Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

5-Aminolevulinic acid (ALA) is a heme precursor that accumulates in acute intermittent porphyria (AIP) due to enzymatic deficiencies in the heme biosynthetic pathway Its accumulation has been associated with several symptoms, such as abdominal pain attacks, neuromuscular weaknesses, neuropsychiatric alterations and increased hepatocellular carcinoma (HCC) incidence. The use of exogenous ALA to elevate porphyrin levels in tumor photodynamic therapy, adds further significance to ALA toxicology. Under ferritin mediated and metal catalyzed oxidation, ALA produces reactive oxygen species that can damage plasmid and isolated DNA in vitro, and increases the steady-state level of 8-oxo-7,8-dihydro-2'-deoxyguanosine in liver, spleen and kidney DNA and 5-hydroxy-2'-deoxycytidine in liver DNA of ALA-treated rats. The in vitro DNA damage could be partially inhibited by SOD, catalase, DTPA, mannitol and melatonin. ALA also promotes the formation of radical-induced base degradation products in isolated DNA. 4,5-Dioxovaleric acid, the final oxidation product of ALA, alkylates guanine moieties within both nucleoside and isolated DNA, producing two diastereoisomeric adducts. Dihydropyrazine derivatives of ALA generated by its dimerization, promote DNA strand-breaks and 8-oxodGuo formation in the presence of Cu2+. Together these results reinforce the hypothesis that the DNA damage induced by ALA may be associated with the development of HCC in individuals suffering from AIP.
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PMID:Is 5-aminolevulinic acid involved in the hepatocellular carcinogenesis of acute intermittent porphyria? 1193 Sep 45

In this study, the vascular and tissue oxygen changes induced by photodynamic therapy in the RIF-1 tumor were examined, using electron paramagnetic resonance (EPR) oximetry. Two photosensitizers, including verteporfin (BPD-MA in a lipid-based formulation) and aminolevulinic acid-induced protoporphyrin IX (ALA-PPIX), were investigated with optical irradiation, sufficient to induce sub-curative damage in the tumor tissue, and the transient changes in PO(2) and vascular perfusion were examined. A large increase in tissue oxygenation (from 3 up to 9.5 mmHg) was observed when treated with ALA-PPIX based photodynamic therapy, which lasted during the treatment and a small residual increase that returned back to baseline levels by 48 h after treatment. With verteporfin-based photodynamic therapy, one group of animals was irradiated 15 min after injection and exhibited a small decrease in oxygenation relative to pre-irradiation levels. The second group was irradiated at 3 h after injection and exhibited a large increase in the average PO(2), (from 3 to 15 mmHg) by the end of the treatment. These observations indicate that photodynamic therapy significantly increases tissue PO(2) under certain treatment conditions, with the potential cause being either increased local blood flow or decreased local oxygen metabolic consumption due to cellular damage.
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PMID:Tumor PO(2) changes during photodynamic therapy depend upon photosensitizer type and time after injection. 1206 7

The ability of 5-aminolaevulinic acid and some of its esterified derivatives to induce porphyrin accumulation has been examined in CaNT murine mammary carcinoma cells growing in culture and as tumours in vivo. Topical or intravenous administration of 5-aminolaevulinic acid-esters to mice bearing subcutaneous tumours produced lower porphyrin levels in the tumour than an equimolar dose of 5-aminolaevulinic acid. Reducing the dose of intravenous hexyl- or benzyl-ALA and topical hexyl-5-aminolaevulinic acid resulted in a dose-dependent reduction in porphyrin accumulation. A number of normal tissues accumulated higher concentrations of porphyrins than tumour tissue following intravenous administration of 5-aminolaevulinic acid-esters. Esterase activity in these normal tissues was greater than that in tumour tissue. In contrast to the situation in vivo, all of the 5-aminolaevulinic acid-esters examined were at least as effective as 5-aminolaevulinic acid when applied to cloned CaNT cells in vitro, with the drug concentration required for maximum porphyrin accumulation varying with ester chain-length. Tumour cells growing in culture released esterase activity into the medium. These findings suggest that the efficacy of 5-aminolaevulinic esters may vary depending on the esterase activity of the target tissue, and suggest caution when interpreting the findings of in vitro studies using these and similar prodrugs.
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PMID:Porphyrin accumulation induced by 5-aminolaevulinic acid esters in tumour cells growing in vitro and in vivo. 1210 50

