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PubMed1994

Structural characterization of modified nucleosides in tRNA hydrolysates by frit-fast atom bombardment liquid chromatography/mass spectrometry.

Feasibility for the structural characterization of modified nucleosides in transfer RNA at low microgram levels has been investigated by using continuous-flow frit-fast atom bombardment liquid chromatography/mass spectrometry (frit-FAB LC/MS). Sample of tRNA(Phe) from brewer's yeast (Saccharomyces cerevisiae) was used as a main model, and enzymatically hydrolysed by nuclease P1 and alkaline phosphatase. The resulting nucleoside mixture was separated by using a microbore reversed-phase LC column (150 mm x 0.5 mm i.d.) with an aqueous ammonium acetate-methanol gradient, and the mass spectra were acquired on both positive and negative ionization modes. The modified nucleosides were characterized by comparison of the relative LC elution times with authentic nucleosides, and further confirmed by the structural information from the frit-FAB mass spectra where both molecular and base ions were in general observed as intense peaks in both ionization modes. Typically, 0.06-0.2 A260 units (3-10 micrograms) of isoaccepting tRNA was enough to obtain full-scan mass spectra of modified nucleosides, often occurring at a frequency of one per tRNA molecule using positive ion detection. The LC/MS system was used to screen modified nucleosides in tRNA of the extremely thermophilic microorganism Pyrodictium occultum.

Archaea↗
PubMed2005

Validity and reliability of existing and modified clinical methods of measuring femoral and tibiofibular torsion in healthy subjects: use of different reference axes may improve reliability.

Previous studies have evaluated reliability and validity of clinical measurements of femoral and tibiofibular torsion, however, the results are conflicting, warranting an alternative method. The authors developed modified methods of measuring femoral and tibiofibular torsion using different reference axes, and validity and reliability of the modified and existing methods were examined in healthy subjects. Reference values were established using magnetic resonance imaging (MRI) for the validity study. There were significant differences between all clinical methods and corresponding MRI outcomes (P <0.05), whereas Pearson's correlation coefficients between the clinical methods and MRI ranged from 0.67-0.92. For modified methods, intraclass correlation coefficients were 0.89-0.97, whereas those of existing methods were 0.75-0.81. Modified methods were more precise, with standard error of measurements (SEM) of 1.5-2.9 degrees , compared to existing methods (SEM=4.0-5.1 degrees). These results indicate that clinical methods available currently do not accurately measure true torsion of the femur and tibia. Nevertheless, the clinical methods may be useful for screening and descriptive purposes as indices of true torsion, and use of different reference axes could improve their reliability.

Adolescent↗
PubMed1994

Retrograde nontransseptal balloon mitral valvuloplasty using a modified Inoue balloon catheter.

Retrograde nontransseptal balloon mitral valvuloplasty, a method developed in our institution for the treatment of symptomatic mitral stenosis, avoids transseptal catheterization. Until recently, the self-positioning Inoue balloon catheter, unlike all other commercially available balloon catheters, had not been employed in this nontransseptal technique due to the short length of its catheter shaft. To employ a self-positioning balloon in retrograde nontransseptal balloon mitral valvuloplasty, we modified the Inoue device by extension of the catheter shaft. After retrograde nontransseptal left atrial catheterization using a steerable cardiac catheter, the modified Inoue balloon catheter was inserted through the femoral artery and advanced to the mitral valve retrogradely. Valvuloplasty was performed in 20 patients, with a successful result achieved in all. The modified Inoue balloon catheter was easy to use in retrograde nontransseptal balloon mitral valvuloplasty and showed excellent stability during inflation. Mean mitral valve area increased from 1.0 +/- 0.29 to 2.23 +/- 0.64 cm2 (P < 0.001) and mean transmitral gradient decreased from 11.4 +/- 6 to 4.3 +/- 2.1 mm Hg (P < 0.001). No major or minor complications were observed. Retrograde nontransseptal balloon mitral valvuloplasty using a modified Inoue balloon catheter is a feasible and effective technique for the treatment of symptomatic mitral stenosis. It appears to combine the advantages of avoiding transseptal catheterization with the advantages of this balloon's special configuration.

