19th-banner-rev.gif

Mendel-Brno 2000

category image Volume: 17
Issue Number 6, Part 2
June 2000

Stabilization of Homologous d(A)·d(T)-Tracts by Paclitaxel

1Martin Luther University Halle-Wittenberg, Institute of Biochemistry,
Kurt-Mothes- Str. 3, D-06120 Halle (Saale), Germany,
bischoff@biochemtech.uni-halle.de
2SENSOBI Sensoren GmbH,
Weinbergweg 22, D-06120 Halle (Saale), Germany

The nucleic acid activity of paclitaxel was investigated with synthetic and natural oligo- and polynucleotides. The polynucleotides poly(dA)·poly(dT), poly(dG)·poly(dC), poly[d(A-T)]· poly[d(A-T)], poly[d(G-C)]·poly[d(G-C)] and calf thymus DNA were used. The oligonucleotides were 24-mers with d(purine)24·d(pyrimidine)24 strands, as well as d[(purine)x -(pyrimidine)x)·d[(purine)x-(pyrimidine)x] sequences.

In a recent study, paclitaxel showed molecular recognition of AT nucleotides with a high affinity to homologous (dA)·(dT) sequences; no interaction with GC nucleotides could be observed [1]. An astonishing stabilization of the DNA-duplex up to DTm ª 25°C was measured by thermal denaturation with poly(dA)·poly(dT)/paclitaxel complexes. Circular dichroism signals of DNA(24-mer) containing homologous (dA·dT)-tracts increased with increasing amount of the drug; for the other oligo- and polynucleotides no change in the spectra could be found.

Simple phosphate backbone interaction in the narrow groove of (dA)·(dT) tracts could be a sufficient explanation for all the results. Hydrophilic side groups of the drug interact with the phosphate and clip the strands together, while the hydrophobic parts of the molecule may disturb the polynucleobase formation. This model would be introduced in the present work by the help of computer simulations.

Scanning Force Microscopy (SFM) observations of the complexes show the formations of toroidal structures in some probes. Intramolecular interaction of the DNA strands triggered by the drug explains their origin.

References

[1] G. Bischoff et al., J. Biomol. Struct. Dynam. (2000) in press; G. Bischoff et al., Nucleos. & Nucleot. 18, 2201-2217 (1999)

G. Bischoff1, U. Gromann1, R. Bischoff2, S. Hoffmann1

1Martin Luther University Halle-Wittenberg, Institute of Biochemistry,
Kurt-Mothes- Str. 3, D-06120 Halle (Saale), Germany,
bischoff@biochemtech.uni-halle.de
2SENSOBI Sensoren GmbH,
Weinbergweg 22, D-06120 Halle (Saale), Germany

$15.00