Delta-aminolevulinic acid-photodynamic therapy (ALA-PDT) has emerged as a useful technique in the treatment of superficial basal cell carcinoma, actinic keratosis, squamous cell carcinoma and tumors of other organs. Earlier reports mention that there is reappearance of protoporphyrin IX (PpIX) after photoirradiation of tumors. This property of reappearance of PpIX is being utilized to treat nodular tumors by fractionated light dose delivery. However, there is still no unanimously accepted reason for this reappearance phenomenon and the rate of resynthesis after PDT. On account of this, studies are carried out on the estimation of the pharmacokinetics of the ALA-induced PpIX in mice tumor models and the surrounding normal tissues before and after PDT. Further, a mathematical model based on a multiple compartment system is proposed to estimate the rate parameter for the diffusion of PpIX from the surrounding normal tissues into the tumor tissue (km) caused by photobleaching during PDT with irradiating fluences of 36.0 and 57.6 J/cm2. The km value at two different fluences, 36.0 and 57.6 J/cm2, are estimated as 3.0636+/-0.7083 h(-1) and 6.9231+/-2.17651 h(-1), respectively. Further, the rate parameter for the cleavage and efflux of ALA (k1) and the rate parameter for the evasion of PpIX from the tumor tissues after PDT (kt) were also estimated by fitting the experimental data to the developed mathematical model. The statistical significance of the estimated parameters was determined using Student's t-test. The experimental results and the rate parameters obtained using the proposed compartment model suggest that in addition to the earlier reported reasons, the invasion or diffusion of PpIX from the surrounding tissues to the tumor tissues after photoirradiation might also contribute to the reappearance of PpIX after PDT.
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PMID:In vivo pharmacokinetics of 8-aminolevulinic acid-induced protoporphyrin IX during pre- and post-photodynamic therapy in 7,12-dimethylbenz(a)nthracene-treated skin carcinogenesis in Swiss mice: a comparison by three-compartment model. 1212 11

As exogenous ALA (5-aminolevulinic acid) esters can induce the production and accumulation of endogenous photosensitizer PpIX (protoporphyrin IX) in tumor tissues more effectively, they have been the most active photosensitizer prodrug in PDT(photodynamic therapy) field. In this article, along with the procedure of ALA esters based PDT, some primary mechanism and experimental results were considered, which include: first, cellular uptake of ALA esters and its conversion into ALA; second, the production and accumulation of endogenous photosensitizer PpIX induced by eNdogenous ALA esters; last, the photosensitization of PpIX.
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PMID:[5-Aminolevulinic acid esters based photodynamic therapy]. 1222 8

No fluorescence of protoporphyrin IX (PpIX) was measured using a fiber optic probe in pigmented B16F10 melanoma in mice after topical application of 5-aminolevulinic acid methylester (ALA-Me). However, chemical extraction of tissues excised from mice after intratumoral administration of ALA-Me or its parent compound ALA revealed that this tumor had the capability to produce PpIX. Small amounts of endogenous porphyrins, mainly PpIX, were found in the melanoma not treated with these drugs. Topical application of ALA-Me followed by exposure with laser light (633nm) delayed the growth of the tumors slightly. Light alone also had a significant effect on the tumor growth.
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PMID:Photosensitizing effect of protoporphyrin IX in pigmented melanoma of mice. 1227 Jan 16

The two major steps in our study on the treatment of bladder tumors by photodynamic therapy (PDT) were the development of a new bladder tumor model in Fischer rats by implantation of tumor cells and the use of fluorescence spectroscopy, a semi-quantitative and non-invasive method, in order to determine the time after general or local administration of a photosensitizer when the tumor:normal bladder ratio was at its highest. 5-Aminolevulinic acid (5-ALA) (250 mg/kg body weight) was injected i.p. or instilled directly into the bladder cavity for 1, 2 or 4 h and fluorescence was measured on normal and bladder tumor tissues every 30 min for 8-10 h after administration, with a special miniaturized optical-fiber captor. The better tumor:normal bladder ratios were 2.85+/-1.2 at 3.5 h after i.p. administration and 3.96+/-1.04 after bladder instillation for 4 h, respectively. These results were confirmed by fluorescence microscopy. PDT with the same dose of 5-ALA as in this pharmacokinetic study must also be carried out in order to compare the toxicity of the two administration routes of the photosensitizer and to determine which one is the better for this bladder tumor model.
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PMID:Determination of the maximal tumor:normal bladder ratio after i.p. or bladder administration of 5-aminolevulinic acid in Fischer 344 rats by fluorescence spectroscopy in situ. 1239 71

