Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was performed to characterize the transport of the endogenous photosensitizer delta-aminolevulinic acid in tumor cells of the extrahepatic biliary duct. Uptake of [(3)H]delta-aminolevulinic acid into human cholangiocarcinoma SK-ChA-1 cells was linear for up to 10 min, independent of a Na(+) gradient, but stimulated 3- to 4-fold by an inwardly directed H(+) gradient. Uptake of delta-aminolevulinic acid was mediated by a single transport system with an apparent affinity (K(t)) of 2.1 mM and a maximal velocity (V(max)) of 60.1 nmol. 10 min(-1). mg of protein(-1). Glycylsarcosine, alanylalanine, and cefadroxil strongly inhibited the [(3)H]delta-aminolevulinic acid uptake with K(i) values of 1.3, 0.2, and 3.6 mM, respectively. In contrast, gamma-aminobutyric acid, glycine, L-glutamic acid, and L-aspartic acid (all 10 mM) had no effect on the total [(3)H]delta-aminolevulinic acid uptake, neither at pH 6.0 nor at pH 7.5. Applying a Dixon type of experiment and the ABC test revealed that glycylsarcosine and delta-aminolevulinic acid are transported via the same system, PEPT1. Treatment of the cells with phorbol 12-myristate 13-acetate, a phorbol ester that activates protein kinase C, resulted in a significant inhibition of the transport rate. This inhibition could be blocked by cotreatment with staurosporine. We conclude that delta-aminolevulinic acid is transported by the H(+)/peptide cotransporter PEPT1 into epithelial cells of the extrahepatic biliary duct. delta-Aminolevulinic acid can be accumulated specifically in bile duct tumor cells before photodynamic therapy.
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PMID:Delta-aminolevulinic acid transport in cancer cells of the human extrahepatic biliary duct. 1264 72

The purpose of this study was to investigate the potential use of 5-aminolevulinic acid (5-ALA, 5-amino-4-oxovaleric acid) induced protoporphyrin IX (PPIX) for photodynamic therapy (PDT) of nasopharyngeal carcinoma (NPC) and its related mechanisms of inducing cell death. PPIX biosynthesis at I to 8 h after incubation of a cultured NPC cell line (HNE1) with 5-ALA (10-5,000 microg ml(-1)) was determined via fluorescence analysis HNEI cells were irradiated at 4 h after incubation with 5-ALA (10-200 microg ml(-1)) by diode laser (lambda = 630 nm) at various energy levels (1-50 J cm(-2)). The survival rates at 6, 12, 24 and 48 h after PDT were determined by MTT assay. Mechanisms of PDT-induced cell death were investigated via Anncxin-V/propidium iodide staining and DNA electrophoresis After incubation with 5-ALA, a time- and dose-dependent increase of cellular PPIX-fluorescence was recorded up to a threshold concentration of 1,000 microg ml(-1) 5-ALA, above which a decline of fluorescence intensities occurred. Similar values of PPIX-fluorescence were found at 100-1,000 microg ml(-1) of 5-ALA. Unlike sole incubation with 5-ALA or sole laser irradiation, the combination of both factors lead to a significant, concentration-, energy- and time-dependent increase of cell death (p < 0.01). At 100 microg ml(-1) ALA and 10 J cm 2 laser irradiation, cellular survival was <5% after 48 h. More than 80% of induced cell deaths thereby occurred via apoptosis within the first 12 h following irradiation; necrosis was accountable for less than 20%. High level induction of apoptosis by 5-ALA-PDT was confirmed by DNA electrophoresis. Our investigations show promising results of 5-ALA based PDT of nasopharyngeal carcinoma in vitro and set the basis for future studies in tumor models or humans, respectively.
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PMID:In vitro photodynamic therapy of nasopharyngeal carcinoma using 5-aminolevulinic acid. 1265 68

