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R Reszka

Publications and source records attributed to R Reszka.

At least 37 records · Page 2Linked to original sources
PubMed1998

Evidence that glypican is a receptor mediating beta-amyloid neurotoxicity in PC12 cells.

Docking of beta-amyloid fibrils to neuronal or glial cell membranes may be an early, necessary and intervenable step during the progression of Alzheimer's disease. Formation of neurofibrillary tangles and amyloid plaques as well as neurotoxicity and inflammation may be direct or indirect consequences. In an attempt to find a receptor that mediates those effects, we assessed rat pheochromocytoma PC12 cell 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) reduction after addition of beta-amyloid to the culture medium. Presence of competitive substances in the medium, cell-surface treatment and specific block of cellular synthesis pathways helped to identify the heparan sulphate moiety of a glycosylphosphatidylinositol-anchored protein likely to represent glypican as a possible receptor mediating beta-amyloid neurotoxicity.

Amyloid beta-Peptides↗
PubMed1998

[Liposome encapsulation of cystostatic drugs and starch microspheres improve tumor targeting in locoregional therapy. An animal experiment study of CC 531 liver tumor].

Systemic adjuvant chemotherapy achieves unsatisfactory results for inoperable liver tumors and metastases. Various clinical studies have shown that locoregional chemotherapy increased the survival rate by a few months. The aim of this study was to investigate tumor targeting of the most frequently used cytostatic 5-fluouracil by modifying systemic and locoregional therapy by liposome encapsulation. The tumor concentration of 5-FU encapsulated in SUV-PEG liposomes increases by a factor of 27 in systemic therapy and a factor of 90 in locoregional therapy. The tumor concentration of 5-FU increases by a factor of 8000, if the blood flow is additionally slowed by starch microspheres (Spherex) during locoregional therapy with liposome-encapsulated 5-FU.

Adenocarcinoma↗
PubMed1997

Simultaneous determination of 5-fluorouracil and its active metabolites in serum and tissue by high-performance liquid chromatography.

In order to observe the biodistribution of 5-fluorouracil (5-FU) and its main metabolites in different kinds of tissue (tumor, liver, kidney, spleen, mucosa, lungs, heart, peritoneum, pancreas) and serum according to various novel application forms, a simple and rapid method for the simultaneous determination of 5-FU and its active metabolites 5-fluorouridine (5-FUrd) and 5-fluoro-2'-deoxyuridine (5-FdUrd) has been established. Proteins in serum and tissue samples were precipitated by perchloric acid after addition of the internal standard 5-bromouracil. The compounds were separated using an ODS Hypersil (5 microm) column and detected by UV absorbance (254 nm). Specificity, linearity, reproducibility, intermediate precision and accuracy of the method were established. The lower limit of quantitation (LOQ) for the compounds in serum and various tissue samples was determined. Data on the recovery of the compounds and the internal standard are provided.

Animals↗
PubMed1997

Superoxide-mediated reduction of the nitroxide group can prevent detection of nitric oxide by nitronyl nitroxides.

Nitronyl nitroxides (NN), a class of compounds which react with nitric oxide forming imino nitroxides, were applied in different systems for the detection of nitric oxide. Addition of a NN to planar monolayers of bovine aortic endothelial cells (BAEC) activated by Ca2+ ionophore A23187 immediately resulted in a strong decrease of the ozone-mediated .NO chemiluminescence. Simultaneously, a rapid diminution of the electron spin resonance (ESR) signal intensity of the NN (without detectable formation of the corresponding imino nitroxide) was observed; superoxide dismutase partially inhibited this decrease in the NN concentration. Model experiments using hypoxanthine/xanthine oxidase in aqueous solution and KO2 in dimethylsulfoxide as sources of O2.- revealed that there is a rapid reduction of nitronyl nitroxides by superoxide. The second order rate constant for the reaction of the water soluble NN with O2.- was determined to be 8.8 x 10(5) M-1s-1, which is more than two orders of magnitude higher than the value reported previously for reaction with .NO (Woldman et al., BBRC 202, 195-203, 1994). Reduction of the nitronyl nitroxide was also observed in the presence of glutathione, ascorbic acid or rabbit liver microsomes. Incorporation of both nitronyl and imino nitroxides into liposomes strongly decreased reduction by superoxide and other reductants, however, in the presence of microsomes, there was no protective effect by liposomal encapsulation of NN. The results indicate that in biological systems (in addition to other reducing agents) the presence of superoxide can prevent the detection of nitric oxide using nitronyl nitroxides.

