A redox pathway leading to the alkylation of nucleic acids by doxorubicin and related anthracyclines: application to the design of antitumor drugs for resistant cancer.
Doxorubicin has been a constituent of antitumor drug protocols for a broad spectrum of cancers for more than two decades. Side effects and resistance continue to be important limitations. Drug targets responsible for both side effects and anti-tumor activity are cell membrane receptors, cell membrane lipids, nucleic acids and topoisomerase. Induction of oxidative stress is responsible for most if not all biological activity. An important consequence of oxidative stress is the production of formaldehyde which can subsequently be utilized by the drug for covalent bonding to nucleic acids and other targets as shown by in vitro experiments. Multidrug resistance mechanisms inhibit drug-induced DNA damage, drug uptake, and drug-induced oxidative stress. Synthetic anthracyclines conjugated to formaldehyde circumvent some if not all of the resistance mechanisms. Consequently, anthracycline-formaldehyde conjugates have potential for the treatment of resistant cancer.