Vol. 5 No. 4 December 2000
| Volume 5 (2000) pp 415-422 | |
| Title | THE PHYSICOCHEMICAL PROPERTIES OF SOME NEW AMINOPHOSPHONATES |
| Authors | Halina Kleszczyńska, Janusz Sarapuk and Anna Dziamska |
| Abstract | The hemolytic activity of some newly synthesized aminomethanephosphonic acid derivatives was studied. The compounds studied differed in their polarity and the hydrophobicity of the electronic substituents at their nitrogen and carbon atoms. It was found that acyclic aminophosphonates exhibited significantly stronger hemolytic properties than cyclic aminophosphonates. To cause the same level of hemolysis of pig erythrocytes, it was necessary to use about a tenfold higher concentration of cyclic aminophosphonates than acyclic ones. The hemolytic activities of the compounds were related to the possibilities of their incorporation into the lipid phase of erythrocyte membranes. Once incorporated, they changed the fluidity of those membranes; the changes were more pronounced in the case of cyclic aminophosphonates. Acyclic compounds were also found to exhibit a slight antioxidative activity, which may be a consequence of their stronger interaction with the membrane lipids. The results obtained in the experiments performed with the use of planar lipid membranes were similar to those obtained in the hemolytic studies, i.e., acyclic aminophosphonates interacted more effectively with those membranes. The general conclusion is that both stereochemistry and hydrophobicity are the factors that determine the efficiency of the interaction of the compounds studied with the model membranes used, and that most likely location of aminophosphonates is the lipid phase of the erythrocyte membrane. Another conclusion is that newly synthesized aminophosphonates may be used as potentially good pesticides. |
| Address and Contact Information | Department of Physics and Biophysics, Agricultural University, Wroclaw, Norwida 25, 50-375, Poland |
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| Volume 5 (2000) pp 423-431 | |
| Title | THE DETECTION AND CHARACTERIZATION OF RAT PROTEIN RECOGNIZING DNA DAMAGED BY N-ACETOXYACETYLAMINOFLUORENE |
| Authors | Monika Pietrowska1, Joanna Łanuszewska1, Zofia Walter2, Joanna Rzeszowska-Wolny1 and Piotr Widłak1* |
| Abstract | Proteins recognizing DNA damaged by the chemical carcinogen Nacetoxy- acetylaminofluorene (AAAF) were analyzed in nuclear extracts from rat tissues, using a 36 bp oligonucleotide as the substrate and an electrophoretic mobility shift assay. Two major proteins that form complexes with DNA damaged by AAAF were detected; one of them also bound DNA damaged by cis-diammine-dichloroplatinum. The complex specific for AAAF-damaged DNA contained protein loosely attached to nuclear components. It was extracted with 0.1 M NaCl. The amount of this protein was estimated at about 105 copies per liver cell nucleus, and its probable size was about 42 kDa as detected by the Southwestern blotting assay. Its affinity for DNA damaged by AAAF was ~10-fold higher than that for undamaged DNA. Analogous AAAFDDB (damaged-DNA-binding) proteins were also detected in extracts from rat brain, testis and kidney tissue. The levels of such proteins were not affected in rats treated with the carcinogen 2-acetylaminofluorene. |
| Address and Contact Information | 1Department of Experimental and Clinical Radiobiology, Center of Oncology, 44-100 Gliwice, Poland 2Department of Molecular Genetics, University of Lodz, 90-237 Lodz, Poland. * Corresponding author: phone: (48 32) 278 9672. fax: (48 32) 231 3512.e-mail: widlak@onkol.instonko.gliwice.pl |
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| Volume 5 (2000) pp 433-440 | |
| Title | THE MACROMOLECULAR AGGREGATE AS A DRUG CARRIER |
| Authors | Marek Langner1 and Maciej Ugorski*,2,3 |
| Abstract | Traditionally, a drug is expected to be biologically active and at the same time be able to ensure some sort of tissue or organ specificity. The latter property is necessary to avoid undesirable side effects when toxic drugs are being used. Such requirements are difficult to achieve only by changing the chemical formula of the drug. For these reasons, within the last few years a new pharmacological concept has been developed regarding delivery of biologically active compounds by the use of macromolecular aggregates. The purposespecific design of macromolecular aggregates, able to deliver drugs to a desired location, is based on the assumption that different functions can be assigned to the separate chemical entities forming the aggregate. With the help of such an aggregate, the biologically active compound can be designed with solely its pharmacological potency in mind and without