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 antiturnor drug protocols for a broad spectrum of cancers for more than two decades. Side effects and resistance continue to be important limitations. Drug targets responsi ble for both side effects and anti-tumor activity are cell membrane re ceptors, cell membrane lipids, nucleic acids and topoisomerase . Induc tion of oxidative stress is responsible for most if not all biological activity. An important consequence of oxidative stress is the product ion of formaldehyde which can subsequently be utilized by the drug for covalent bonding to nucleic acids and other targets as shown by in vi tro experiments. Multidrug resistance mechanisms inhibit drug-induced DNA damage, drug uptake, and drug-induced oxidative stress. Synthetic anthracyclines conjugated to fermaldehyde circumvent some if not all o f the resistance mechanisms. Consequently, anthracycline-formaldehyde conjugates have potential for the treatment of resistant cancer.