Nuclear targeting and retention of anthracycline antitumor drugs in sensitive and resistant tumor cells

Recent and new results which support a drug-DNA covalent bonding mechanism for cell toxicity of the clinical antitumor drugs, daunorubicin, doxorubici n, and epidoxorubicin, are summarized. The mechanism involves the iron comp lex of the drugs inducing oxidative stress to yield formaldehyde, which the n mediates covalent attachment to G-bases of DNA. At NGC sites the combinat ion of covalent and non-covalent drug interactions serve to virtually cross link the DNA. Structural data for virtual crosslinks are compared as a func tion of drug structure. Elucidation of the mechanism led to the synthesis a nd evaluation of drug formaldehyde conjugates, Daunoform, Doxoform, and Epi doxoform, as improved chemotherapeutics. Drug uptake, nuclear targeting, dr ug release, and cytotoxicity of the clinical drugs by sensitive and resista nt breast and prostate cancer cells are contrasted with those of the corres ponding formaldehyde conjugates. Conjugates are taken up better, retained l onger, and are more toxic to a wide variety of tumor cells. The kinetics of drug release from Doxoform and Epidoxoform treated MCF-7/Adr cells are bie xponential and correlate with the biexponential kinetics of drug release fr om extracellular DNA. The results of the lead conjugate, Epidoxoform, in th e National Cancer Institute 60 human tumor cell screen are presented and di scussed in terms of some resistance mechanisms. Epidoxoform shows increased toxicity to all panels relative to doxorubicin and epidoxorubicin, and thi s enhanced toxicity is especially evident with the more resistant cell line s.