Animals↗
PubMed1997

Body distribution of free, liposomal and nanoparticle-associated mitoxantrone in B16-melanoma-bearing mice.

B16-melanoma-bearing mice were treated with four different formulations containing equivalent doses of the highly effective antineoplastic drug mitoxantrone. The formulations were: A mitoxantrone solution, a negatively charged liposome preparation (small unilamellar vesicles), a 14C-labeled polybutylcyanoacrylate- (PBCA) nanoparticle suspension, and a suspension of poloxamine 1508-coated 14C-PBCA-nanoparticles. After 1, 4 and 24 hr, three animals of each group were killed and the mitoxantrone concentrations in the blood, tumor, liver, spleen, heart and bone marrow were determined using an high performance liquid chromatography technique. Additionally, the concentrations of PBCA particles in the same tissues were measured by scintillation counting to compare the mitoxantrone distribution with the corresponding PBCA nanoparticle distribution. Each formulation led to a different body distribution profile of the drug. Liposomes drastically increased the blood level of mitoxantrone even after 24 hr, although free drug was cleared quickly. Liposomes also raised the concentration in the liver and spleen, but not the drug level in the tumor. PBCA-nanoparticles considerably increased the mitoxantrone concentrations in tumor, heart and spleen. However, the increase in tumor concentrations was not statistically significant due to the high variability. Nevertheless, the tumor growth was reduced significantly (P < .05) compared to both, the liposome and the solution preparation. The nanoparticle polymer concentrations did not completely mirror those of the drug concentrations. Especially in the heart, where no nanoparticle polymer radioactivity was found, the particle concentration did not completely correspond to the mitoxantrone concentration, revealing that a part of the drug was lost from the particles. These pharmacokinetic results correspond to parallel therapeutic effects obtained with mitoxantrone-loaded nanoparticles and liposomes in the B16 melanoma.

Animals↗
PubMed1997

Liposome-encapsulated superparamagnetic iron oxide particles as markers in an MRI-guided search for tumor-specific drug carriers.

Three different types of liposomes containing superparamagnetic iron oxide particles (SPIOs) as the contrast agent were tested for intratumoral enrichment by magnetic resonance imaging (MRI). The liposome-encapsulated SPIOs were investigated in comparison with AMI-227, dextran-coated SPIOs in two different dosages using the CC531 adenocarcinoma in the liver of WAG/RIJ rats as a model. Reduction of the relative signal intensity (SI) in the tumor in T2-weighted MR images was assumed as a measure of the liposome enrichment in the tumor or adjacent tissue. The samples were tested at dosages with isomolar iron content and at dosages producing the same MR relaxivity R2. For reverse phase evaporation vesicles and small unilamellar vesicles behavior differed remarkably according to the applied dosage. A steady, strong reduction in SI, starting immediately after injection and extending up to 48 h, was observed for small unilamellar vesicles sterically stabilized with polyethylene glycol.

Adenocarcinoma↗
PubMed1996

Evaluation of efficient chemoembolization mixtures by magnetic resonance imaging therapy monitoring: an experimental study on the VX2 tumor in the rabbit liver.

To find effective chemoembolization mixtures, we tested combinations of carboplatin with the embolizates Spherex and Gelfoam in comparison to a therapy with NaCl-solution, a treatment with the cytostatic drug only, and a therapy with each of the embolizates alone. The experiments were carried out using as a model the VX2 tumor in the liver of male chinchilla rabbits (five for each group). Carboplatin was revealed by the 3-(4,5-dimethylthiazole-2)-yl-2,5-diphenyltetrazolium bromide test to be a potent cytostatic drug for VX2 rabbit tumor cells. We used magnetic resonance imaging to examine the tumor volume and signal intensity enhancement up to 15 min after Gd-DTPA administration within the tumor and liver before and after the different therapies. These parameters allowed us to evaluate tumor growth and vitality as well as liver injury for the different therapy types. The results found by magnetic resonance imaging corresponded very well to those obtained by histological analysis of the tumors. The chemoembolization therapies were significantly more efficient than the other therapies, as indicated by the reduction of signal intensity enhancement after contrast agent administration within the tumor and by the histologically determined necrotic fraction after therapy. In addition, we found a significant decrease of the tumor volume and no significant live injury for a therapy with Carboplat and Gelfoam.

