WFU Physics Colloquium

Most platinum-based cancer drugs target DNA and induce changes in the DNA conformation. Cisplatin, which belongs to this group of drugs, has a success rate of ~ 90 % against testicular and ovarian cancer; but a much lower success rate in other cancers, such as lung cancer. The discrepancy in success rates may be due to differing responses of the cellular DNA repair machinery to drug-induced DNA conformational changes. Cisplatin induces a bend in DNA, but despite decades of clinical use and substantial research of cisplatin-DNA interactions, the cisplatin-induced change in DNA conformation, such as bend angle and bend flexibility, is still not fully understood.

Platinum Acramtu (Pt-Acramtu) is another platinum-based molecule. It has shown encouraging results in the treatment of small cell lung cancer (SCLC), in animal models. Instead of bending DNA Pt-Acramtu is thought to lengthen DNA.

We developed a method, based on statistical analyses of AFM images and simulations, to determine DNA conformational properties, such as bend angle, bend flexibility and persistence length. We applied this method to investigate the change in DNA conformation and mechanical properties due to its interaction with cisplatin and Pt-Acramtu with DNA at the single molecule level to determine the change in the DNA mechanical properties due to these interactions. We found that a GG-cisplatin biadduct induces a 35^o - 38^o bend angle and a slight softening the DNA around the bend. An AG-cisplatin biadduct induces almost no change in DNA conformation. Moreover, we found that Pt-Acramtu lengthens DNA by about 0.6 nm per incorporated drug molecule. DNA uptake of Pt-Acramtu saturates at a 15% drug to base pair ratio. Treatment of DNA with Pt-Acramtu does not change the persistence length of DNA, even at saturating concentrations, but it does cause the DNA to aggregate and degrade.

Elucidation of these drug-induced DNA conformational changes enhances our understanding of how proteins interact with Platinum drugs and may, thus, enhance our understanding of the successes and limitations of Platinum drugs.