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)

Spin-trapping and electron spin resonance (ESR) spectroscopy were used to detect free radicals generated during light exposure of lymphoma cells sensitized in vitro by metallotetrasulfophthalocyanines (Al-PcS4 and Zn-PcS4). 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) and alpha-phenyl-beta-tert-butylnitrone (PBN) were used as spin-trapping agents. Hydroxyl radical spin-adducts were detected under conditions of both extracellular and intracellular photosensitization. In addition, organic radicals of different origin and/or variable yields were trapped, depending on the photosensitization conditions and the spin-trap used. For comparison, analogous experiments were carried out with another tumor-localizing photosensitizer, Photofrin II.
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PMID:Spin-trapping of free radicals during phthalocyanine photosensitization of lymphoma cells in vitro. 134 48

The possibility of using the porphyrin precursor 5-aminolevulinic acid to cause selective porphyrin accumulation in tumors was examined. Syngeneic colon carcinomas CC531 were implanted in the livers of Wag/Rij rats. Groups of three to six animals each were given 2 mg/mL of 5-aminolevulinic acid in drinking water from the 8th, 14th, or 17th day after tumor implantation. Two other groups received either 2.5 or 5 mg/kg of Photofrin II (Photomedica Inc., Raritan, NJ) intravenously on day 17. On day 19 the livers were removed and porphyrin concentrations were measured in normal livers and tumors by solvent extraction and high-performance liquid chromatography. Protoporphyrin accumulated progressively in tumors with increasing duration of 5-aminolevulinic acid administration (P = 0.0001), whereas no increase was found in normal livers. After 11 days of 5-aminolevulinic acid administration the porphyrin concentration ratio between tumors and livers was 4:1. In contrast, after Photofrin II administration the concentration was higher in normal livers than in tumors (1:3 ratio, tumor to liver). Enzyme measurements showed a threefold decrease in ferrochelatase activity in tumors compared with livers (P less than 0.001). In conclusion, oral administration of 5-aminolevulinic acid results in progressive accumulation of protoporphyrin in a transplantable colon carcinoma without accumulation in the surrounding liver tissue. This selective accumulation of porphyrins appears to be caused by a relative ferrochelatase deficiency in malignant tissue. 5-Aminolevulinic acid administration may be a suitable approach to photosensitizing liver tumors for photodynamic therapy or to early detection of tumors by fluorescence in ultraviolet light.
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PMID:Selective accumulation of endogenously produced porphyrins in a liver metastasis model in rats. 138 52

DBA mice bearing CaD2 mammary carcinomas were used to determine the effect of giving small doses of light to the tumor area 1.5 hr after injecting Photofrin II (PII). The smallest light dose applied (12.5 J/cm2) had no effect on the uptake of PII in the tumor and its surrounding tissues, as measured 24 hr after the i.p. injection. However, several higher light doses increased the uptake of PII in the tumor significantly, the uptake in skin slightly, while the uptake in muscle tissue was decreased rather than increased. Thus, the PII concentration ratio between the tumor and the surrounding normal tissues was significantly improved. The rates of clearance of PII from irradiated tissues and non-irradiated tissues were not significantly different. Most likely, the present observations are due to transient pH lowering in the tumor resulting from vascular damage.
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PMID:Effects of light exposure on the uptake of photofrin II in tumors and normal tissues. 138 41

Porphyrins used as sensitizers for the photodynamic therapy (PDT) of tumors are progressively destroyed (photobleached) during illumination. If the porphyrin bleaches too rapidly, tumor destruction will not be complete. However, with appropriate sensitizer dosages and bleaching rates, irreversible photodynamic injury to the normal tissues surrounding the tumor, which retain less sensitizer, may be significantly decreased. This paper surveys the quantum yields and kinetics of the photobleaching of four porphyrins: hematoporphyrin (HP), Photofrin II (PF II), tetra(4-sulfonatophenyl)porphine (TSPP) and uroporphyrin I (URO). The initial quantum yields of photobleaching, as measured in pH 7.4 phosphate buffer in air, were: 4.7 x 10(-5), 5.4 x 10(-5), 9.8 x 10(-6), and 2.8 x 10(-5) for HP, PF II, TSPP and URO respectively; thus, the rates of photobleaching are rather slow. Low oxygen concentration (2 microM) significantly reduced the photobleaching yields. However, D2O increased the yields only slightly, and the singlet oxygen quencher, azide, had no effect, even at 0.1 M. Photosensitizing porphyrins in body fluids, cells and tissues may be closely associated with various photooxidizable molecules and electron acceptors and donors. Therefore, selected model compounds in these categories were examined for their effects on porphyrin photobleaching. A number inhibited and/or accelerated photobleaching, depending on the compound, the porphyrin and the reaction conditions. For example, 1.0 mM furfuryl alcohol increased the photobleaching yields of HP and URO more than 5-fold, with little effect on PF II or TSPP. In contrast, the electron acceptor, methyl viologen, increased the photobleaching yield of TSPP more than 10-fold, with little accelerating effect on the other porphyrins. These results suggest that the mechanism(s) of the photobleaching of porphyrin photosensitizers in cells and tissues during PDT may be complex.
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PMID:Quantum yields and kinetics of the photobleaching of hematoporphyrin, Photofrin II, tetra(4-sulfonatophenyl)-porphine and uroporphyrin. 140 88