Adult↗
PubMed2006

A modified balloon crush approach improves side branch access and side branch stent apposition during crush stenting of coronary bifurcation lesions.

OBJECTIVES: Despite the advent of drug eluting stents and newer interventional techniques designed to treat the main vessel and side branch in bifurcation stenoses, optimal treatment of the side branch remains problematic. We aimed to assess the feasibility of a modified balloon crush technique for percutaneous treatment of coronary bifurcation stenoses. BACKGROUND: Use of the crush technique in bifurcation stenoses remains limited by access to the side branch after main vessel stent deployment, as well as limitations of side branch stent deployment. The modified balloon crush technique aims to improve side branch access and stent apposition. METHODS: The modified balloon crush is similar to the previously described balloon crush technique. Following side branch stent deployment, a balloon positioned in the main vessel is deployed to crush the proximal side branch stent. A guide wire is then placed into the side branch with a subsequent high-pressure balloon inflation at the side branch ostium. This opens the stent struts at the ostium of the side branch, facilitating future passage of the guide wire following main vessel stent deployment, prior to kissing balloon inflation. RESULTS: We performed this modification of the crush technique safely in 10 patients. We were successful in obtaining side branch access in nine of ten patients following initial main vessel stent deployment. In the only failure, there was a 90 degrees angle between the main vessel and side branch. CONCLUSIONS: The modified balloon crush technique can be safely performed, while optimizing side branch access and side branch stent apposition.

Aged↗
PubMed2005

Host-guest interactions in the supramolecular incorporation of fullerenes into tailored holes on porphyrin-modified gold nanoparticles in molecular photovoltaics.

Novel gold nanoparticles modified with a mixed self-assembled monolayer of porphyrin alkanethiol and short-chain alkanethiol were prepared (first step) to examine the size and shape effects of surface holes (host) on porphyrin-modified gold nanoparticles. The porphyrin-modified gold nanoparticles with a size of about 10 nm incorporated C60 molecules (guest) into the large, bucket-shaped holes, leading to the formation of a supramolecular complex of porphyrin-C60 composites (second step). Large composite clusters with a size of 200-400 nm were grown from the supramolecular complex of porphyrin-C60 composites in mixed solvents (third step) and deposited electrophoretically onto nanostructured SnO2 electrodes (fourth step). Differences in the porphyrin:C60 ratio were found to affect the structures and photoelectrochemical properties of the composite clusters in mixed solvents as well as on the SnO2 electrodes. The photoelectrochemical performance of a photoelectrochemical device consisting of SnO2 electrodes modified with the porphyrin-C60 composites was enhanced relative to a reference system with small, wedged-shaped surface holes on the gold nanoparticle. Time-resolved transient absorption spectroscopy with fluorescence lifetime measurements suggest the occurrence of ultrafast electron transfer from the porphyrin excited singlet states to C60 or the formation of a partial charge-transfer state in the composite clusters of supramolecular complexes formed between porphyrin and C60 leading to efficient photocurrent generation in the system. Elucidation of the relationship between host-guest interactions and photoelectrochemical function in the present system will provide valuable information on the design of molecular devices and machines including molecular photovoltaics.

Journal Article↗
PubMed1979

The clonal analysis of cytotoxic lymphocytes against 2,4,6-trinitrophenyl (TNP)-modified cells.

The frequency and specificity of clones of cytotoxic lymphocytes (CL) produced when (CBA X C57BL)F1 spleen cell populations were cultured with 2,4,6-trinitrophenyl (TNP)-modified syngeneic F1 cells, was examined. The frequency of clones which lysed F1-TNP targets was 1/3.3 X 10(4) spleen cells, and the frequency of clones which lysed the modified parental cells, CBA-TNP and C57BL-TNP was 1/6.7 X 10(4) and 1/2.9 X 10(5) spleen cells, respectively. Using a clonal analysis of the specificity of the CL, it was shown that the majority of the clones of CL which lysed the two modified parental tarets, were specific for one or the other of the targets. Activity against modified allogeneic DBA/2-TNP targets was also detected. The activity against DBA/2-TNP targets was due mainly to clones of CL which were specific for DBA/2-TNP targets. Only a minor part of the activity was due to clones which were cross-reactive for both F1-TNP and DBA/2-TNP target cells.

