of paclitaxel (Taxol) has a promising clinical activity against a wide variety of tumors, it has significant toxic side effects, some of which are associated with its formulation in a 1:1 (v/v) mixture of Cremophor EL and dehydrated alcohol. One of the problems associated with the intravenous administration of paclitaxel is its low solubility in water. Our study was designed to evaluate the pharmacokinetics, tissue distribution, toxicity and efficacy of a paclitaxel (Genexol)-containing biodegradable polymeric micellar system (Genexol-PM) in comparison to Taxol. Genexol-PM was newly developed by using a low molecular weight, nontoxic and biodegradable amphiphilic diblock copolymer, monomethoxy poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA) and paclitaxel (Genexol, Samyang Genex Co., Seoul, Korea). In a human cancer cell line model, Genexol-PM and Taxol showed comparable in vitro cytotoxicity against human ovarian cancer cell line OVCAR-3 and human breast cancer cell line MCF7. The maximum tolerated dose (MTD) of Genexol-PM and Taxol in nude mice was determined to be 60 and 20 mg/kg, respectively. The median lethal dose (LD(50)) in Sprague--Dawley rats was 205.4 mg/kg (male) and 221.6 mg/kg (female) for Genexol-PM, while 8.3 mg/kg (male) and 8.8 mg/kg (female) for Taxol. After intravenous administration of Genexol-PM in murine B16 melanoma-induced female SPF C57BL/6 mice at a dose of 50 mg/kg, the area under the plasma concentration-time curve (AUC) was similar to Taxol((R)) at a dose of 20 mg/kg, but biodistribution of paclitaxel after administration of Genexol-PM showed 2 to 3-fold higher levels in tissues including liver, spleen, kidneys, lungs, heart and tumor as compared to Taxol. The in vivo antitumor efficacy of Genexol-PM as measured by reduction in tumor volume of SKOV-3 human ovarian cancer implanted in nude (nu/nu) athymic mice and MX-1 human breast cancer implanted in Tac:Cr:(NCr)-nu athymic mice was significantly greater than that of Taxol. The results of cytotoxicity, MTD, LD(50) and antitumor efficacy suggest that Genexol-PM may have a great advantage over present-day chemotherapy with Taxol.
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PMID:In vivo evaluation of polymeric micellar paclitaxel formulation: toxicity and efficacy. 1138 98

Programmable fusogenic vesicles (PFV) are liposomes composed of non-bilayer lipid components stabilized by the inclusion of an exchangeable poly(ethylene glycol) (PEG)-lipid conjugate. Vesicle destabilization by loss of the PEG-lipid results in recovery of the inherent fusogenic character. As a result, PFV can be designed to display a long circulation lifetime after i.v. administration, high accumulation at disease sites and full bioavailability of an encapsulated compound. In the present study, we investigated the potential application of PFV as carriers for intracellular delivery of antisense oligodeoxynucleotides (ODN). Antisense phosphorothioate ODN were encapsulated into PFV containing dioleoylphosphatidylethanolamine, cholesterol, dioleyldimethylammonium chloride and PEG-ceramides with different carbon chain length (C(8), C(14) and C(20)). In vitro fluorescent microscopy and flow cytometry analysis demonstrated that PFV containing PEG-ceramide C(14) provided enhanced intracellular delivery of FITC-labelled antisense ODN compared to PFV displaying faster or slower rates of destabilization (containing PEG-ceramide C(8) or C(20), respectively). Therapeutic efficacy of PFV-encapsulated antisense ODN against two proto-oncogenes, c-myc and bcl-2, was examined in various cell lines. At antisense concentrations of 0.5 microM, no significant downregulation of c-myc mRNA levels was observed in HEK293, B16 and MCA207 cells. However, treatment of 518A2 melanoma cells with PFV-encapsulated antisense targeting bcl-2 at concentrations of 0.5 microM and 1.0 microM resulted in reduced bcl-2 mRNA level by about 20% and 25% after 48 h incubation. Free antisense ODN did not affect bcl-2 mRNA expression at the concentrations used in this study and encapsulated control antisense (reverse polarity) led to a non-specific increase in mRNA levels. Our results suggest that PFV carriers displaying appropriate rates of destabilization have the potential to act as intracellular delivery vehicles and may improve the bioavailability and potency of antisense oligonucleotides.
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PMID:Programmable fusogenic vesicles for intracellular delivery of antisense oligodeoxynucleotides: enhanced cellular uptake and biological effects. 1151

