Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Photodynamic therapy (PDT) with Photofrin has already been authorized for certain applications in Japan, the USA and France, and powerful second-generation sensitizers such as meta-(tetrahydroxyphenyl) chlorin (m-THPC) are now being considered for approval. Although sensitizers are likely to localize within the cytoplasm or the plasma membrane, nuclear membrane can be damaged at an early stage of photodynamic reaction, resulting in DNA lesions. Thus, it is of critical importance to assess the safety of m-THPC-PDT, which would be used mainly against early well-differentiated cancers. In this context, m-THPC toxicity and phototoxicity were studied by a colorimetric MTT assay on C6 cells to determine the LD50 (2.5 microg/ml m-THPC for 10 J/cm2 irradiation and 1 microg/ml for 25 J/cm2 irradiation) and PDT doses inducing around 25% cell death. Single-cell electrophoresis (a Comet assay with Tail Moment calculation) was used to evaluate DNA damage and repair in murine glioblastoma C6 cells after LD25 or higher doses for assays of PDT. These results were correlated with m-THPC nuclear distribution by confocal microspectrofluorimetry. m-THPC failed to induce significant changes in the Tail Moment of C6 cells in the absence of light, whereas m-THPC-PDT induced DNA damage immediately after irradiation. The Tail Moment increase was not linear (curve slope being 43 for 0-1 microg/ml m-THPC and 117 for 1-3 microg/ml), but the mean value increased with the light dose (0, 10 or 25 J/cm2) and incubation time (every hour from 1 to 4 h) for an incubation with m-THPC 1 microg/ml. However, cultured murine glioblastoma cells were capable of significant DNA repair after 4 h, and no residual DNA damage was evident after 24-h post-treatment incubation at 37 degrees C. An increase in the light dose appeared to be less genotoxic than an increase in the m-THPC dose for similar toxicities. Our results indicate that m-THPC PDT appears to be a safe treatment since DNA repair seemed to not be impaired and DNA damage occurred only with lethal PDT doses. However, the Comet assay cannot give us the certainty that no mutation, photoadducts or oxidative damage have been developed so this point would be verified with another mutagenicity assay.
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PMID:Use of alkaline Comet assay to assess DNA repair after m-THPC-PDT. 1107 72

In this study we investigated the feasibility of mixed liposomes formed by dimyristoyl-sn-glycero-phosphatidylcholine (DMPC) and cationic gemini surfactant (Gemini 1) loaded with the chlorin m-tetrahydroxyphenylchlorin (m-THPC), in photodynamic therapy (PDT) for glioma. To this aim, an in vitro study was carried out by employing various human glioblastoma cell lines (A172, DBTRG, LN229, U118). The following liposomal formulations were tested: (i) DMPC and Gemini 1; (ii) m-THPC in DMPC in the absence or (iii) in the presence of Gemini 1 in the molar ratio 8:2; 7:3, and 6:4. The presence of Gemini 1 significantly increased the intracellular uptake of chlorin in all cell tested although with a different extent: LN229>U118>A172>DBTRG. The cytotoxicity of chlorin-loaded liposomes was then tested by cloning efficiency performed on different cultures, before and after irradiation with laser light at 652nm, at a Fluence Rate of 200mW/s for 100s, with a total Fluence of 20J/cm(-2). In the absence of irradiation, the different liposomal formulations induced a cytotoxicity in less than 30% of glioblastoma cells. On the contrary, irradiation induced total destruction of all cultures treated with m-THPC/DMPC+Gemini 1 in the ratios 8:2, or 7:3, or 6:4.
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PMID:Cationic liposomes, loaded with m-THPC, in photodynamic therapy for malignant glioma. 1706 75

Malignant gliomas represent the most common primary brain tumor: more than 50% of them are glioblastoma multiforme (GBM). Photodynamic therapy may offer a very good chance of targeted destruction of infiltrating GBM cells, thus increasing the survival time and recurrence-free interval of GBM patients. Among photosensitizing agents, meta-tetrahydroxyphenylchlorin (m-THPC) is promising for the treatment of brain tumors. In previous studies, we investigated the transfection activity of dimyristoyl-sn-glycero-phosphatidylcholine (DMPC) liposomes, containing a cationic gemini surfactant, loaded with m-THPC on human colon adenocarcinoma and glioblastoma cell lines. In this paper, the uptake and the intracellular distribution of m-THPC, loaded in several formulations of cationic liposomes, were analyzed, by making a comparison with those obtained using the same chlorin in the pharmaceutical form (Foscan(R)). Moreover, by cloning efficiency assay the potential therapeutic efficiency of chlorin delivered by liposome formulations was compared with that of the pharmaceutical compound, before and after irradiation with laser light at 652 nm. The obtained results indicated that cationic liposomes (i) transferred m-THPC in glioblastoma cells more efficiently than pharmaceutical formulation; (ii) significantly (p < 0.001) increased the m-THPC cytotoxic effect after laser irradiation; (iii) seemed to exert their cytotoxic action in the early phase of interaction with the cells, during adhesion to the plasma membrane.
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PMID:m-THPC-mediated photodynamic therapy of malignant gliomas: assessment of a new transfection strategy. 1747 62

Liposomes formulated with dimyristoyl-sn-glycero-phosphatidylcholine, DMPC, and either one of the cationic gemini surfactants (S,S)-2,3-dimethoxy-1,4-bis(N-hexadecyl-N,N-dimethylammonio)butane bromide, 1a, and (S,R)-2,3-dimethoxy-1,4-bis(N-hexadecyl-N,N-dimethylammonio)butane bromide, 1b, were investigated as vehicles of the photosensitizer m-tetrahydroxyphenylchlorin, m-THPC, to cell models of malignant glioma. The delivery efficiency of DMPC/1a and DMPC/1b liposome formulations were evaluated on the murine glioblastoma cell line C6 and on the human glioblastoma cell line LN229 by flow cytometry and laser scanning confocal microscopy. The stereochemistry of the spacer of the gemini was found to strongly influence the delivery efficiency of m-THPC to cells, the mode of interaction with the cell membrane, and the intracellular distribution of m-THPC. The physicochemical features of liposomes were investigated with the aim of explaining the parameters that control their biological features. Differences that could account for the different biological activity of the formulations concern the values of surface potential and the environment of m-THPC at the water/liposome interface.
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PMID:Efficiency of liposomes in the delivery of a photosensitizer controlled by the stereochemistry of a gemini surfactant component. 1992 6