Animals↗
PubMed1982

Delayed-type hypersensitivity induced in immunodeficient mice with syngeneic modified self antigens: a suggestive model of autoimmune response.

Previous studies suggested that trinitrophenyl (TNP)-modified syngeneic red cells induced humoral autoimmune response in mice with defective T cell function but not in normal mice. The ability of modified self antigen to induce autoimmune response in immunodeficient mice was further explored using the delayed-type hypersensitivity (DTH) as an assay system. Mice were immunized with syngeneic TNP-modified spleen cells (TNP-SC) and challenged by syngeneic nonmodified concanavalin A (Con A) or lipopolysaccharide (LPS)-stimulated spleen cells injected into their footpads. The DTH response was assessed 24, 48 and 72 h later by measuring the footpad swelling and was transferred to naive recipients with enriched T cells from TNP-SC-immunized irradiated A mice but not with serum or non-T cells. Adult thymectomized, X-irradiated (250 rds) and cyclophosphamide-treated mice injected with syngeneic TNP-SC generated a DTH response when subsequently challenged with syngeneic lymphoblasts (induced with Con A or LPS) but not when challenged with allogeneic blast cells. In contrast, normal mice treated in a similar manner exhibited a much less significant DTH response. SC incubated 1 to 3 h with Con A failed to elicit the DTH response of immunodeficient mice previously injected with TNP-SC. Both lymphoblasts that were induced in vitro with Con A diluted in fetal calf serum or in normal mouse serum-containing media, and lymphoblasts that were induced in vivo by interleukin 2 elicited DTH responses in X-irradiated, TNP-SC immunized mice. The syngeneic DTH response of the immunodeficient mice injected with TNP-SC was abrogated when they were simultaneously transplanted with syngeneic SC or nylon wool-passed syngeneic SC. If the transplanted splenocytes had been treated with anti-Thy-1 antiserum and complement they failed to abrogate the syngeneic-DTH response of the above mentioned mice. This result suggests that suppressor cells are programmed to control the autoimmune response induced with modified self antigens.

Animals↗
PubMed1984

Human T cell antigens involved in cytotoxicity against allogeneic or autologous chemically modified targets. Association of the Leu 2a/T8 antigen with effector-target cell binding and of the T3/Leu 4 antigen with triggering.

Monoclonal antibodies (mAb) recognizing human T cell differentiation antigens were employed to analyze the role of these antigens on T cell-mediated cytotoxicity against autologous 2,4,6-trinitrophenyl (TNP)-modified targets. The OKT3/anti-Leu 4 and anti-Leu 2a/OKT8 mAb inhibited T cell-mediated cytotoxicity against autologous or unrelated TNP-modified targets, in the absence of complement and at the effector cell level. These cytotoxic effector cells were T3+, T8+, T11+, T4-. To analyze the role of the T3/Leu 4 and Leu 2a/T8 T cell differentiation antigens in the cytolytic process, we investigated the stages of this process that were inhibited by the OKT3/anti-Leu 4 and anti-Leu 2a/OKT8 mAb. Using: (a) visual adhesions, and (b) a single cell cytotoxicity assay in agarose, we observed that the OKT3 and anti-Leu 4 mAb did not inhibit binding of effector cells to allogeneic targets or to autologous E rosette-negative TNP-modified targets, although they significantly inhibited both the proportions of target cells in conjugates that were lysed, and the 51Cr release. In contrast, the anti-Leu 2a and OKT8 mAb blocked cytotoxicity by inhibiting binding of effector cells to the allogeneic or to autologous chemically modified targets. To further analyze the stages of the cytolytic process (adhesion; programming for lysis or lethal hit; and cytotoxic cell-independent lysis) that were inhibited by these mAb, we employed the detachment and dispersion method. This method is based on the differential temperature requirements of adhesion (which occurred both at 37 degrees C or 20 degrees C) and of programming for lysis (which occurred at 37 degrees C but not at 20 degrees C). Operational adhesions were determined by the 51Cr-release assay after dispersion of effector and target cells in a 10% solution of dextran (mol. wt. 500 000). Programming for lysis was determined by the 51Cr-release assay after detachment of effector-target cell conjugates with 10 mM EDTA and dispersion in 10% dextran solution. Using this method we determined that mAb recognizing the Leu 2a/T8 antigen blocked cytotoxicity by inhibiting adhesion and binding of effector cells to target cells. These antibodies do not affect post-adhesion stages of the cytolytic process. In contrast, the OKT3 and anti-Leu 4 mAb inhibit a post-adhesion step of the cytolytic process, that occurs before irreversible events of the programming for lysis stage have taken place.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1995

