Poster Presentation 25th Lorne Cancer Conference 2013

Shifting doxorubicin activity from topoisomerase2 poison to adduct formation reduces cardiotoxicity while maintaining anticancer efficacy (#328)

David M Rayner 1 , Ada Rephaeli 2 , Abraham Nudelman 3 , Salvatore Pepe 4 , Don R Phillips 1 , Suzi M Cutts 1
  1. La Trobe University, Bundoora, VIC, Australia
  2. Sackler Faculty of Medicine, Tel-Aviv University, Petach-Tikva, Israel
  3. Chemistry, Bar-Ilan University, Ramat-Gan, Israel
  4. Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia

Doxorubicin (DOX) is an anthracycline antibiotic that is potent against a wide variety of solid and blood cancers. However DOX treatment is associated with irreversible cardiotoxicity, limiting the lifetime dose of DOX to less than 550mg/m2. So enhancing the efficacy of DOX requires the reduction of associated cardiotoxicity while maintaining DOX anticancer potential.

Combining DOX with a formaldehyde-releasing prodrug called AN-7 induced the formation of DOX-DNA adducts, covalent interactions with DNA that enhance the killing of breast cancer cells. The combination of DOX and AN-7 induced significantly more DOX-DNA adducts in rat cardiomyocyte cells compared to human or rat breast cancer cells, which was associated with a reduction in the cell death of rat cardiomyocytes. DOX-DNA adduct formation signalled a shift in DOX activity from a topoisomerase2 poison to an adduct forming compound, as shown by a significant reduction in DNA double strand breaks occurring in response to DOX-AN-7combination treatments compared to DOX or AN-7 alone. The increase in DOX-DNA adducts in rat cardiomyocytes was mirrored in the reduction of DNA double strand breaks, where the cardiomyocyte cell line showed significantly greater adduct formation and significantly less DNA strand breaks compared to both the rat and human breast cancer cells.

The cardiomyocyte protection observed as a result of combination treatments of DOX and AN-7 raises the possibility of making DOX a safer and more effective chemotherapeutic agent by employing similar combinations in the clinic.