Abstract 1766: Persistence of drug-induced DNA interstrand cross-links distinguishes bendamustine from conventional DNA cross-linking agents

Abstract

Abstract Bendamustine has demonstrated substantial clinical efficacy in the treatment of hematologic malignancies and continues to distinguish itself from other alkylating agents. The mechanistic and clinical differences associated with bendamustine may be directly related to its unique structural features, although the precise mechanism of action is still poorly understood. We have undertaken a detailed study of the drug-DNA interactions of bendamustine. It alkylates DNA primarily at guanine-N7 positions with a sequence selectivity similar to other nitrogen mustards. It produces DNA interstrand cross-links (ICLs) in both solid tumor and hematological tumor cells at doses that cause growth inhibition. ICLs peak at 8h following a 1h treatment and persist over 48h in tumor cells including those that are proficient at repairing (unhooking) ICLs formed by melphalan or cisplatin. This persistence of ICLs is also observed in multiple myeloma cells from patients who have relapsed on melphalan therapy and which efficiently repair melphalan-induced ICLs compared to cells from treatment naive patients. The peak γ-H2AX response follows the ICL peak and also persists beyond 48h. Cells defective in ICL unhooking proteins ERCC1 and XPF, or defective in homologous recombination repair, show increased sensitivity to bendamustine, but at a level less than observed for other nitrogen mustards or cisplatin. Real time PCR profiling showed that at equivalent peak levels of DNA ICLs bendamustine induced fewer changes in DNA damage signaling and DNA repair gene expression compared to either cisplatin or melphalan. These data suggest that the critical DNA damage produced by bendamustine induces a different signaling and repair response to conventional cross-linking agents, including other nitrogen mustards, which may be an important contribution to its clinical efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1766. doi:1538-7445.AM2012-1766