considering any limitations imposed by inaccurate delivery, such as undesired side effects. Specific molecules of the aggregate would ensure desired compound distribution within the organism. Furthermore, other molecules forming the aggregate should fulfill additional functions, e.g. protecting the drug from degradation. Additionally, aggregates formed from amphiphilic molecules should be capable of carrying drugs that are difficult to use as therapeutic agents due to low solubility in biological fluids (e.g. Taxol) or degradation (e.g. peptides, DNA). Such aggregates can be constructed from natural or/and synthetic compounds. Taken together, this creates possibilities of extending the spectrum of drug application and allows for the introduction of new technological modifications. |
| Address and Contact Information | 1Institute of Physics, Wroclaw University of Technology, Wyb. Wyspianskiego 27, 50-370 Wroclaw, Poland, 2Faculty of Veterinary Medicine, Agricultural University, ul. Norwida 25, 50-375 Wroclaw, Poland, 3Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. Weigla 12, 53-114 Wroclaw, Poland |
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| Volume 5 (2000) pp 441-450 | |
| Title | DNA DAMAGE AND APOPTOSIS INDUCTION IN L1210 CELLS BY CIS-DIAMMINEDICHLOROPLATINUM(II) AND ITS NEW AMINOFLAVONE ANALOGUE |
| Authors | Ewa Ciesielska1, Kazimierz Studzian1, Elżbieta Zyner2, Justyn Ochocki2 and Leszek Szmigiero1 |
| Abstract | This work compares the biological properties of cis-diamminedichloroplatinum (cisplatin) and its new analogue cis-[Pt(AF)2Cl2] (AF stands for 3-aminoflavone), which contains two aminoflavone substituents as nonleaving ligands. Both compounds were tested for their antiproliferative activity against cultured L1210 cells, and their DNA interstrand crosslinking activity in cells and in a cell-free system. Cisplatin was found to be an approximately 6 times more cytotoxic drug than its new analogue. Platinum complexes reacted with purified calf thymus DNA in a cell-free system producing DNA interstrand crosslinks. The kinetics of crosslink formation was very similar for both compounds but the maximal level of crosslinks was 20% higher for cisplatin. In cells, however, crosslinks were produced by cisplatin, whereas this type of DNA lesion was almost undetected in cells treated with the aminoflavone analogue as assayed by DNA alkaline elution. At higher drug concentrations, strong degradation of DNA was observed in L1210 cells treated with cis- [Pt(AF)2Cl2] but not in the cells incubated with cisplatin. This DNA degradation seems to reflect very efficient apoptosis induction by cis-[Pt(AF)2Cl2] as the electrophoretic patterns of DNA from cells incubated with this drug showed a ladder typical for apoptotic cells. |
| Address and Contact Information | 1Department of General Chemistry, Medical University of Lodz, 2Department of Inorganic Chemistry, Medical University of Lodz, Poland |
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| Volume 5 (2000) pp 451-467 | |
| Title | THE CHICKEN α- AND β-GLOBIN GENE DOMAINS AND THEIR CHROMATIN ORGANIZATION |
| Authors | Félix Recillas-Targa |
| Abstract | The eukaryotic genome is organized into discrete chromatin domains. The globin groups of genes have been two of the classical biological systems to study the relationship between gene regulation and chromatin structure during development. The individual promoters, enhancers and silencers of the globin genes are stage- and tissue-specific regulatory elements that are controlled by the interaction of ubiquitous and erythroid nuclear factors. Such regulated activation requires an optimal chromatin organization. Erythroid and constitutive DNase I hypersensitive sites (DHs) contribute to chromatin domain remodeling mediated by locus control region (LCR) activity and defined by domain boundaries. A comparative analysis of the chicken α- and β-globin domains will outline the relevance and effect of chromatin structure on gene regulation. |
| Address and Contact Information | Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Departamento de Genética Molecular, Apartado Postal 70-242 México D.F. 04510 |
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| Volume 5 (2000) pp 469-481 | |
| Title | EVALUATION OF THE IMMUNOMODULATORY ACTIVITY OF FOUR COMPOUNDS EXERTING ANTIMUTAGENIC EFFECTS ON HUMAN LYMPHOCYTES IN VITRO |
| Authors | Kazimierz Gąsiorowski*, Barbara Brokos and Helena Tabaka |
