Stabilization of Double Stranded Homologous Poly(dA)·Poly(dT) by Taxol.

Area of Science:

• Biochemistry
• Molecular Biology
• Drug-Nucleic Acid Interactions

Background:

• Taxol and paclitaxel are known for their biological activities.
• Understanding their interaction with nucleic acids is crucial for elucidating their mechanisms of action.
• Previous studies suggested molecular recognition of AT nucleotides by these drugs.

Purpose of the Study:

• To investigate the nucleic acid activity of taxol and paclitaxel.
• To characterize their binding affinity and effects on DNA structure and stability.
• To explore potential mechanisms of interaction with different DNA sequences.

Main Methods:

• Spectroscopic methods (e.g., Circular Dichroism)
• Calorimetric methods (e.g., Differential Scanning Calorimetry, Thermal Denaturation)
• Studies using synthetic and natural oligo- and polynucleotides (poly(dA)·poly(dT), poly(dG)·poly(dC), calf thymus DNA)

Main Results:

• Taxol and paclitaxel exhibit high affinity for AT-rich DNA sequences, specifically (dA)·(dT) tracts.
• Significant stabilization of the DNA duplex was observed, with thermal denaturation showing up to a 25°C increase in melting temperature (ΔT(m)).
• Circular dichroism indicated drug binding to AT-rich DNA, though signal changes varied between dilute and condensed states, suggesting complex interactions.

Conclusions:

• Taxol and paclitaxel demonstrate specific molecular recognition and binding to AT-rich DNA sequences.
• The drugs stabilize DNA duplexes through interactions with the phosphate backbone in the narrow groove of (dA)·(dT) tracts.
• These findings provide insights into the molecular mechanisms underlying the interaction of taxol and paclitaxel with DNA.