Animals↗
PubMed1996

Paclitaxel partitioning into lipid bilayers.

Paclitaxel (taxol) is diterpenoid anticancer drug with a new mechanism of cytostatic action. It is under investigation in clinical trials for treatment of various types of human cancer. A major difficulty in developing paclitaxel as a chemotherapeutic agent in its poor water solubility. In order to improve the bioavailability of paclitaxel, novel vehicle systems such as mixed micelles or liposome-based formulations are being developed. In this study we determined the partition coefficient of paclitaxel partitioning into small unilamellar lipid vesicles composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine using two different methods, namely high-sensitivity titration calorimetry and fluorescence spectrometry. We measured a partition coefficient of Kp approximately equal to 9,500 M-1, a partition enthalpy of Delta H = -25 +/- 3 kcal mol-1 and a free energy of binding of Delta G = -7.9 kcal mol-1. The binding reaction is enthalpy-driven, which can be explained by van der Waals interactions between the hydrophobic drug and the strong temperature dependence of the partition equilibrium. A temperature increase of 10 degrees C reduces the paclitaxel solubility in the lipid phase by a factor of 4.

Lipid Bilayers↗
PubMed1996

A continuous intracerebral gene delivery system for in vivo liposome-mediated gene therapy.

Using a minipump combined with stereotaxic techniques allows continuous delivery of therapeutic genetic materials into the brain. We investigated the therapeutic efficacy of liposome-mediated HSVtk gene transfer of experimental brain F98 glioma followed by treatment with ganciclovir. A single injection of DNA-liposome complexes showed a therapeutically significant decrease in the tumor volume. Continuous intracerebral delivery of DNA-liposome complexes using an osmotic minipump led to complete tumor regression in 36.4% of the treated animals. The safety and toxicity of this gene delivery system were also assessed. No organ pathology was observed in the experimental animals. The continuous gene delivery system could be a useful means of achieving higher doses with less toxicity and without the need for frequent injections.

Animals↗
PubMed1995

Global cerebral ischemia in the rat: online monitoring of oxygen free radical production using chemiluminescence in vivo.

Using online in vivo chemiluminescence (CL), we studied for the first time continuously the production of reactive oxygen species (ROS) after global cerebral ischemia and the relationship of ROS production to CBF. In anesthetized rats equipped with a closed cranial window, the CL enhancer, lucigenin (1 mM), was superfused onto the brain topically. CL was measured through the cranial window with a cooled photomultiplier, and CBF was measured simultaneously with laser-Doppler flowmetry. Reperfusion after 10 min (n = 8) of global cerebral ischemia led to a CL peak to 188 +/- 77% (baseline = 100%) within 10 +/- 4 min. After 2 h of reperfusion, CL had returned to 102 +/- 28%. Reperfusion after 20 min (n = 8) of ischemia increased CL to 225 +/- 48% within 12 +/- 3 min. After 2 h, CL was still increased (150 +/- 44%, p < 0.05 compared with 10 min of ischemia). CL after 10 min of ischemia was neither affected by brain topical free CuZn-superoxide dismutase (SOD) (100 U/ml, n = 3) nor by i.v. administration of free CuZn-SOD (104 U/kg, followed by 104 U/kg/h, n = 3). The CBF hyperfusion peak on reperfusion preceded the CL peak in all experiments by several minutes. In additional in vitro experiments we investigated the source of CL: Intracellular loading of lucigenin was demonstrated in cultured CNS cells, and a very similar pattern of CL as in the in vivo preparation after ischemia developed in rat brain slices after 15 min of hypoxia, which was unaffected by free CuZn-SOD (100 U/ml) but strongly attenuated by liposome-entrapped CuZn-SOD. We conclude that lucigenin-enhanced CL is a promising tool to study ROS production continuously from the in vivo brain of experimental animals and brain slices, and that the CL signal most likely derives from the intracellular production of superoxide. The production of ROS is preceded by reperfusion, is burst-like, and is dependent on the duration of the ischemic interval.

Acridines↗
PubMed1995

In vivo gene transfer: focus on the kidney.

