Stabilization of double stranded homologous poly(dA)center dot poly(dT) bytaxol

The nucleic acid activity of taxol and paclitaxel was investigated with syn thetic 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)] pol y[d(G-C)] and calf thymus DNA were used. The oligonucleotides are 24-mers w ith d(purine)(24).d(pyrimidine)(24) strands, as well as d[(purine)(x)-(pyri midine)(x)].d[(purine)(x)-(pyrimidine)(x)] sequences. The study was perform ed with spectroscopic and calorimetric methods in dilute and condensed DMA- solutions. In a recent study, taxol and paclitaxel showed molecular recognition of AT nucleotides with a high affinity to homologous (dA). (dT) sequences; no int eraction with GC nucleotides could be observed. An astonishing stabilizatio n of the DNA duplex up to DeltaT(m) - = 25 degreesC was measured by thermal denaturation with poly(dA). poly(dT)/paclitaxel complexes. Circular dichro ism signals of DNA (24-mer) containing homologous (dA). (dT) tracts increas ed with increasing amount of the drug; for the other oligo- and polynucleot ides no change in the spectra could be found. Contrary to this findings, ci rcular dichroism (CD) spectra of poly(dA). poly(dT)/pacilitaxel complexes d isplayed reduced intensities of the signals at increasing drug concentratio ns. These findings in dilute solutions were complemented by differential scanni ng calorimetric investigations in condensed states (only calf thymus DNA te sted). Increasing enthalpies by increasing amount of the drug point to a st abilization. Simple phosphate backbone interaction in the narrow groove of (dA). (dT) tr acts could be a sufficient explanation for all the results. Hydrophilic sid e groups of the drug interact with the phosphate and clip the strands toget her, while the hydrophobic parts of the molecule may disturb the polynucleo base formation.