Recent and new results which support a
drug-
DNA covalent bonding mechanism for cell toxicity of the clinical
antitumor drugs,
daunorubicin,
doxorubicin, and epidoxorubicin, are summarized. The mechanism involves the
iron complex of the drugs inducing oxidative stress to yield
formaldehyde, which then mediates covalent attachment to G-bases of
DNA. At NGC sites the combination of covalent and non-covalent drug interactions serve to virtually crosslink the
DNA. Structural data for virtual crosslinks are compared as a function of
drug structure. Elucidation of the mechanism led to the synthesis and evaluation of
drug formaldehyde conjugates,
Daunoform,
Doxoform, and
Epidoxoform, as improved chemotherapeutics.
Drug uptake, nuclear targeting, drug release, and cytotoxicity of the clinical drugs by sensitive and resistant breast and
prostate cancer cells are contrasted with those of the corresponding
formaldehyde conjugates. Conjugates are taken up better, retained longer, 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 biexponential and correlate with the biexponential kinetics of drug release from extracellular
DNA. The results of the lead conjugate,
Epidoxoform, in the National Cancer Institute 60 human
tumor cell screen are presented and discussed in terms of some resistance mechanisms.
Epidoxoform shows increased toxicity to all panels relative to
doxorubicin and epidoxorubicin, and this enhanced toxicity is especially evident with the more resistant cell lines.