In photodynamic therapy (PDT), 5-aminiolevulinic acid (5-ALA) applied topically is converted, via the heme cycle, into protoporphyrin IX (PpIX), a photosensitizing agent, which upon excitation with light can induce tumor destruction. Due to its hydrophilic and zwitterionic characteristics, 5-ALA has limited penetration into the skin. More lipophilic 5-ALA ester derivatives are expected to cross stratum corneum more easily than 5-ALA. According to the determination of the partition coefficients of 5-ALA methyl, n-butyl, n-hexyl and n-octyl esters, these compounds showed an increased affinity to the SC, with 5-ALA hexyl ester and 5-ALA-octyl ester having the highest partition coefficients. Our in vitro skin permeation studies demonstrated an increased permeated amount for hexyl-ALA after 6 h of incubation, compared to other esters and 5-ALA. After 6 h, more 5-ALA-hexyl ester and -octyl ester were retained at viable epidermis and dermis than 5-ALA. According to these results, and considering that the conversion of 5-ALA into PpIX occurs preferentially in epidermis, it can be supposed that topical use of ester derivatives with longer chains (C(6) or C(8)) is an interesting proposal to optimize topical 5-ALA-PDT
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PMID:In vitro skin permeation and retention of 5-aminolevulinic acid ester derivatives for photodynamic therapy. 1271 49

A prospective monocentre randomized parallel-group Phase III trial was performed to investigate whether primary transurethral resection (TUR) with 5-aminolevulinic acid induced Fluorescence diagnosis (FD) allows for a more thorough TUR of superficial Bladder Carcinoma compared to conventional white light (WL). Evaluation of residual tumor rate and recurrence free survival were defined as the two primary study endpoints. The residual tumor rate was 25.2% in the WL arm (n=103) vs. 4.5% in the (n=88) FD arm (p<0.0001). Median follow up of the patients in the WL arm was 42 months (range 25-61) compared to 43 (range 24-61) in the FD arm. Recurrence free survival in the fluorescence diagnosis group was 90.9%, 90.9% und 85 % after 12, 24 and 48 months compared with 78.6%, 69.9% und 60.7 %, respectively, in the white light group (p=0.0005). This superiority proved to be independent of risk group. The adjusted hazard ratio of fluorescence diagnosis versus white light transurethral resection was 0.29 (95% CI: [0.15; 0.56]). ALA induced FD is statistically significantly superior to conventional WL TUR with respect to both residual tumor rate and recurrence-free survival. The differences in RFS imply that FD offers a clinically relevant procedure to reduce the number of tumor recurrences.
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PMID:[Reducing the risk of superficial bladder cancer recurrence with 5-aminolevulinic acid-induced fluorescence diagnosis. Results of a 5-year study]. 1456 86

Oxidative stress-related changes in tumors upon localized hyperthermia (HT), 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) and their combination (ALA+HT) were examined after the observation that the antitumor effects of ALA-PDT could be significantly enhanced upon simultaneous application of HT. Rats bearing s.c. DS-sarcomas (0.6-1.0 ml) on the hind foot dorsum were anesthetized and underwent one of the following treatments: (i) ALA-PDT (375 mg/kg 5-ALA i.v.); (ii) localized HT, 43 degrees C for 60 min; (iii) combined ALA-PDT and HT [=ALA+HT]. Appropriate control experiments were also performed. After treatment, tumors were excised and rapidly frozen for later analysis of nitrosative stress (protein nitration), apoptotic events (TUNEL, caspase activation, DNA and RNA fragmentation), expression of heat shock proteins (hsp70 and HO-1), glutathione (GSH) levels and glutathione peroxidase (GPx) activity. Protein nitration was found to increase upon treatment, being especially pronounced in the ALA+HT group, and could partially be related to areas surrounding microvessels. The extent of nitrosative stress also correlated well with the appearance of the markers of apoptosis and the inhibition of in vivo tumor growth as seen in a previous study. GSH levels decreased upon treatment, the reduction being most prominent in the ALA-PDT and ALA+HT groups. GPx activity, however, showed a significant decrease only in the ALA-PDT group. Whereas hsp70 expression increased upon HT, ALA-PDT caused a decrease, and these opposing effects were nullified with ALA+HT. The results obtained point to a number of cellular mechanisms-including effects on cellular defense mechanisms and an abrogation of the heat shock defense mechanism-that may interact to achieve the potentiated tumor response rate seen in vivo upon combined treatment.
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PMID:Intensified oxidative and nitrosative stress following combined ALA-based photodynamic therapy and local hyperthermia in rat tumors. 1460 Oct 53