Photodynamic therapy (PDT), as a novel treatment modality, is based on the use of a photosensitizing agent with an excitation light source for the treatment of various malignancies. Its effect is mediated through reactive oxygen species and nitric oxide (NO), which are shown to be present in apoptosis. Individual differences among patients and even in different areas of the same tumor in one patient may cause a major problem with PDT: dose calculation during application of the light. An electrochemical sensor is proposed for online monitoring of NO generation as a solution of this problem. 5-Aminolevulinic acid (ALA) was administered as the photosensitizer in rat cerebellum. An amperometric sensor, selective to NO, was designed and tested both in vitro and in vivo during PDT. ALA-mediated PDT resulted in rapid generation of NO, starting as early as the application of light on the tissue. Simultaneous amperometric recordings have been carried out for 5 min during PDT. The progressive increase in NO concentration peaked at 1.10 min and then the response current began to decrease until it reached a plateau at around 70% of its peak value. This study, for the first time, electrochemically demonstrates the generation of NO during PDT. Rapid and stable responses obtained by the experimental setup confirmed that this method could be used as an online monitoring system for PDT-mediated apoptosis.
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PMID:Online electrochemical monitoring of nitric oxide during photodynamic therapy. 1244 80

5-Aminolevulinic acid (ALA)-induced protoporphyrin IX (PPIX) fluorescence has been shown to have high tumor cell selectivity in various organs, including the gastrointestinal (GI) tract. To better understand and to possibly find new approaches to therapeutic application, we investigated the uptake kinetics and consequent metabolism of ALA and PPIX, respectively. Three colon carcinoma (CaCo2, HT29, SW480) and a stromal cell line (fibroblast, CCD18) were chosen to mimic important aspects of malignant mucosa of the GI tract. Because differential PPIX concentrations in these cell lines represented the in vivo observations (ratio tumor vs normal 10:1-20:1), we analyzed the ALA uptake, mitochondrial properties and key molecules of PPIX metabolism (porphobilinogen deaminase [PBGD], ferrochelatase [FC], iron content, transferrin receptor content). The tumor-preferential PPIX accumulation is strongly influenced, but not solely determined, by activity differences between the PPIX-producing PBGD and the PPIX-converting FC, when compared with fibroblasts. Tumor-specific PPIX accumulation is generated by ALA conversion rather than by initial ALA uptake because no significant overall difference in uptake (about 0.6 microg ALA/mg protein) of ALA is seen. In conclusion, further research of tumor cell selectivity of PPIX fluorescence should focus on the mechanisms responsible for an altered PPIX metabolism to find tumor-specific target molecules, thus leading to an improved clinical practicability of ALA application and consequent endoscopy.
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PMID:Metabolic characterization of tumor cell-specific protoporphyrin IX accumulation after exposure to 5-aminolevulinic acid in human colonic cells. 1246 47

Photodynamic therapy (PDT) may be an attractive option for treatment of early stage prostate cancer. Aminolevulinic acid (ALA) acts as a prodrug leading to a selective accumulation of a photosensitizer, protoporphyrin IX (PpIX), in epithelial cells. We investigated the efficacy of ALA-mediated PDT for rat R3327-H prostate cancer, compared with the AY-27 bladder tumor. Rats bearing either AY-27 or R3327-H tumors were randomized to different groups when their tumors reached approximately 1000 mm3. At the day of PDT, animals were administered 500 mg/kg ALA intravenously 4 hours prior to laser therapy. The argon-pumped dye laser light (630 nm) was coupled to multiple quartz fibers with cylindrical diffusing tips, which were inserted into the tumor in icosahedral pattern. Light exposure was varied to yield doses of 1000 to 3000 J/tumor. Animals bearing R3327-H tumors were imaged with 99mTc-HMPAO scintigraphy to evaluate tumor perfusion changes induced by PDT. There was a light-dose dependent tumor response in both tumor models. The mean time for R3327-H tumor to re-grow to 4 x treatment volume was 79.7 days in the control group (light only), 159 days in 1000 J group, and 169 days in 2000 J group (P < 0.05). Tumors treated with 3000 J were clinically cured (P < 0.01). Likewise, for AY-27 tumors, the average time to re-grow to 4 x treatment volume was 13.7 days in the control group, 179.3, 183.3, and 185.7 days in groups of 1000, 1500, and 2000 J (P < 0.05), respectively. Tumors treated with 3000 J were clinically cured (P < 0.01). 99mTc-HMPAO scintigraphy demonstrated a mild perfusion impairment following PDT. Interstitial PDT with ALA/PpIX is equally effective in treating prostate cancer and TCC in these heterotopic rat models.
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PMID:Interstitial photodynamic therapy in subcutaneously implanted urologic tumors in rats after intravenous administration of 5-aminolevulinic acid. 1247 46


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