Renal gene transfer techniques are being developed as a novel experimental approach to understand the pathogenesis of renal disease and to potentially develop new therapeutic tools. We review the currently available technology to introduce foreign genetic material into renal tissue, i.e., retroviral, adenoviral, and liposomal transfer systems with their respective advantages and caveats. Today, the transfer efficiency of these methods appears to be sufficiently high to study the effects of transduced genes on renal function and morphology in rat kidney. This will allow (i) the elucidation of the function of genes on the course of renal disease in experimental animal models and (ii) the modulation of local expression of endogenous genes which presumptively contribute to renal pathology in these models. One strategy to accomplish this aim is the use of recombinant DNA technology to design antisense DNA constructs or oligonucleotides, which interfere with the renal expression of target genes. We will also discuss some of the shortcomings of the currently used techniques with respect to potential therapeutic use of gene transfer systems and gene modulation.

Animals↗
PubMed1994

Carboplatin-liposomes (CPL) in immunodeficient mice: improved antitumor activity for breast carcinomas and stimulation of hematopoiesis.

Carboplatin-liposomes (CPL) have been shown to possess a strong stimulatory activity on the hematopoiesis in immunocompetent mice. As we were interested in studying this pharmacological characteristic in parallel with any antitumour effects which might be expected for the encapsulated cytostatic, we used a panel of six human breast carcinomas xenotransplanted to nude mice. The antitumor activity as well as the hematopoietic effects of the vesicles were studied in comparison to, and in combination with, the free drug. Carboplatin was encapsulated into reverse phase evaporation vesicles (REV) and injected i.p. as a single dose of 75 mg kg-1 into tumor-free and breast-carcinoma-bearing animals, respectively. Following a single application of CPL in nude mice, a significant increase of the WBC numbers to about three times for that of the normal level could be observed over a period of at least 28 days. The elevation was due to an increase in both circulating granulocytes and lymphocytes. The peripheral effect was accompanied by a relative decrease of spleen cellularity, while the number of bone marrow cells was hardly affected. There was no influence detectable on circulating blood cells in SCID mice. However, a rather high toxicity of CPL for this immunodeficient mouse strain was noticed. In the panel of breast carcinomas used, free carboplatin and CPL displayed a different pattern of therapeutic efficiencies. In four of the five tumor models tested, a combination of the free with the liposomal drug showed a significant inhibition of tumor growth while effectively preventing a drug-induced leukopenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Carboplatin-liposomes as activators of hematopoiesis.

Recombinant colony stimulating factors are studied in clinical trials with the purpose being the relief of the side effects of high dose chemotherapy and to make an optimized treatment regimen possible. The broad use of such factors is hindered by their relatively high costs, their short elimination half-lives, the occurrence of mild side effects, and the limitation of their action to the stimulation of mainly neutrophils. Therefore, exogenous preparations inducing an endogenous activation of hematopoiesis are being sought. In experiments in mice we have shown that carboplatin-liposomes injected intraperitoneally in a single dose of 100 mg/kg led to a strong two-peak increase in white blood cell counts. A maximum 10-fold elevation compared to controls of free carboplatin or empty liposomes was observed on day 2 and was probably due to the release and mobilization of cells from storage compartments. The second peak of about a 6-fold increase occurred on day 7-8 and can be seen as an indicator of bone marrow stimulation. Differentiation of blood cells revealed that neutrophils, lymphocytes and platelets multiplied. We presume that this effect of carboplatin-liposomes is due to a relatively fast uptake of these vesicles by macrophages as their natural target. Within these cells carboplatin is metabolized, leading to an almost total loss of antineoplastic activity against the murine P388 leukemia. Concomitantly, cytokines are apparently induced in and released from macrophages producing secondarily hematopoietic growth factors either directly or in combination with other cytokines. An involvement of macrophages is indicated by the fact that an intraperitoneal pretreatment of mice with zymosan caused a partial but significant suppression of hematopoietic stimulation. In an in vitro colony forming assay of serum of mice treated 1, 3, or 7 days with carboplatin-liposomes, the number of colonies increased 20-fold compared to serum from saline treated animals. Additionally, a combined intraperitoneal treatment of mice with 100 mg/kg of cyclophosphamide followed by carboplatin-liposomes one hour later demonstrated that prevention of cytostatic-induced leukopenia is possible by this method. Although the mechanism of stimulation of hematopoiesis by carboplatin-liposomes is still partially unknown our results suggest that there should be further development of such a preparation for possible use in the treatment of cancer or other inherited or acquired hematopoietic disorders.

Animals↗
PubMed1991

Pharmacokinetic behavior of [57Co]bleomycin liposomes in mice: comparison with the unencapsulated substance.

