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)

2-(Diethylamino-2-ethyl)9-hydroxyellipticinium-chloride, HCl (DHE), a new congener of the antitumor agent elliptinium acetate (Celiptium) (NMHE), has recently been selected for phase I clinical trials. NMHE has a methyl group at nitrogen 2 on the ellipticine ring while DHE possesses a basic diethylaminoethyl chain at this position. Compared to NMHE, the presence of the diethylaminoethyl side chain results in the following: a significant increase in the lipophilicity of the drug; no significant modification in either the binding constant values to DNA or the ability to intercalate between DNA base pairs; a marked decrease in the unwinding angle value of supercoiled DNA; and no significant change in the alteration of the catalytic activity of topoisomerase II in vitro. DHE appears to act as a simple reversible intercalating agent as shown by the selective mutagenic effect on Salmonella TA 1977 tester strain and by its inability to induce the SOS functions in a sfiA lac fusion containing Escherichia coli strain. From a pharmacological point of view, the presence of the diethylaminoethyl chain results in a 2-fold increase in the cytotoxicity to L1210 cultured cells, a strong increase in the antitumor efficiency on experimental murine tumors such as L1210 and P388 leukemia, B16 melanoma, M 5076 reticulosarcoma, and colon 38 adenocarcinoma, and finally an objective decrease in the acute and subacute toxicity in mice, rat, and macaque. The absence of significant differences in the interaction of NMHE and DHE with their potential targets in vitro leads to the hypothesis that the superiority of DHE in terms of cytotoxicity and antitumor efficiency may be due to an increase in the diffusion across cellular membrane and a more favorable biodistribution in vivo.
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PMID:Physicochemical and pharmacological properties of the antitumor ellipticine derivative 2-(diethylamino-2-ethyl)9-hydroxy ellipticinium-chloride, HCl. 367 74

The role of photodynamic therapy (PDT) in the treatment of primary non-melanoma skin cancer is examined. Prolonged systemic skin photosensitivity limits the usefulness of PDT using conventional photosensitisers such as Photofrin-II. However in exceptional circumstances, such as multiple or widespread basal cell carcinomas, this therapy provides a useful and seemingly effective alternative mode of treatment. For Bowen's disease, PDT using topical 5-aminolaevulinic acid (ALA) yields high response rates and excellent cosmetic results. For large lesions and those in anatomically difficult sites or in poorly vascularised skin, ALA-based PDT can be considered the treatment of choice. Recent pharmacological and technological developments may further enhance the efficacy and convenience of photodynamic therapy, and make it more generally available in non-specialist centres.
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PMID:Photodynamic therapy of primary skin cancer: a review. 755 8

Photodynamic therapy (PDT) involves the sequential administration of photosensitizing drugs and light for the treatment of diseased tissue. The first photosensitizer systematically evaluated for PDT was hematoporphyrin derivative (HPD). Porfimer sodium (Photofrin; manufactured by Lederle Parenterals, Carolina, Puerto Rico, under license from Quadra Logic Technologies, Inc, Vancouver, British Columbia, Canada) is a chemically related photosensitizing agent. Preliminary trials suggest a role for PDT in the treatment of primary, recurrent, and metastatic nonmelanoma skin cancers. Both HPD and porfimer sodium appear to be limited by generalized cutaneous photosensitivity, which lasts up to 6 to 8 weeks after administration. Benzoporphyrin derivative (BPD verteporfin; BPD-Quadra Logic Technologies, Inc, Vancouver, British Columbia, Canada) is a second-generation porphyrin that has shown promise in clinical studies as a safe and effective photosensitizer for PDT of non-melanoma cutaneous malignancies. Benzoporphyrin derivative is activated by a longer, more penetrating wavelength of light than is porfimer sodium, and has a shorter duration of cutaneous photosensitivity following systemic administration. The use of BPD for PDT of nononcologic conditions also had been studied. Recent trials have shown efficacy in the treatment of psoriasis by BPD-sensitized PDT using drug and light doses lower than those used for malignant tumors.
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PMID:Photodynamic therapy in dermatology with porfimer sodium and benzoporphyrin derivative: an update. 799 1