The potent immunomodulatory, antiproliferative and antiviral properties of interferons (IFNs), together with their availability in large amounts thanks to the recombinant DNA technique, have resulted in their widespread clinical use in a variety of viral and nonviral proliferative disorders. In dermato-oncology, IFNs have been used primarily in melanoma, but also in nonmelanoma skin cancer, such as squamous and basal cell carcinomas, Kaposi sarcomas and lymphomas. Trials with IFNs have been performed in patients with melanoma in an adjuvant setting (stage II and III) and in metastatic disease (stage IV). While the response rates with IFNs as single agents in stage IV disease usually do not exceed 15%, the use of adjuvant IFNs has been claimed to increase disease-free survival (stage II), or even overall survival (stage III), in low- or high-dose regimens, respectively; the latter, however, involved numerous side-effects and were beset with lack of compliance and acceptance, as well as being very costly. Pegylated IFN (PEG-IFN) is a form of recombinant human IFN that has been chemically modified by the covalent attachment of a branched metoxpolyethylene glycol moiety. Pharmacogenetic and pharmacodynamic data obtained in animal and in phase I studies have indicated that PEG-IFN injected once a week has the potential to be superior in efficacy to human IFN injected three times a week. The safety profiles of PEG-IFN and IFN are comparable in healthy volunteers and in chronic hepatitis C (CHC) patients. PEG-IFN is currently being evaluated for the treatment of CHC, renal cell carcinoma, chronic myelogenous leukaemia, and malignant melanoma, the last in both stage IV and stage III disease.
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PMID:Perspectives of pegylated interferon use in dermatological oncology. 1207 10

RNase A (bovine pancreatic ribonuclease) and BS-RNase (bovine seminal ribonuclease) are monomeric and dimeric enzymes, respectively, with aspermatogenic and antitumor activities. While the aspermatogenic and, in some experimental situations, the antitumor effects of the RNase A are only minor, the activity of BS-RNase in these phenomena is very significant. These differences can be annulled by means of conjugation of the enzymes with PEG (polyethylene glycol) chains. Aspermatogenic activity was studied histologically following subcutaneous injections of RNase A and BS-RNase conjugates in ICR mice, and the antitumor activity in athymic nude mice with growing human melanoma with i.p. injection of these conjugated ribonucleases. The experiments proved that RNase A, when conjugated to PEG, produced identical aspermatogenic and antitumour effects as BS-RNase conjugated to this polymer. Immunogenicity of RNase A and BS-RNase did not change substantially after the conjugation with PEG polymers. Binding of produced antibodies to both ribonucleases attached to PEG, however, was substantially reduced.
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PMID:PEG chains increase aspermatogenic and antitumor activity of RNase A and BS-RNase enzymes. 1210 74

Malignant melanoma has been shown to be susceptible to T cell-mediated immunity and, therefore, is a candidate for vaccination approaches. Clinical trials using dendritic cells (DC) loaded with peptides corresponding to tumor antigens are ongoing in several institutions, and some promising results have already been published. However, every single peptide-based vaccine can only be used in a patient with a given single HLA type, and this strategy is not appropriate for patients with rare HLA types or with tumors without defined antigens. A clinical pilot study in patients with disseminated melanoma refractory to standard therapy was initiated using a different approach. The authors generated autologous monocyte-derived DC and fused these DC with gamma-irradiated primary autologous tumor cells by incubation in polyethylene glycol. In previous experiments, the authors had shown that these fused cell products are potent inducers of a T-cell response in a mixed lymphocyte tumor cell culture. Seventeen patients were immunized with the cell product by s.c. injection in monthly intervals without any serious side effects. Of these patients, one had a partial response with decrease in size of all evaluable tumor manifestations. In one patient, some of the metastases were regressing despite an overall progressive disease, and one patient achieved disease stabilization for six months. In the responding patient, in parallel to tumor regression, circumscript hair depigmentation occurred. These data show, that a hybrid vaccine of DC and tumor cells can be safely applied and can induce tumor regressions, however, the clinical efficacy of the approach in its present form is insufficient.
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PMID:The treatment of patients with disseminated malignant melanoma by vaccination with autologous cell hybrids of tumor cells and dendritic cells. 1221 80

Some murine melanomas and hepatocellular carcinomas (HCCs) have been shown to be auxotrophic for arginine. Arginine deiminase (ADI; EC 3.5.3.6.), an arginine-degrading enzyme isolated from Mycoplasma, can inhibit growth of these tumors. We found that ADI was specific for arginine and did not degrade other amino acids. Although arginine is not an essential amino acid for most cells, all human melanomas and HCCs tested were found to be inhibited by ADI in vitro. Arginine is synthesized from citrulline in two steps by argininosuccinate synthetase and argininosuccinate lyase. Melanomas and HCCs did not express argininosuccinate synthetase mRNA but did express argininosuccinate lyase mRNA, suggesting that the arginine auxotrophy of these cells was a result of an inability to produce argininosuccinate synthetase. Human melanomas and HCCs were transfected with an expression plasmid containing argininosuccinate synthetase cDNA. The transfected cells were much more resistant to ADI than the parental cells in vitro and in vivo. Initial attempts to use ADI in vivo indicated that this enzyme had little efficacy, consistent with its short circulation half-life. Formulation of ADI with polyethylene glycol to produce ADI-SS PEG(20,000 mw) resulted in an enzyme with a much longer circulation half-life that, and although equally effective in vitro, was more efficacious in the treatment of mice implanted with human melanomas and HCCs. These data indicate that sensitivity of melanoma and HCC is due to the absence of argininosuccinate synthetase in these cells and that an effective formulation of ADI, which causes a sustained decrease in arginine, may be a useful treatment for arginine auxotrophic tumors including melanoma and HCC.
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PMID:Pegylated arginine deiminase (ADI-SS PEG20,000 mw) inhibits human melanomas and hepatocellular carcinomas in vitro and in vivo. 1235 51