| Abstract | Four compounds previously described as antimutagenic for human lymphocytes in vitro were tested on their immunomodulatory activity in lymphocyte cultures. The standard immunocytochemical methods were applied for microscopic examination of the percentual representation of the main lymphocyte subpopulation. The results imply that all of the tested compounds exhibited significant immunomodulatory effect, with that of fluphenazine being the strongest, whereas that of todralazine is the weakest. Two of the tested compounds: anthocyanins from Aronia melanocarpa fruit, and alkylresorcinols from cereal grains, also exhibited a distinct immunomodulatory activity, and it deserves adequate attention as an activity exerted by natural products, commonly present in regular human diet. The analysis of the proliferating cell fraction, and the estimation of the cell proliferation rate suggest that the effect of the tested compounds might depend on an increase in the number of lymphocytes which expressed their differentiation antigens on the cell membranes. |
| Address and Contact Information | Wroclaw Medical University, Department of Basic Medical Sciences,
14 Kochanowskiego Str., 51-601 Wroclaw, Poland. *Corresponding author, fax:(+48 71) 3479211, e-mail: kaz@basmed.am.wroc.pl |
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| Volume 5 (2000) pp 483-493 | |
| Title | EFFECT OF LIPOSOME COMPOSITION AND CHOLESTEROL ON THE CELLULAR UPTAKE OF STAVUDINE BY HUMAN MONOCYTE/MACROPHAGES |
| Authors | Arun Katragadda, Roger Bridgman1 and Guru Betageri2 |
| Abstract | The objective of this study was to determine the cellular uptake of stavudine (an approved drug for AIDS treatment) by human monocyte/macrophages (U 937). The effect of lipid used, cholesterol concentration and the presence of charge on the liposome bilayer, on the cellular uptake by monocyte/macrophages was investigated. Liposomes employed in the study were prepared by reverse phase evaporation. The lipids egg PC, DMPC, DPPC, DSPC, DMPG and sphingomyelin were employed in this study. The effect of cholesterol on cellular uptake was studied by using liposomes containing a constant amount of lipid and varying amounts of cholesterol. Stearylamine or dicetylphosphate (10 mol%) was used to induce positive or negative charge on the bilayer. The cells were separated from liposomes by centrifugation in membrane filters and the amount of stavudine taken up by macrophages was estimated using tritium labeled drug as a marker. Stavudine uptake was found to be the maximum (approximately 950 ng/million cells) in liposomes containing dipalmitoyl phosphatidylcholine (DPPC). The presence of sphingomyelin, which increases bilayer rigidity decreased cellular uptake of stavudine and the presence of negative charge on the bilayer, enhanced the uptake of stavudine compared to positive charge. There is no apparent difference in uptake when varying amounts of cholesterol was added to liposomal formulations. The present study shows that the sensitivity of macrophages to different charge and lipid type can be used to either decrease or increase cellular uptake as desired. |
| Address and Contact Information | Department of Pharmacal Sciences, School of Pharmacy, Auburn University, Auburn, AL 36849 and 1Hybridoma Facility, A.U Research Park, Auburn University, Auburn, AL 36849. 2Western University of Health Sciences, College Plaza, 309 E. Second Street, Pomona, CA 91766. |
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| Volume 5 (2000) pp 495-509 | |
| Title | IDENTIFICATION OF mRNA ENCODING HOMEOBOX PROTEINS HOX b4 AND HOX b5 IN DEVELOPING CHICKEN GIZZARD TISSUES |
| Authors | Rebecca A. Fillmore and Warren E. Zimmer* |
| Abstract | Combining reverse transcriptase-polymerase chain reaction (RTPCR) and molecular cloning technologies, we have investigated the expression of homeodomain proteins in chicken gizzard tissues undergoing differentiation. We demonstrate that homeodomain encoding transcripts are found in developing chicken gizzard. An RT-PCR generated 117 bp homeodomain DNA probe was used to screen a gizzard library and resulted in the identification of ~60 potential homeodomain encoding cDNAs. Sequence analysis of the two longest clones identified them as Hox b4 and Hox b5, paralogues of Drosophila Deformed (Dfd) and Sex combs reduced (Scr), respectively. Northern blotting analysis demonstrated an increase in the Hox b4 and Hox b5 mRNAs just prior to the onset of smooth muscle cell differentiation as judged by the expression of the smooth muscle g-actin gene. Thus, Hox b4 and Hox b5 display the appropriate temporal expression pattern to be involved in the development/differentiation of the chicken gizzard. |
| Address and Contact Information | Department of Cell Biology and Neuroscience,
University of South Alabama, College of Medicine,
Mobile, Alabama, 36688, USA *Corresponding author |
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