A quantitative study on the effect of organic modifiers in micellar electrokinetic chromatography.

A quantitative study was made on the effect of organic modifiers in micellar electrokinetic chromatography (MEKC). A linear relationship between 1/k' and organic modifier concentration ([L]) at lower concentration range was derived and experimentally verified. This linearity was also examined at higher concentrations of organic modifier. The results showed that the linear relationship between 1/k' and [L] can only be observed under the situation that no significant change on micellar structure occurs upon the addition of organic modifiers. The mobility ratio of the solute which characterizes the properties of the solute was found to be mainly independent of [L]. A resolution equation for the neutral solutes was also derived in term of mobility ratio.

1-Propanol↗
PubMed2003

Cyclodextrin-modified monolithic columns for resolving dansyl amino acid enantiomers and positional isomers by capillary electrochromatography.

We describe beta- and gamma-cyclodextrins (beta- and gamma-CD)-modified monolithic columns prepared by sol-gel process and chemical modifications. The monolithic silica column was fabricated inside a fused-silica capillary with 100 microm inner diameter by sol-gel process. The monolithic silica matrix was chemically modified chiral selectors of beta- or gamma-CDs with a spacer of 3-glycidoxypropyltrimethoxysilane by on-column reactions. Gamma-CD-modified monolithic column has successfully been applied for the separation of dansyl amino acid enantiomers. Beta-CD-modified monolithic column has been used for the separation of the positional isomers of o-, m-, and p-cresols and the enantioseparation of racemates of benzoin and several dansyl amino acids by capillary electrochromatography, respectively. For the separation of neutral positional isomers, a positive electric field was applied. However, for the separation of negatively charged analytes, a negative electric field was applied at the inlet of column. The separation efficiency of 5.0 x 10(4) theoretical plates/m for dansyl-L-threonine was obtained at electric field strength of -300 V/cm in the mobile phase of 50 mM 2-(N-morpholino)ethanesulfonic acid (MES)-Tris/methanol (70/30) buffer at pH 7.0. L-enantiomers were eluted as the first peak. Scanning electron micrograph showed that monolithic columns have the morphology of continuous skeleton and large through-pores.

Amino Acids↗
PubMed2003

Enantioselectivity of alcohol-modified polymeric surfactants in micellar electrokinetic chromatography.

A novel method of modifying sodium undecanoyl-L-leucinate (SUL) micelles employed in chiral separation of analytes in micellar electrokinetic chromatography (MEKC) to enhance selectivity toward specific analytes is discussed. The current study aimed at modifying the SUL micelles by introducing different alcohols into the mono-SUL micelles. The micellar solutions were then polymerized in the presence of alcohols followed by postpolymerization extraction of the alcohols to yield alcohol-free polymeric surfactants (poly-L-SUL). The effects of hexanol (C(6)OH) and undecylenyl alcohol (C(11)OH) on micellar properties of this surfactant were investigated by use of surface tensiometry, fluorescence spectroscopy, pulsed field gradient-nuclear magnetic resonance (PFG-NMR), and MEKC. The surface tension and PFG-NMR studies indicated an increase in the critical micelle concentration (cmc) and micellar size upon increasing the alcohol concentration. Fluorescence measurements suggested that alcohols induce closely packed micellar structures. Coumarinic and benzoin derivatives, as well as (+/-)-1, 1'-binaphthyl-2,2'-dihydrogen phosphate (BNP) were used as test analytes for MEKC experiments. Examination of MEKC data showed remarkable resolutions and capacity factors of coumarinic derivatives obtained with modified poly-L-SUL as compared to the unmodified poly-L-SUL. Evaluation of fluorescence, PFG-NMR, and MEKC data suggest a strong correlation between the polarity and hydrodynamic radii of alcohol-modified micelles and the resolution of the test analytes.