To investigate the contribution of hyperthermia on local tumour eradication by photodynamic therapy (PDT) we quantified PDT induced tumour heating and evaluated its biological effect in vivo. Syrian Golden hamsters bearing an amelanotic melanoma implanted into the dorsal skin received intravenous injections of Photofrin (5 mg kg-1). Twenty-four hours later tumours were illuminated by red light (630 nm; total energy: 100 J cm-2) at 100 and 200 mW cm-2 and tumour surface and tumour centre temperature were measured. The tumoricidally threshold temperature of 43 degrees C was exceeded at 200 mW cm-2 only, revealing a calculated equivalent treatment time at 43 degrees C of about 10 min. Melanomas treated by PDT at both light intensities disappeared within 48 h and did not reappear locally within the observation period of 32 days. Tumours treated by hyperthermia (water bath) at the maximum temperatures measured during illumination at 200 mW cm-2 (45.5 degrees C for 500 s) or animals receiving laser light at 200 mW cm-2 alone showed a significant growth delay compared to controls (p < 0.05), whereas illumination at 100 mW cm-2 alone or hyperthermia corresponding to the maximum temperature obtained at 100 mW cm-2 (39.5 degrees C for 1000 s) did not alter tumour growth. These data indicate that tumour temperature increased during PDT and exceeded the hyperthermic threshold temperature of 43 degrees C at 200 mW cm-2. In our tumour model hyperthermia was not necessary for a complete tumour eradication by PDT. Although a combination of PDT and hyperthermia might act in an additive or synergistic manner, an unrecognized overlap of both effects might complicate the interpretation of studies on the mechanisms of PDT.
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PMID:Evaluation of photodynamic therapy-induced heating of hamster melanoma and its effect on local tumour eradication. 806 87

Cellular fluorescence intensity (CFI) after incubation with varying concentrations of the photosensitizer Photofrin and the photodynamically induced dose-response relationships of hamster melanoma cells (A-MEL-3) were studied in a recently developed in vitro model. After administration of Photofrin to the extracellular serum-free medium, CFI was evaluated by flow cytometry together with constantly fluorescing latex particles used as a reference. After 5 min, 50% of maximal CFI was found, and after 60 min CFI was maximal. No further increase was obtained during the exposure to Photofrin over the incubation period of 4 h. During this plateau phase, CFI was significantly related to the concentration of Photofrin in the extracellular medium (r = 0.94; P < 0.001). Subsequent to increasing intervals of Photofrin exposure, cells were irradiated with laser light at 630 nm (40 mW/cm2, 4J). Cell viability as evaluated by trypan blue exclusion was significantly decreased with increasing concentrations of Photofrin in the medium, and significantly correlated with CFI during the plateau phase. After photodynamic treatment (PDT) cell fluorescence was reduced by about 15%. This was neither dose- nor time-dependent. On the basis of these findings we propose that CFI indicates photosensitizer uptake. This is also supported by the relation between CFI and phototoxicity. The latter also suggests that CFI might be useful to predict the PDT in vivo efficacy by this in vitro model. Besides measurements of photosensitizer uptake and cell photoxicity, the model demonstrates an excellent opportunity to study the molecular mechanisms of action associated with PDT.
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PMID:An in vitro model to study cellular photosensitizer uptake and photodynamic dose-response relationships of tumor cells. 812 41

For efficacy of photodynamic therapy, selective uptake and retention of photoactive substances has been postulated. Therefore, measurements were performed to find out whether the photosensitiser Photofrin is taken up differently in malignant and non-malignant cells in vitro. In addition, the sensitivity of malignant cells and non-malignant cells to photodynamic exposure was investigated, by quantifying viability and volume alterations of the cells. Bovine aortic endothelial cells, mouse fibroblasts and amelanotic hamster melanoma cells were suspended in a specially designed incubation chamber under controlled conditions (e.g. pH, pO2, pCO2 and temperature). After establishing constant baseline conditions, the cellular fluorescence intensity per cell volume, indicative of the uptake of Photofrin, and cell volume were assessed by flow cytometry, and cell viability was quantified by the trypan blue exclusion test. Photodynamic exposure of cells was performed using an argon-pumped dye laser system via a 600 microns optical fibre at energy density of 4 Joules at the cell surface (40 mW/cm2, 100 s). In comparison to endothelial and fibroblast cells, the melanoma cells exhibited no increased uptake of Photofrin, and no enhanced sensitivity to photodynamic therapy (PDT). However, the fluorescence intensity/volume of endothelial cells was two to three times higher at each concentration of the photosensitiser. Following PDT, reduction in cell viability was dependent on the concentration of Photofrin, and directly correlated with fluorescence intensity per cell volume. In addition, the cells of all three lines, treated by PDT, revealed dose-dependent changes in cell volume. Melanoma cells exhibited the most excessive increase. It is suggested that selective uptake of photosensitiser in vitro is not characteristic for tumour cells. The high uptake of Photofrin by endothelial cells may indicate that the vascular endothelium is a major target for PDT, leading to cessation of tumour blood flow and subsequent destruction of tumour tissue. In addition, PDT-induced swelling of tumour cells might represent and effect synergistically impairing tumour perfusion, and thereby promoting tumour death.
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PMID:Relation of early Photofrin uptake to photodynamically induced phototoxicity and changes of cell volume in different cell lines. 814 70