The presence of oxygen in tissue is a requirement for photodynamic therapy (PDT)-induced destruction of solid tumors, otherwise no cell death occurs. Since many tumors have been shown to have significant populations of hypoxic cells, it is of clinical interest to determine if pre-existing tumor hypoxia limits phototherapy. This question was examined using RIF tumors where tumor response to PDT of completely oxygenated tumors was compared to tumors with an induced hypoxic fraction. Tumor hypoxia was induced by using vasoactive drugs (epinephrine, chlorpromazine, or isoproterenol), given 30 min prior to PDT, or by a surgical method. PDT consisted of 5 mg/kg Photofrin II ip 24 hr prior to treatment and 135 J/cm2 630-nm light. The administration of the various vasoactive agents induced hypoxic fractions of 2.2 to 10%. The surgical method induced hypoxic fractions of 35%. Tumor response and cure in animals given vasoactive agents did not differ from controls, suggesting that low levels of pre-existing tumor hypoxia do not limit photodynamic therapy in this tumor model. Animals with tumors made hypoxic by a surgical method showed significantly reduced tumor response to PDT. Only 14% of these animals had tumors which became flat and necrotic by the day following PDT, compared to nearly 100% for animals given vasoactive drugs or controls. Furthermore, no tumor cure was observed in animals treated by this method. The higher level of tumor hypoxia in these animals likely represents one point where large proportions of PDT-resistant cells can survive after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Implications of a pre-existing tumor hypoxic fraction on photodynamic therapy. 143 4

The photodynamic therapy of tumors (PDT) is a recent and promising technique for the treatment of tumors which can be reached by the light (directly or by endoscopic illumination). Excellent results are now obtained with hematoporphyrin derivatives such as Photofrin II, provided the concerned tumors are small and well delimited. Porphyrins are transported in blood mainly by lipoproteins, and the low density lipoprotein (LDL) receptor-mediated pathway is probably one of the important factors involved in the selective accumulation of porphyrins by tumor tissues, as cancer cells generally express much more LDL receptors than normal cells. In the present paper, after a brief presentation of the biochemical basis of the light-dependent cytotoxicity of porphyrins, we shall examine the role of lipoproteins, especially LDL, in the transport and the cellular uptake of these compounds. We shall also present recent approaches for the improvement of the PDT efficiency.
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PMID:[Antitumor photochemotherapy: biochemical bases, therapeutic uses and perspectives]. 145 Sep 93

Immunotoxicity studies have been performed on the photosensitizing agent Photofrin II (PHFR), a porphyrin derivative used in photodynamic therapy. Hybrid CD2F1 (H-2d/H-2d) or inbred C57Bl/6 (H-2b) male mice were injected with graded doses of the agent (from 1.2 to 12 mg/Kg ip) on day -5, -3 and -1 before assays. The animals, or spleen cells collected from them on day 0 with respect to PHFR treatment, were tested for: a) competence of producing GVHD upon cell transfer into allogeneic, immunosuppressed recipients; b) graft response against challenge with allogeneic lymphoma cells; c) delayed-type hypersensitivity (DTH) against sheep red blood cells; d) in vitro response to mitogens; e) NK cell activity; f) in vitro generation of alloreactive cytotoxic T lymphocytes (CTL); g) resistance against the challenge of a sublethal dose of Pseudomonas aeruginosa. Moreover the LD50 of the drug given ip has been determined in male CD2F1 mice. The results show that PHFR, even at the highest doses used, does not affect most of the immunological parameters studied, except for a marginal inhibition of CTL generation and increment in proliferative responses to Con A or LPS. These data along with parallel studies performed by our group on human models in vitro, showing increased susceptibility of PHFR-treated tumors to NK or LAK effector cells, point out that PHFR, in the absence of systemic photoactivation, is essentially non-immunotoxic in vivo and could render tumor cells more susceptible to natural immunity.
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PMID:Experimental studies of immunotoxicity of a photosensitizing agent (Photofrin II) in mice. 147 18