Alcohols↗
PubMed2005

Microchip capillary electrophoresis with a cellulose-DNA-modified screen-printed electrode for the analysis of neurotransmitters.

A microfluidic chip based on capillary electrophoresis coupled with a cellulose-single-stranded DNA (cellulose-ssDNA) modified electrode was used for the simultaneous analysis of dopamine (DA), norepinephrine (NE), 3,4-dihydroxy-L-phenylalanine (L-DOPA), 3,4-dihydroxyphenylacetic acid (DOPAC), and ascorbic acid (AA). The modification of the electrode improved the electrophoretic analysis performance by lowering the detection potential and enhancing the signal-to-noise characteristic without surface poisoning of the electrode. The sensitivity of the modified electrode was about 12 times higher than those of the bare ones. The test compounds were separated using a 62 mm long separation channel at the separation field strength of +200 V/cm within 220 s in a 10 mM phosphate buffer (pH 7.4). The most favorable potential for the amperometric detection was 0.7 V (vs. Ag/AgCl). A reproducible response (relative standard deviation of 1.3, 1.3, 2.1, 3.1, 3.4% for DA, NE, L-DOPA, DOPAC, and AA, respectively, for n = 9) for repetitive sample injections reflected the negligible electrode fouling at the cellulose-ssDNA modified electrode. Square-wave voltammetric analyses reflected the sensitivities of the modified electrode for DA, NE, L-DOPA, DOPAC, and AA which were 1.78, 0.82, 0.69, 2.45, and 1.23 nC/microM with detection limits of 0.032, 0.93, 1.13, 0.31, and 0.62 microM, respectively. The applicability of this microsystem to real sample analysis was demonstrated.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2006

Simultaneous analysis of nitrate and nitrite in a microfluidic device with a Cu-complex-modified electrode.

A CE microsystem coupled with a microchip and a copper-(3-mercaptopropyl) trimethoxysilane (Cu-MPS) complex-modified carbon paste electrode (CPE) was developed for the simultaneous analysis of nitrite and nitrate. The method is based on the electrocatalytic reduction of both analytes with the modified electrode. The Cu-MPS complex was characterized by voltammetric, XPS, and FT-IR analyses. Experimental parameters affecting the sensitivity of the modified electrode were assessed and optimized. The best separation was achieved in a 60 mm separation channel filled with a 20 mM acetate buffer of pH 5.0 containing 3.0 mM CTAB at separation field strength of -250 V/cm within 90 s. The detection potential for the simultaneous analysis of nitrite and nitrate was found to be -225 mV versus Ag/AgCl. A reproducible response (RSD of 3.2% (nitrite) and 2.8% (nitrate), n = 8) for repetitive sample injections reflected the negligible electrode fouling at the modified CPE. The interference effect was examined for other inorganic ions and biological compounds. A wide hydrodynamic range between 0.25 and 120 microM was observed for analyzing nitrite and nitrate with the sensitivities of 0.069 +/- 0.003 and 0.065 +/- 0.002 nA/microM, and the detection limits, based on S/N = 3, were found to be 0.09 +/- 0.007 and 0.08 +/- 0.009 microM, respectively. The applicability of the method to water and urine samples analyses was demonstrated.

Copper↗
PubMed2005

Modulation of the genotoxicity of pesticides reacted with redox-modified smectite clay.