Three porphycenes with fast pharmacokinetics were tested for their ability to photosensitize amelanotic hamster melanoma A-Mel-3 at short time intervals after injection. Laser light irradiation was performed at the time of maximal photosensitizer level in tumor tissue. Photodynamic therapy as short as 5 min after injection led to complete local tumor remission at a dosage of 1.4 mumol/kg for the porphycene CBPn. In comparison, Photofrin required 8.4 mumol/kg for local tumor remission in 5 of 6 animals with 24 hr accumulation time after injection. We propose a swift photodynamic protocol which can compete favorably with conventional techniques of tumor treatment.
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PMID:Photodynamic eradication of amelanotic melanoma of the hamster with fast acting photosensitizers. 856 24

Chlorophyll (Chl) and bacteriochlorophyll (Bchl) have been made water soluble by transesterification with serine (Ser) at the propionyl residue and tested as potential reagents for photodynamic therapy (PDT). Photocytotoxicity of the conjugates Chl-Ser and Bchl-Ser in M2R mouse melanoma was tested in cell cultures. Tissue uptake and clearance of the photosensitizers in CD1 nude and C57B1 mice implanted with M2R tumors are described. Photocytotoxicity in cell cultures was determined microscopically and by [3H]thymidine incorporation. The LD50 values in vitro were 0.05-0.1 microM for both sensitizers while that of the commercially available hematoporphyrin derivative (HPD, Photosan) was over 100 times higher for the same light intensity (45 mW/cm2). Pigment concentrations were determined fluorometrically in acetone extracts of the tissues of interest at different times after intraperitoneal injection of 20 mg pigment/kg body weight. The distribution pattern of Chl-Ser in the different tissues resembled that reported for Photofrin, chlorin and bacteriochlorin derivatives. Clearance from normal tissues was essentially completed within 16 h for Bchl-Ser and 72 h for Chl-Ser with mean half-lives (t 1/2) of about 2 and 7 h, respectively. In contrast, the clearance rates of these pigments and their metabolites from melanoma tumor tissue were significantly longer: t 1/2 = 20 h for Chl-Ser and 15 h for Bchl-Ser and metabolites. The clearance rates showed biphasic or single exponential decay patterns in normal tissues and in tumors, respectively. Cumulatively the high phototoxicity, simple mode of delivery and fast tissue clearance rates reported here suggest that polar conjugates of Chl and Bchl promise to be highly effective PDT reagents.
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PMID:Serine conjugates of chlorophyll and bacteriochlorophyll: photocytotoxicity in vitro and tissue distribution in mice bearing melanoma tumors. 878 11

Laser Doppler perfusion imaging offers a new modality for in vivo monitoring of the superficial blood perfusion in biological tissue. In this study, the superficial blood perfusion of malignant non-melanoma skin tumours and the surrounding normal skin was measured in conjunction with photodynamic therapy (PDT) using topical delta-aminolaevulinic acid (ALA)-induced protoporphyrin IX as a photosensitizer. The results clearly show that, in contradiction to PDT with the intravenously administered photosensitizer Photofrin, no direct vascular damage can be seen. With the topical sensitization the blood perfusion is increased immediately after the treatment irradiation. The increased blood flow is seen up to a week after treatment, in a similar way as for an inflammatory reaction. Despite this, all basal cell carcinoma and squamous cell carcinoma in situ lesions in this study healed without any sign of residual tumour after the treatment, suggesting an efficient direct tumour cell destruction induced by PDT.
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PMID:Superficial blood flow following photodynamic therapy of malignant non-melanoma skin tumours measured by laser Doppler perfusion imaging. 906 29

Many potentially therapeutic macromolecules, e.g. transgenes used in gene therapy, are taken into the cells by endocytosis, and have to be liberated from endocytic vesicles in order to express a therapeutic function. To achieve this we have developed a new technology, named photochemical internalization (PCI), based on photochemical reactions inducing rupture of endocytic vesicles. The aim of this study was to clarify which properties of photosensitizers are important for obtaining the PCI effect improving gene transfection. The photochemical effect on transfection of human melanoma THX cells has been studied employing photosensitizers with different physicochemical properties and using two gene delivery vectors: the cationic polypeptide polylysine and the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP). Photochemical treatment by photosensitizers that do not localize in endocytic vesicles (tetra[3-hydroxyphenyl]porphyrin and 5-aminolevulinic acid-induced protoporphyrin IX) do not stimulate transfection, irrespective of the gene delivery vector. In contrast, photosensitizers localized in endocytic vesicles stimulate polylysine-mediated transfection, and amphiphilic photosensitizers (disulfonated aluminium phthalocyanine [AlPcS2a] and meso-tetraphenylporphynes) show the strongest positive effect, inducing approximately 10-fold increase in transfection efficiency. In contrast, DOTAP-mediated transfection is inhibited by all photochemical treatments irrespective of the photosensitizer used. Neither AlPcS2a nor Photofrin affects the uptake of the transfecting DNA over the plasma membrane, therefore photochemical permeabilization of endocytic vesicles seems to be the most likely mechanism responsible for the positive PCI effect on gene transfection.
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PMID:Evaluation of different photosensitizers for use in photochemical gene transfection. 1133 34


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