In this work, the development and applications of a fluorescence detection system using optical parametric oscillator (OPO) laser excitation for in vivo disease diagnosis including oral carcinoma are described. The optical diagnosis system was based on an OPO laser for multi-wavelength excitation and time-resolved detection. The pulsed Nd-YAG-pumped OPO laser system (6 ns, 20 Hz) is compact and has a rapid, broad, and uniform tuning range. Time-gated detection of intensified charge-coupled device (ICCD) making use of external triggering was used to effectively eliminate the laser scattering and contribute to the highly sensitive in vivo measurements. Artificial tissue-simulating phantoms consisting of polystyrene microspheres and tissue fluorophores were tested to optimize the gating parameters. 51-ns gate width and 39-ns gate delays were determined to be the optimal parameters for sensitive detection. In vivo measurements with the optical diagnosis system were applied to esophagus, stomach, and small intestine using an endoscope in canine animal studies. The rapid tuning capability of the optical diagnosis system contributed greatly to the optimization of wavelength for the observation of porphyrin in the small intestine. When the small intestine was thoroughly washed with water, the emission band which corresponds to porphyrin disappeared. Based on this observation, it was concluded that the detected signal was yielded by porphyrin-containing bile secretion. Also, multispectral analyses using multiple excitations from 415 to 480 nm at 5 nm intervals confirmed the porphyrin detection in the small intestine. The optical diagnosis system was also applied to the detection of human xenograft of oral carcinoma in mice using 5-aminolevulinic acid (5-ALA) which is a photodynamic therapy (PDT) drug. Significant differences in protoporphyrin IX fluorescence intensity between normal and tumor tissue could be obtained 2 hours after the injection of 5-ALA into mice due to the preferential accumulation of 5-ALA in tumors. Results reported herein demonstrate potential capabilities of the LIF-OPO system for in vivo disease diagnosis.
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PMID:Development of a fluorescence detection system using optical parametric oscillator (OPO) laser excitation for in vivo diagnosis. 1464 Jul 63

Photodynamic therapy (PDT) of tumors with 5-aminolevulinic acid hexylester (h-ALA) causes photo-oxidative reactions in treated tissues. In order to study cytotoxic and/or mutagenic effects, cells of the tumor cell line RPMI 2650 as well as fibroblasts of the cell line WS 1 were given photodynamic treatment in vitro. The cells were photosensitized with a 1mM h-ALA-medium solution for 5h and illuminated with different light doses (0.5, 1.0, 1.5 and 2.0 J/cm2) using red light (633+/-20 nm). PDT-induced cytotoxic effects were determined by measurement of the mitotic index (MI) and the nuclear division index (NDI). Chromosome aberrations (CA) and micronuclei (MN) were recorded to study mutagenicity. After treatment of the photosensitized RPMI 2650 cells with a light dose of 2.0 J/cm2, the MI was significantly decreased to 16.9 per thousand in comparison with that of the h-ALA control (33.8 per thousand ). In photosensitized WS 1 cells, light doses up to 2.0 J/cm2 showed no significant effect. The NDI of photosensitized RPMI 2650 cells was significantly decreased by light doses from 1.0 to 2.0 J/cm2, whereas no significant effect was seen in WS 1 cultures. Thus, h-ALA-PDT only induced desirable cytotoxic effects in tumor cells, but not in the fibroblasts. After application of light doses from 0.5 to 2.0 J/cm2, photosensitized RPMI 2650 cultures showed CA in 7.0-7.5% of the metaphases, which was not a significant increase (h-ALA control: 5.5%). In WS 1 cultures metaphases containing CA varied non-significantly from 5.0 to 7.5%. The MN rates were approximately the same in illuminated RPMI 2650 cultures and in the corresponding h-ALA control (4.4-4.9 per thousand ). The MN rates of the illuminated WS 1 cultures also varied non-significantly from 4.5 to 5.0 per thousand in comparison with the h-ALA control (5.5 per thousand ). In the mutagenicity tests the h-ALA-PDT had no significant effect, neither on the tumor cells nor on the fibroblasts. In addition to the cytogenetic analysis, spectral karyotyping (SKY) was used to characterize the cell lines and gain more detailed information on possibly PDT-induced CA. The SKY evaluation also showed no significant increase of the CA rate, but confirmed the result of the CA test. Thus, within the scope of the experiments performed, a mutagenic potential of the h-ALA-PDT can be excluded.
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PMID:In vitro evaluation of the cytotoxic and mutagenic potential of the 5-aminolevulinic acid hexylester-mediated photodynamic therapy. 1523 34