Pesticides are toxic agents intentionally released into the environment; their use raises public health and environmental concerns. In recent years there has been much attention to the biotic degradation of pesticides. Abiotic mechanisms in the soil can contribute to pesticide degradation yet the toxicological impact of such degradation is unclear. This study combines for the first time an investigation into abiotic mechanisms of degradation coupled with toxicological endpoints in mammalian cells. The genotoxicity of three commonly used agricultural pesticides was assessed before and after exposure to redox-modified clay minerals. The objectives of the study were to determine the genotoxicity of 2,4-dichlorophenoxy acetic acid (2,4-D), dicamba, and oxamyl, using single cell gel electrophoresis with Chinese hamster ovary (CHO) cells, and to determine the effect of the iron oxidation state in clay minerals (ferruginous smectite SWa-1) on the genotoxic potency of the pesticides. 2,4-D alone or following reaction with redox-modified clays did not induce DNA damage in CHO cells. Oxamyl alone induced a concentration-dependent increase in genomic DNA damage; however, its genotoxicity declined after reaction with reduced clay minerals. Dicamba was not genotoxic when directly analyzed. When dicamba was reacted with reduced clay, a concentration-dependent increase in genomic DNA damage was observed. This is the first reported case of a pesticide being converted into a genotoxin after exposure to redox-modified smectites. These data introduce a new paradigm on the interaction between redox-modified clays and pesticide-related environmental genotoxicity.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1999

Albumin modified with mannose 6-phosphate: A potential carrier for selective delivery of antifibrotic drugs to rat and human hepatic stellate cells.

The hallmark of liver fibrosis is an increased extracellular matrix deposition, caused by an activation of hepatic stellate cells (HSC). Therefore, this cell type is an important target for pharmacotherapeutic intervention. Antifibrotic drugs are not efficiently taken up by HSC or may produce unwanted side-effects outside the liver. Cell-specific delivery can provide a solution to these problems, but a specific drug carrier for HSC has not been described until now. The mannose 6-phosphate/insulin-like growth factor II (M6P/IGF-II) receptor, which is expressed in particular upon HSC during fibrosis, may serve as a target-receptor for a potential carrier. The aim of the present study was to examine if human serum albumin (HSA) modified with mannose 6-phosphate (M6P) is taken up by HSC in fibrotic livers. A series of M6Px-modified albumins were synthetized: x = 2, 4, 10, and 28. Organ distribution studies were performed to determine total liver uptake. The hepatic uptake of M6Px-HSA increased with increasing M6P density. M6Px-HSA with a low degree of sugar loading (x = 2-10) remained in the plasma and accumulated for 9% +/- 0.5% or less in fibrotic rat livers. An increase in the molar ratio of M6P:HSA to 28:1 caused an increased liver accumulation to 59% +/- 9% of the administered dose. Furthermore, we determined quantitatively the in vivo intrahepatic distribution of M6Px-HSA using double-immunostaining techniques. An increased substitution of M6P was associated with an increased accumulation in HSC; 70% +/- 11% of the intrahepatic staining for M6P28-HSA was found in HSC. We also demonstrate that M6P-modified bovine serum albumin (BSA) accumulates in slices of normal and cirrhotic human livers. After incubation of this neoglycoprotein with human tissue, the protein is found in nonparenchymal liver cells. Because M6P-modified albumins are taken up by HSC in fibrotic livers, this neoglycoprotein can be applied as a selective drug carrier for HSC. This technology may create new opportunities for the pharmacological intervention of liver fibrosis.

Animals↗
PubMed2004

Post-translationally modified S12, absent in transformed breast epithelial cells, is not associated with the 26S proteasome and is induced by proteasome inhibitor.

