The interactions of various low-molecular weight substances with DNA are naturally relevant mechanisms in the cellular cycle and so also used in medicinal treatment. Depending on the particular drug structure, DNA-binding modes like groove-binding, intercalating and/or stacking, give rise to supramolecular assemblies of the polynucleotides, as well as influence the DNA-protein binding. In this review, we compare the underlying molecular structures, including general aspects of DNA sequences, with the benefit in medicinal treatment. While so far interest in this field had mainly been devoted to isolated nucleic acid/drug interactions, the present paper will focus on drug efficiencies generating and influencing supramolecular organizations and their complex sequence-dependent structure-activity codes. In particular, the attention will be directed to stereoelectronic relationships. Spatial enantioselective properties are discussed in details. As examples, the drug self-assemblies, as well as the influence of drugs on supramolecular DNA formations are described. A hypothetical connection between drug-influenced DNA-toroids and the formation of micronuclei in tissues will be interpreted.
Information on the regulation of steroid hormone receptors and their distinct functions within the human endometrial epithelium is largely unavailable. We have immortalized human primary endometrial epithelial cells (EECs) isolated from a normal proliferative phase endometrium by stably transfecting the catalytic subunit (hTERT) of the human telomerase complex and cultured these hTERT-EECs now for over 350 population doublings. Active hTERT was detected in hTERT-EECs employing the telomerase repeat amplification assay protocol. hTERT-EECs revealed a polarized, non-invasive epithelial phenotype with apical microvilli and production of a basal lamina when grown on a three-dimensional collagen-fibroblast lattice. Employing atomic force microscopy, living hTERT-EECs were shown to produce extracellular matrix (ECM) components and ECM secretion was modified by estrogen and progesterone (P4). hTERT-EECs expressed inducible and functional endogenous estrogen receptor-alpha (ER-alpha) as demonstrated by estrogen response element reporter assays and induction of P4 receptor (PR). P4 treatment down-regulated PR expression, induced MUC-1 gene activity and resulted in increased ER-beta transcriptional activity. Gene activities of cytokines and their receptors interleukin (IL)-6, leukemia inhibitory factor (LIF), IL-11 and IL-6 receptor (IL6-R), LIF receptor and gp130 relevant to implantation revealed a 17 beta-estradiol (E2)-mediated up-regulation of IL-6 and an E2-and P4-mediated up-regulation of IL6-R in hTERT-EECs. Thus, hTERT-EECs may be regarded as a novel in vitro model to investigate the role of human EECs in steroid hormone-dependent normal physiology and pathologies, including implantation failure, endometriosis and endometrial cancer.
The interactions of the drugs 2,7-bis[(diethylamino)-ethoxy]-fluoren-9-one dihydrochloride (Tilorone), 2,7-bis[(dipropylamino)-acetamido]-fluoren-9-one dihydrochloride (FA-2), 2'-(4-hydroxyphenyl)-5-(4-methyl-1-piperazinyl)-2,5'-bi-1H-benzimidazole trihydrochloride (Hoechst 33258), and hematoporphyrin IX derivative (HPD) with synthetic self-complementary DNA (36-b.p.; 5'-biotin-spacer-[d(CGCTATATAGCG)]3-3') were studied by SPR (Surface Plasmon Resonance). Monolayers of biotinylated DNA were immobilized on a streptavidin-dextran-gold triple-layer. Small portions of the drugs (approximately 30 pmol/ml) were injected in continuous flow. The mass corresponded to the amount of the bound molecules. Injections of 50 mM sodium hydroxide pulses separated the DNA double strands, releasing the effector molecules. Subsequent treatments with the effectors gave reproducible results. The maximum interaction between drug and DNA was observed in the case of Tilorone. 41 molecules could bind to the 36-b.p. DNA duplex. To investigate the microscopic behavior in condensed nucleic acid phases, SFM (Scanning Force Microscopy)-imaging and polarizing microscopic observations of DNA-effector complexes were carried out. Supplementary UV-absorption thermal denaturation curves of DNA with the above-mentioned effectors in dilute solutions were measured. As an additional aid to understand the geometries of DNA-drug interactions, computer simulations were performed and compared with the experimental data.
The interaction of synthetic polynucleotide double strands with a natural lipid, oleic acid, was examined in diluted aqueous solutions by circular dichroism spectra, UV-absorption measurements, and surface plasmon resonance biosensor investigations. The investigations were performed with defined double and triple stranded oligo- and polydeoxyribonucleotides. Whereas duplexes are influenced by oleic acid ligandation, which could not be removed by ethanol dialysis procedure, no binding occurs to triple stranded DNA. The spectroscopic results indicate that oleic acid shows molecular recognition to AT b.p. motifs by groove binding. GC tracts - in particular alternating d[G-C] motifs - are strongly influenced by ligand interaction up to a ratio of one molecule per two base pairs. Likewise, the spectroscopic and morphologic changes in the supramolecular association of the complexes after treatment occur even after dialysis procedure. This was monitored with scanning force microscopy (SFM) as well. Additionally, monolayers of biotinylated DNA duplexes were immobilized on a streptavidin sensor-layer for surface plasmon resonance (SPR) observations. Small portions of the ligand were injected in continuous flow. Loosely bound molecules were removed by washing procedure. Injections of sodium hydroxide denature the DNA, releasing the tightly bound effectors. The amount of tightly bound oleic acid molecules was determined at one molecule per 2-3 base pairs. As consequence, a new mechanism of regulation of gene expression at nuclear membrane or by lipids inside DNA double helix has to be discussed.
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