Squamous cell carcinomas account for more than 80 % of esophageal malignancies in Germany. Alcohol and tobacco smoke are two of the most important risk factors. In superficial esophageal squamous cell carcinoma, endoscopic mucosal resection (EMR) is a very useful and effective treatment modality. However, in patients with submucosal esophageal cancer, radical esophageal resection is regarded as the gold standard for treatment at present. We report the case of a 71-year-old female patient with alcohol-induced liver cirrhosis with esophageal varices and a - therefore inoperable - early esophageal squamous cell carcinoma. Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) seemed not to be an effective treatment modality due to its limited penetration depth (< 2 mm) and the liver toxicity of 5-ALA. PDT using Photofrin(R) with a higher penetration depth seemed to be associated with a high risk of bleeding due to the esophageal varices. Furthermore, this sensitizer is associated with a high rate of strictures and a long-lasting skin sensitivity. In contrast, arguments against an endoscopic mucosal resection (EMR) were endosonographically suspected submucosal tumor growth and a high risk of bleeding. Nevertheless, with respect to the lack alternatives we decided to perform an EMR after ligation of esophageal varices. The tumor could be resected in sano without major bleeding complication. Histology demonstrated a carcinoma in situ without submucosal invasion. After 3 months a second EMR was necessary due to recurrence. Meanwhile after a follow-up period of 18 months only low grade intraepithelial neoplasia without macroscopically suspicious lesions was observed.
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PMID:[Endoscopic mucosal resection for early esophageal cancer with esophageal varices]. 1524 10

5-aminolevulinic acid (5-ALA) is a precursor in synthesis of endogenous porphyrins used to sensitize tumor tissues in photodynamic therapy (PDT). It is administered topically into a tumor which after the certain time, required for porphyrins to accumulate, is irradiated with visible light from the proper source at established wavelength. Our main aim in the present study was to increase the penetration of 5-ALA through the skin and other tissues by addition of glycolic acid (GA) to 5-ALA on cell lines in vitro and on animals. We also applied 5-ALA ointment with glycolic acid to patients suffering from squamous cell carcinoma (SCC). In our study, we used 5-ALA, dimethyl sulfoxide (DMSO), ethylenediaminetetraacetic acid, disodium salt (EDTA) and GA together in one formulation (5-ALA-GA) on eucerin support. We compared both therapeutic and cosmetic effects in 5-ALA-GA-PDT and in control group of patients. Our results showed that modification of 5-ALA ointment by addition of 5% GA caused that the treated lesions responded with rapid regression. In 12 patients with single lesions of SCC type subjected to 5-ALA-GA-PDT, we observed 100% regression of tumors following single or repeated two-three times PDT. In vitro and in vivo in animals total porphyrin levels after addition of 5% GA increased significantly (P<0.01). These results provide evidence that addition of glycolic acid should be considered as the agent which enhances 5-ALA penetration in tissues and thus increases the effectiveness of photodynamic therapy.
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PMID:Enhancement of photodynamic therapy by use of aminolevulinic acid/glycolic acid drug mixture. 1550 95

Photodynamic diagnosis could be a useful tool for improving the diagnostic yield of tumor biopsy, especially for mesothelioma tumors that are sclerotic and particularly hypocellular. For PDD, the use of low doses of a sensitizing drug, such as 5-ALA, must be investigated further. The initial results of 5-ALA-mediated PDD are promising. The role, if any, for PDT in the treatment of mesothelioma has yet to be established. The number of centers exploring this technology is limited because the procedure is labor intensive and requires not only specialized equipment but also physician support. The number of patients treated in the different trials is small, and no definitive conclusions can be drawn. Further complicating the interpretation of published results is the number of variables (i.e., type of sensitizer, light dose, drug dose, drug light interval, methods of light measurement, technique of light delivery, surgical debulking techniques), which differ between studies. Most reports are phase I and II studies. The final outcome of these studies with respect to survival is of limited value. The only phase III study, which was performed with an earlier generation photosensitizer, reported no advantage to the use of PDT in combination with surgery and immunochemotherapy. To date, the most that can be said is that intraoperative PDT can be performed safely in experienced centers and that there are some encouraging results, especially in patients with stages I and II MPM, particularly with the newer generation photosensitizers. One attractive aspect of this adjuvant treatment is that PDT, as opposed to some of the other adjuvant treatments combined with surgery, may offer the option of effecting adequate tumor debulking with a pulmonary-sparing procedure.
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PMID:Innovative therapies: photodynamic therapy. 1555 63


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