Micronuclei Formation of Polynucleotides by Drug Influence
DNA was found in a wide variety of condensed tertiary and quaternary structures in vivo and in vitro. In cells of higher organisms, DNA exists condensed as a left-handed superhelix wound around cationic histone protein octamers in the repeating nucleosomal arrays that comprise the basic chromatin fiber. The tight DNA package makes intrahelical interactions under formation of liquid crystalline phases possible. Changes in the secondary structure lead to organism annihilating, as well as protecting mechanisms. Medicinal therapies with drugs take advantages of these reactions. For instance, cytogenic damage under micronuclei formation is a frequently observed parameter during chemotherapeutic treatment. The influence of secondary DNA structure to the formation of microsatellites in cells seems to enter a key position in the structure-function relationship of cancer therapies. Supramolecular assemblies of double strands induced by some drugs may be used as a model to investigate the relevant aspects.
Common methods and Scanning Force Microscopy (SFM) investigated DNA/drug complexes in highly condensed packages as well as tumor cells treated with drugs. A broad range of ambivalent drug-types was studied, for instance fluorenones (FA-2 and Tilorone), benzimid-azoles (Hoechst 33258), and Taxol. All used drugs stabilize the DNA double helix .
SFM studies of DNA show primarily parallel-aligned double strands, which varied in length from 500 nm to a few microns. By investigating the pure drugs, no evidences for nanoscopic agglomeration were observed. Our SFM-study of the DNA/Tilorone, /FA-2, /Taxol, and /DIBA complexes showed impaired strands and spherical domains in a ratio of around 1 : 2, which are statistically distributed over the surface. DNA/Hoechst 33258 on the other hand showed only the parallel-aligned strand patterns of typical DNA formation without intramolecular associations. There the DNA-stabilization by minor groove binding without any overall geometry disturbances seems to be preferred, while the other drugs with their multivalent reaction possibilities, are able to induce intramolecular collapse into toroidal formations .
As a result, we found that the drug Hoechst33258, acting mainly as groove binder, do not support intramolecular collapse into toroidal structures, such as observed with ambivalent or multivalent molecules (including ions). In literature the micronuclei preventing power of this drug is described .
 G. Bischoff et al., Nucleosides&Nucleotides 18, 2201-2217 (1999); G. Bischoff et al., J. Biomol. Struct. Dynam. 16, 187-203 (1998)
G. Bischoff1, R. Bischoff2, S. Hoffmann1
1 Martin Luther University Halle-Wittenberg, Institute of Biochemistry,