Immunophototherapy of cancer combines the specificity of a monoclonal antibody (MAb) to an overexpressed tumor marker with the phototoxic properties of a conjugated dye. Aluminum tetrasulfophthalocyanine (AlPcS4) was ...
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Immunophototherapy of cancer combines the specificity of a monoclonal antibody (MAb) to an overexpressed tumor marker with the phototoxic properties of a conjugated dye. Aluminum tetrasulfophthalocyanine (AlPcS4) was covalently coupled to a 35A7 MAb directed against carcinoembryonic antigen (CEA) via a five-carbon spacer chain (A(1)) to yield conjugates with a molar ratio ranging from 5 to 16 mol of AlPcS4 per mel of 35A7 MAb. Conjugates were labeled with radioiodine for characterization. The immunoreactivity of the conjugates, determined in a direct binding assay on CEA coupled to sepharose, was net modified by the coupled AlPcS(4)A(1) molecules. In vivo, these conjugates were evaluated in nude mice bearing human colon carcinoma xenografts (T380), 35A7 MAb-(AlPcS(4)A(1))(5), 35A7 MAb-(AlPcS(4)A(1))(12) and 35A7 MAb-(AlPcS(4)A(1))(16) conjugates displayed a tumor uptake of 35 +/- 5.0%, 40 +/- 5.7% and 32 +/- 3.3% of the injected dose per gram of tumor tissue, respectively, corresponding to an uptake of 97%, 104% and 91% as compared to that of the unconjugated 35A7 MAb. In each experimental group, the tumor-to-normal tissue ratios obtained with the conjugates were almost identical to those obtained with unconjugated 35A7 MAb. Average values of 1.8, 7 and about 30 were obtained for blood, liver and muscle, respectively. Phototoxic efficacy of the 35A7 MAb-(AlPcS(4)A(1))(12) conjugate was demonstrated in vitro on the LoVo cell line giving a 91% growth inhibition for a 2.50 mu g/mL AlPcS4A(1), concentration. We conclude that these conjugates demonstrate clear in vivo tumor-seeking capacity and in vitro photocytotoxic properties. Such conjugates could thus be promising candidate drugs for clinical photodynamic therapy of cancers expressing CEA.
The mycotoxic tremorgens penitrem, paxilline and lolitrem B had profound effects on electromyographic (EMG) activity of smooth muscle of the reticulorumen in conscious sheep, with a similar time course of action to th...
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The mycotoxic tremorgens penitrem, paxilline and lolitrem B had profound effects on electromyographic (EMG) activity of smooth muscle of the reticulorumen in conscious sheep, with a similar time course of action to their respective characteristic effects on the induction (1 to 2, 15 to 20 and 20 to 30 minutes) and the duration (1 to 2, 1 to 2 and 8 to 12 hours) of tremoring. Responses to penitrem revealed a greater sensitivity of smooth muscle than skeletal muscle. Effects included an inhibition of the vagally-dependent cyclical A and B sequences of contraction of the reticulorumen, an increase in their amplitude and an excitation of local intrinsic activity contributing to elevated baselines and the occurrence of chaotic activity of the reticulum. The excitatory local effects were partially blocked by atropine, indicating that stimulation of muscarinic cholinoceptors was involved. Increased local activity may mediate a reflex inhibition of cyclical contractions. A non-tremorgenic isomer of lolitrem B (31-epilolitrem B) had no effect on the reticulorumen. The intensity and duration of the effects of lolitrem B, up to 12 hours, indicate that severe disruption of digestion may occur in animals grazing endophyte-infected pasture.
Soluble melanin precursors are present in serum and mag act as skill chromophores contributing to UVR-induced oxidative damage. Our study aimed to determine whether the soluble eumelanin precursor 5,6-dihydroxyindole-...
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Soluble melanin precursors are present in serum and mag act as skill chromophores contributing to UVR-induced oxidative damage. Our study aimed to determine whether the soluble eumelanin precursor 5,6-dihydroxyindole-2-carboxylic acid (DHICA) photosensitizes DNA damage in human keratinocytes exposed to UVA irradiation. The HaCaT keratinocytes were incubated with and without DHICA, before irradiation with broadband UVA (320-400 nm). The DNA photodamage was assessed using the comet assay that detects frank single-strand breaks (SSB) and specific oxidative lesions with the addition of endonuclease III. Without DHICA incubation, there was no significant increase in SSB, compared to unirradiated cells, for doses up to 48.5 J/cm(2) (<1 minimum erythemal dose). Preincubation with 0.5 mu M DHICA caused an increase in SSB at every UVA dose (significant from 12.1 to 48.5 J/cm(2)), while varying the DHICA concentration (0.125-2 mu M) showed this effect to be concentration dependent such that SSB increased and endonuclease III-sensitive sites decreased with increasing DHICA concentration. The irradiation of cells in the presence of antioxidants (catalase, mannitol and histidine) suggests that DHICA-induced photosensitization is mediated via singlet oxygen and, to a lesser extent, hydroxyl radicals. These results indicate that DHICA can induce strand breaks with UVA at clinically relevant doses via a mechanism involving reactive oxygen species.
B. epichloe (Weese) is a clavicipitaceous fungus which parasitizes pasture grasses. This class of fungi may be involved with ergot-type syndromes observed in cattle grazed on infected pastures. Three indole alkaloids ...
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B. epichloe (Weese) is a clavicipitaceous fungus which parasitizes pasture grasses. This class of fungi may be involved with ergot-type syndromes observed in cattle grazed on infected pastures. Three indole alkaloids were isolated from laboratory cultures of B. epichloe and their identities were determined by UV, IR, NMR and mass spectroscopy as: 4-(3-indolyl)butane-1,2,3-triol;3-(3,3-diindolyl)propane-1,2-diol;and 3-(3-indolyl)propane-1,2,3-triol. The alkaloids were toxic to fertile leghorn eggs.
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