The distribution and excretion of [57Co]Bleomycin, dissolved in saline or encapsulated in liposomes, was studied in normal or tumor-bearing [P388 leukemia, reticulum cell sarcoma (RS)] mice. The free substance is cleared relatively quickly from the organism both after intravenous and intraperitoneal administration (t1/2 0.17 and 2.41 h, respectively), and is excreted predominantly via the urinary tract. In contrast, following entrapment in small unilamellar vesicles (SUV) or multilamellar vesicles (MLV), the 57Co radioactivity remains 7- to 30-fold longer in the blood stream and is detectable in considerable amounts in liver, spleen, lung and tumor of the RS model even after 48 h. Concomitantly, the renal excretion is diminished to about 50% of the free drug and the feces excretion is slightly increased, possibly due to the higher concentrations in the liver. Whereas the renal levels of radioactivity were similar with all application forms of [57Co]Bleomycin, there were marked differences in all the other tissues studied. After administration of SUV there was a higher activity in liver, brain and tumor, whereas MLV were more concentrated in spleen and lung. Therapeutic experiments confirmed the favorable results obtained with liposomes. While the free Bleomycin in the P388 leukemia had only a moderate influence on the lifetime of the animals with a treated/control value of 111%, encapsulation of the drug in SUV or MLV improved the results to 194 and 167%, respectively. In the intramuscular transplanted RS model, the SUV in a day 1 schedule had the same effect on tumor growth as the free drug in a day 1-4 schedule.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Antiviral and antiproliferative properties of liposome-associated human interferon-gamma.

Recombinant human interferon-gamma (rHuIFN-gamma) was associated with liposomes in an attempt to improve its therapeutic efficiency. It was associated with liposomes composed of phosphatidylserine (PS) and phosphatidylcholine (PC) at a ratio of 3:7, and of PS:PC and cholesterol (CHOL) at a ratio of 1:4:5 with efficiencies of 13% and 21%, respectively. The lipid composition influenced the antiviral activity of the liposome-complexed IFN-gamma tested against vesicular stomatitis virus. IFN associated with PS:PC liposomes was fully bioavailable and degraded by trypsin treatment. In contrast, PS:PC:CHOL-IFN was resistant to trypsin, and appeared latent as its full biological activity was seen only after disruption of the liposomes with detergent. Four human tumor cell lines were exposed to free and liposome-associated IFN-gamma. The growth of three solid tumor lines (colon, bladder, and lung) was inhibited by similar concentrations of free IFN and PS:PC-IFN. In contrast, less PS:PC-IFN than free IFN was needed to inhibit histiocytic lymphoma cells. Higher concentrations of PS:PC:CHOL-IFN than of free IFN were needed to inhibit growth of all four cell lines. The specificity of these effects of liposome-associated IFN-gamma were shown by their partial or complete neutralization by antibody to IFN-gamma. When liposome-IFN complexes of either type were stored at 4 degrees C, 30% of the IFN activity remained after 7 days; thereafter, decay was minimal over the next 3 weeks. These data show the formation of stable HuIFN-gamma-liposomes and indicate that the lipid components of these complexes influence their antiviral and antiproliferative activity for several different cell types.

Antineoplastic Agents↗
PubMed1984

Cardiotoxicity of free and liposomally encapsulated rubomycin (daunorubicin) in mice.

Different serum enzyme levels (creatine kinase, CK; lactate dehydrogenase, LDH; alanine amino-transferase, ALAT; aspartate aminotransferase, ASAT) were determined after treatment of mice with rubomycin in free or liposomally encapsulated form. Especially increase in CK activity, measure for cardiac toxicity, was significantly altered in animals that were treated with rubomycin-containing liposomes. Organ distribution studies showed a significantly lower uptake of encapsulated drug in heart tissues. Electron microscopic studies confirmed these results by indicating only small anthracycline-induced cardiac lesions using the liposomal form.

Alanine Transaminase↗
PubMed1983

[Preparation, properties and therapeutic effect of Daunorubicin-containing liposomes].

Preparation and analytic characterization of uni- and multilamellar lipid vesicles with different lipid composition, charge and size, containing Daunorubicin are described. A critical review is given for the methods of preparation of lipids and other amphiphilic compounds. Variations of the lipid composition, charge and size of the liposomes do not alter the therapeutic effectiveness.

Animals↗