Angiogenesis is an absolute requirement for tumor growth and metastasis. The purpose of this study was to evaluate the antiangiogenic activity of interferon-alpha2b (IFN-alpha2b) and thalidomide, as single agents and in combination. The murine dermis model was used to assess tumor-induced angiogenesis in nude mice. Human ACHN (renal), NIH-OVCAR-3 (ovarian), LNCaP (prostate), and SK-Mel-1 (melanoma) tumor cells were inoculated intradermally into the flanks of nude mice. IFN-alpha2b and thalidomide, administered daily, were effective inhibitors of angiogenesis induced by all four tumor types. The combination of IFN-alpha2b and thalidomide caused a synergistic decrease in mean vessel count in tumors that were resistant to the antiproliferative effects of IFN-alpha2b and thalidomide in vitro. This enhanced suppression of angiogenesis translated into synergistic antitumor activity in a xenograft model. Pegylated IFN-alpha (PEG-IFN-alpha2b) (10(6) U) administered once in 10 days was as effective as daily IFN-alpha2b treatment (10(6) U x 10 days). IFN-alpha2b and thalidomide have potentiated antiangiogenic activity when used in combination. A single dose of PEG-IFN-alpha2b (10(6) U) was as effective at suppressing vessel growth as an equivalent dose of IFN-alpha2b given daily for 10 days.
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PMID:IFN-alpha2b and thalidomide synergistically inhibit tumor-induced angiogenesis. 1263 93

The relative activities of interferon-alpha2b (IFN-alpha2b) and polyethylene glycol(12000)-IFN-alpha2b (PEG-IFN-alpha2b) were assessed in cell culture studies using WM9 melanoma or ACHN renal cell carcinoma cell lines. Interferon-alpha2b and PEG-IFN-alpha2b had identical antiproliferative activities when tested in cell proliferation studies conducted with equivalent antiviral units of each IFN preparation. Neither IFN formulation was effective in inducing apoptosis in WM9 melanoma cells, but both increased slightly the percentage of ACHN cells undergoing apoptosis as assessed by Annexin V staining. Interferon-alpha2b and PEG-IFN-alpha2b both activated signal transducer and activator of transcription complexes, and the duration of complex activation was similar for both IFN formulations. Induction of different IFN-stimulated genes was assessed by Northern blotting and the quantitative real-time reverse transcription-coupled polymerase chain reaction (RT-PCR) in WM9 melanoma, ACHN renal cell carcinoma, U937 lymphoma, and MOLT-4 and Mono Mac 6 leukemia cell lines. Interferon-alpha2b and PEG-IFN-alpha2b had equivalent gene-modulatory activities within each of these tumor cell lines, although cell line-specific induction patterns were observed. When compared with the antiviral 50% inhibitory concentration (IC(50)) values, the dose-dependent gene expression data correlated with cell sensitivity to IFN treatment. Together, the drug comparability and cell sensitivity data suggest a predictive relation between dose, time, antiviral activity, and gene transcription effects. Therefore, although the specific activity of IFN-alpha2b is approximately three times greater than PEG-IFN-alpha2b, the two preparations have identical in vitro biologic activities when applied to cells at equivalent antiviral units.
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PMID:Biologic activity of polyethylene glycol12000-interferon-alpha2b compared with interferon-alpha2b: gene modulatory and antigrowth effects in tumor cells. 1280 74

Systemic application of surface-shielded transferrin-polyethylenimine/DNA complexes leads to predominant DNA uptake and gene expression in Neuro2a tumors in syngeneic A/J mice. Similarly, high expression levels were found in Huh-7 and HepG2 human tumor xenografts in SCID mice after systemic application of surface-shielded EGF-PEG-PEI/DNA complexes. Significant DNA uptake but low gene expression were found in the M-3 melanoma while no DNA uptake and no gene expression were found in KB, 518A2, A549, and SW480 xenograft tumor models. To elucidate the reasons for these differences, the tumors were analyzed for vascularization and infiltration of macrophages. Neuro2a, Huh-7, and HepG2 tumors are well vascularized, with a high density of partially immature blood vessels and low numbers of infiltrating macrophages. The M-3 melanoma is well vascularized correlating with significant DNA uptake, however, necrosis and intensive infiltration by macrophages lead to rapid degradation of DNA. In contrast, the KB, 518A2, A549, and SW480 tumors are poorly vascularized, correlating with undetectable DNA uptake and gene expression. Using two different vector systems the data indicate that gene delivery to tumors in vivo is affected by tissue-dependent factors. Uptake of DNA into the tumor depends on vascularization of the tumor, while necrosis and macrophage infiltration may facilitate degradation of the DNA.
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PMID:Tissue-dependent factors affect gene delivery to tumors in vivo. 1280 38


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