Anthracyclines have been a mainstay of cancer chemotherapy over the last few decades. However, their use has been hampered by the associated potentially lethal dose-limiting cardiotoxicity. As such, newer drugs have been designed and tested to equal or better the therapeutic outcomes while minimizing or completely eliminating their adverse effects. Pixantrone, a potent new anthracenedione derivative has shown a lot of promise in preclinical studies, hence is currently undergoing Phase III clinical trials in the treatment on aggressive non-Hodgkin’s Lymphoma. It is a second generation mono-aza anthracenedione, synthesized to eliminate the cardiotoxicity of mitoxantrone and the parent anthracycline anticancer agent, doxorubicin.
Like other anthracenediones, pixantrone functions in part by inhibiting topoisomerase II causing DNA double stand breaks and subsequently inducing apoptosis. Also in the presence of formaldehyde, we have shown that pixantrone forms covalent DNA adducts, with the N2 moiety of guanine residues at specific CpG dinucleotides. We now show that pixantrone (unlike the anthracyclines) also exhibits a preference for forming adducts with RNA, and these have similar characteristics to adducts that are formed with DNA.
The ability of anthracyclines to form covalent DNA adducts is also thought to contribute to reduced or no cardiotoxicity. The cytotoxicity associated with pixantrone seems to be a result of more than just the above mechanisms, hence, we investigate other possible mechanisms associated with the enhanced cytotoxicity and reduced or lack of cardiotoxicity. We specifically investigate RNA interactions and topoisomerase II poisoning in both cancer and cardiac cell lines.