The 26S proteasome, consisting of the 20S core and 19S regulatory complexes, regulates intracellular protein concentration through proteolytic degradation of targeted substrates. Composition of the 19S regulatory complex as well as posttranslational modifications of the 19S subunits can effectively regulate the activity of the 26S proteasome. Aberrant activity of the 26S proteasome affects the cell cycle, apoptosis and other cellular processes related to cancer. Recent data show an additional proteasome-independent role of 19S subunits in transcriptional regulation. S12 (Rpn8), the human homologue of mouse Mov-34, is a non-ATPase 19S regulatory subunit of the 26S proteasome. Previous studies have identified phosphorylated S12. In our study, we identify a modified S12 isoform (S12-M) with distinct biochemical properties. The S12-M isoform was found in 6 normal, but not 4 transformed, breast epithelial cell lines. Modification of S12 protein can be induced in vitro by addition of the proteasome inhibitor PSI. Modified and unmodified S12 have similar mass, but different isoelectric points, consistent with phosphorylation. In normal cells, unmodified S12 associates with the 26S proteasome, while modified S12-M does not. Whereas transformed cell line nuclei contain neither S12 isoform, S12-M is predominantly cytosolic in normal cells, with the unmodified S12 present in both the nuclei and cytosol. Together with the role of 19S subunits in transcriptional regulation, homology between S12 and eIF3 and TFIIH subunits, coelution with immunoproteasome subunits, and differential posttranslational modification and nuclear localization, these data suggest a differential nuclear function of modified and unmodified S12 in cancer.

Amino Acid Sequence↗
PubMed2004

Gene transfer to cervical cancer with fiber-modified adenoviruses.

Successful adenoviral (Ad) vector-mediated strategies for cancer gene therapy mandate gene-delivery systems that are capable of achieving efficient gene delivery in vivo. In many cancer types, in vivo gene-transfer efficiency remains limited due to the low or highly variable expression of the primary Ad receptor, the coxsackie Ad receptor (CAR). In this study, we evaluated the expression of CAR on cervical cancer cells as well as CAR-independent targeting strategies to integrins (Ad5.RGD), heparan sulfate proteoglycans (Ad5.pK7) or both (Ad5.RGD.pK7). We used a panel of established cervical cancer cell lines and primary cervical cancer cells isolated from patients to quantify the expression of CAR mRNA and to evaluate the gene-transfer efficiency of fiber-modified Ads. Of the fiber-modified vectors, Ad5.pK7 and Ad5.RGD.pK7 displayed significantly enhanced gene-transfer efficiency in vitro. Gene-delivery efficiency in vivo was evaluated using an s.c. cervical cancer mouse model. Ad5.RGD.pK7 significantly improves tumor targeting in vivo, resulting in a significantly improved tumor/liver ratio in mice. Our results suggest that the double-modified Ad5.RGD.pk7 vector enhances gene transfer to clinically relevant cervical cancer substrates, while the infectivity of nontarget cells in the mouse is not increased and comparable to Ad5. The fiber-modified virus described here can help achieve higher clinical efficacy of cervical cancer gene therapy.

Adenoviridae↗
PubMed1994

Formation of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins in human renal-cell carcinoma.

To study the possible involvement of reactive oxygen species (ROS) in the tumor biology of human renal-cell carcinoma (RCC), we analyzed 35 cases of RCC for 2 parameters of oxidative damage: 8-hydroxy-2'-deoxyguanosine (8-OHdG), a mutation-prone DNA-base-modified product, was measured by means of high-performance liquid chromatography (HPLC) with an electrochemical (EC) detector, and 4-hydroxy-2-nonenal (HNE)-modified proteins were measured with a polyclonal antibody against HNE-modified proteins. A 54% higher content of 8-OHdG was found in RCC than in the corresponding non-tumorous kidney, suggesting that the DNA of RCC is more exposed to ROS than is the DNA of non-tumorous kidneys. Immunohistochemistry for HNE-modified proteins showed a distinct staining pattern of fine to coarse granularity in the cytoplasm of RCC (n = 15), implying that lipid peroxidation products are located in cytoplasmic organelles. These results suggest that RCC constitutionally elaborates more ROS than is produced by the non-tumorous parts of kidneys. No correlation was found between clinical stage, histology, age or sex and the 2 parameters examined.

8-Hydroxy-2'-Deoxyguanosine↗