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PT-ACRAMTU, a platinum-acridine anticancer agent, lengthens and aggregates, but does not stiffen or soften DNA.
- Source :
-
Cell biochemistry and biophysics [Cell Biochem Biophys] 2013; Vol. 67 (3), pp. 1103-13. - Publication Year :
- 2013
-
Abstract
- We used atomic force microscopy (AFM) to study the dose-dependent change in conformational and mechanical properties of DNA treated with PT-ACRAMTU ([PtCl(en)(ACRAMTU-S)](NO3)2, (en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea. PT-ACRAMTU is the parent drug of a family of non-classical platinum-based agents that show potent activity in non-small cell lung cancer in vitro and in vivo. Its acridine moiety intercalates between DNA bases, while the platinum group forms mono-adducts with DNA bases. AFM images show that PT-ACRAMTU causes some DNA looping and aggregation at drug-to-base pair ratio (r b) of 0.1 and higher. Very significant lengthening of the DNA was observed with increasing doses of PT-ACRAMTU, and reached saturation at an r b of 0.15. At r b of 0.1, lengthening was 0.6 nm per drug molecule, which is more than one fully stretched base pair stack can accommodate, indicating that ACRAMTU also disturbs the stacking of neighboring base pair stacks. Analysis of the AFM images based on the worm-like chain (WLC) model showed that PT-ACRAMTU did not change the flexibility of (non-aggregated) DNA, despite the extreme lengthening. The persistence length of untreated DNA and DNA treated with PT-ACRAMTU was in the range of 49-65 nm. Potential consequences of the perturbations caused by this agent for the recognition and processing of the DNA adducts it forms are discussed.
- Subjects :
- Acridines chemical synthesis
Antineoplastic Agents chemical synthesis
DNA metabolism
DNA Adducts chemistry
DNA Breaks, Double-Stranded
Microscopy, Atomic Force
Organoplatinum Compounds chemical synthesis
Particle Size
Thiourea chemical synthesis
Thiourea chemistry
Thiourea pharmacology
Urea analogs & derivatives
Urea chemistry
Acridines chemistry
Acridines pharmacology
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
DNA chemistry
DNA drug effects
Organoplatinum Compounds chemistry
Organoplatinum Compounds pharmacology
Platinum chemistry
Thiourea analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1559-0283
- Volume :
- 67
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell biochemistry and biophysics
- Publication Type :
- Academic Journal
- Accession number :
- 23636685
- Full Text :
- https://doi.org/10.1007/s12013-013-9614-8