title: PT-ACRAMTU, a platinum-acridine anticancer agent, lengthens and aggregates, but does not stiffen or soften DNA.
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.
authors: Department of Physics, Wake Forest University, Winston-Salem, NC, 27109, USA.
authors: Samrat
authors: S
authors: Dutta
authors: Matthew J
authors: MJ
authors: Snyder
authors: David
authors: D
authors: Rosile
authors: Kristen L
authors: KL
authors: Binz
authors: Eric H
authors: EH
authors: Roll
authors: Jimmy
authors: J
authors: Suryadi
authors: Ulrich
authors: U
authors: Bierbach
authors: Martin
authors: M
authors: Guthold
mesh_terms: D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry; D053903:DNA Breaks, Double-Stranded; D018625:Microscopy, Atomic Force; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010316:Particle Size; D010984:Platinum / Q000737:chemistry*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: C471910:1-(2-(acridin-9-ylamino)ethyl)-1,3-dimethylthiourea; D000166:Acridines; D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D010984:Platinum; D014508:Urea; D004247:DNA; D013890:Thiourea
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