Five newly synthesised monophosphates of two pyrimidine acyclonucleoside series, namely 1-N-[(2'-hydroxy)ethoxymethyl] and 1-N-[(1',3'-dihydroxy)-2'-propoxymethyl] derivatives of 5- and 5,6-alkylated uracils were tested in vitro for chromosome aberrations and sister chromatid exchanges (SCE). Metaphase plates were obtained via microculture of human lymphocytes from heparinized peripheral blood. The compounds were tested in doses: 10, 20, 40, 80 and 150 ?g per mL of culture. The tested compounds induced mainly chromatid gaps, less frequently chromosome gaps. A low number of mitoses with chromatid and chromosome breaks, acentric fragments, dicentric chromosomes and exchange figures were also observed. The tested compounds in doses: 40, 80 and 150 ?g per mL, doubled or tripled the percentage of cells with chromatid gaps and chromosome gaps as compared to the control. The percentage of cells with aberrations (excluding gaps) induced by the tested compounds in all doses did not exceed 2%. The tested compounds induced a higher number of SCE per cell but less than double frequency as compared to the control. SCE frequencies and replication index (RI) values varied depending on the examined compounds. For the highest dose of the tested compounds (150 ? per mL) a significant decrease in RI values was observed for 1-N-[(2'-hydroxy)ethoxymethyl]-5,6-tetramethyleneuracil monophosphate and for 1-N-[(2'-hydroxy)ethoxymethyl] -5,6-dimethyluracil monophosphate. So far, the results have indicated potential clastogenicity of all the tested compounds except acycloguanosine monophosphate.
Single human skin fibroblasts and the skin keratinocyte cell line HaCaT show contact guidance and elongate along narrow (1-2 Fm) scratches in glass substratum. During cell division these cells orientate their mitotic spindles along the long axis of the cell. Immunofluorescence staining of actin, tubulin, chromatin, and the nuclear NuMA protein complex demonstrated that cell elongation along scratches is accompanied by a corresponding rearrangement in the cytoskeleton. The results and literature suggest the following steps in the interplay between outside-in and inside-out signalling in the regulation of cell division orientation by extracellular factors. The interaction of cell surface with an anisotropy in the local environment causes changes in F-actin organization, cell elongation and alignment of stress fibres along the cell axis. This is accompanied by a corresponding reorientation of microtubules. Microtubules mediate between cell shape changes dependent upon cell interaction with substratum or other cells, the cortical actin and the position of centrosomes. Centrosomes determine the position and orientation of the mitotic spindle. The astral and central microtubules of the mitotic spindle control the localization of contraction-relaxation in the cell cortex and the position of the constriction ring and cell division plane.
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