The ability of Adriamycin (AD) to enhance the known in vitro and in vivo tumoricidal effects of photodynamic therapy (PDT) on the H-MESO-1 human malignant mesothelioma cell line was investigated. In vitro cytotoxicity was determined by incubating H-MESO-1 cells in microtiter plates (2 x 10(5) cells/well, 6 wells/group) with the photosensitizer Photofrin II (PF) and varying concentrations of AD (0, 2.5, 5.0, and 10.0 micrograms/ml) for 24 hr followed by exposure to gold vapor laser light (GVL) at a fluence of 6000 J/M2. [3H]Thymidine (1 microCi) was added to each well 24 hr after treatment. Cells were harvested and counted for thymidine incorporation 24 hr later. PDT alone resulted in a decrease in thymidine incorporation of 23% while the addition of AD to PDT at AD concentrations of 2.5, 5.0, and 10.0 micrograms/ml resulted in decreases of 62, 85, and 69%, respectively (P = 0.005) as compared to untreated controls. H-MESO-1 tumor bearing nude mice (n = 5) were injected ip with PF (5 mg/kg) and AD (5 mg/kg) 24 hr prior to illumination of the tumor site with GVL (120 J/cm2). Control groups (n = 5) received PDT, AD, and/or GVL alone. Tumor surface area was measured as the product of the greatest perpendicular dimensions every 5 days for 30 days. Administration of PDT without AD resulted in a decrease in tumor surface area of 50% on Day 10 with regrowth of tumor by Day 30 while AD alone with or without GVL had no impact on tumor growth.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adriamycin enhanced in vitro and in vivo photodynamic therapy of mesothelioma. 152 40

Interstitial photodynamic therapy (IPDT) using Photofrin II (PII) as photosensitizer has been studied in the rat rhabdomyosarcoma R-1, growing on the thigh or flank of WAG-Rij rats. A light dose-response relationship has been established, for 10 mg PII/kg i.v. and irradiation 24 hr later, with local tumor control as the end point for single IPDT treatments using four cylindrical diffusors simultaneously. A light energy fluence of 150-200 Joule/cm2 (wavelength 625 nm), measured in vivo at the tumor periphery, was required for tumor control. Comparison of tumor response at 5 and 2.5 mg PII/kg with the complete dose response relationship at 10 mg PII/kg suggests drug-light dose reciprocity and indicates that in our tumor model treatment failures are not likely to be caused by variations in (tumor) tissue photosensitizer level, but rather by insufficient light dose or inadequate light dose distribution. Increasing the interval between PII administration and irradiation from 24 hr to 48 hr had no great effect on tumor response to IPDT in this study. Inspection of the original tumor site 100 days after tumor control revealed obvious loss of thigh muscle tissue. Also, recurrent tumors showed a reduced growth rate. Therefore, the relationship between tumor (re)growth and PDT-induced normal tissue damage was studied and the existence of a tumor bed effect was confirmed. The present study indicates that tumor control after a single IPDT treatment is feasible, but that PDT induced damage to a margin of the adjacent normal tissue is probably required.
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PMID:Tumor and normal tissue response to interstitial photodynamic therapy of the rat R-1 rhabdomyosarcoma. 153 69

Nitroimidazoles are good quenchers of triplet state porphyrins in chemical systems, thereby inhibiting singlet oxygen formation and type II photodynamic reactions. Photobiological studies were performed with EMT-6 tumor cells in vitro utilizing Photofrin II (PII) in combination with etanidazole (ETAN), misonidazole (MISO), and trifluoromisonidazole (TF-MISO). After short-term (1 h) exposure of cells to PII, 5 mM ETAN and MISO had no effect on photoinactivation while 5 mM TF-MISO had a small but significant protective effect. When the intracellular oxygen level was equilibrated with 0.3% oxygen in the gas phase, all three nitroimidazoles produced significant photoprotection at concentrations as low as 0.3 microM. After long-term (24 h) exposure of cells to PII, all three nitroimidazoles demonstrated large photoprotective effects under both aerobic and 0.3% oxygen conditions. At equal concentrations of nitroimidazole, photoprotection was greatest for the most lipophilic compound (TF-MISO) and least effective for the most hydrophilic compound (ETAN). These studies suggest that nitroimidazoles can quench triplet state porphyrins (within cells) to reduce intracellular concentrations of singlet oxygen, the putative toxin in PII photoinactivation. In addition, after long-term exposures to PII when porphyrins have partitioned into cellular membranes and lipid environments, the lipophilicity of this class of photoprotector correlates with effectiveness in these mammalian cells.
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PMID:Protection against light-activated photofrin II killing of tumor cells by nitroimidazoles. 153 56


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