Potential oncogenicity must be
a factor of concern in the design and development of novel bioreductive drugs. In the present studies, the cytotoxicity and oncogenic transforming potential of a series of heterocyclic mono-N-
oxides, designed to be used as bioreductive drugs, were examined using the mouse C3H 10T1/2 cell system. Exponential phase cultures of 10T1/2 cells were treated with graded doses of the bioreductive drugs for a 4 h period, either in air or
hypoxia, at 37 degrees C.
After treatment, cultures were replated for both survival and transformation assays. The fused
pyrazine mono-N-
oxide RB 90740 and its N-deoxy analogue, RB 92816, demonstrated a dose-dependent cytotoxicity and oncogenic transforming potency under aerobic conditions. Similarly, the indoloquinone E09 and the structurally related
mitomycin C demonstrated dose dependence in both toxicity and oncogenic transforming potential. The most cytotoxic aromatic-N-
oxides tested, RB 92816, also demonstrated the highest oncogenic transformation incidence. In
hypoxia, the bioreductive metabolites of
RB 90740 were substantially more cytotoxic and induced a higher oncogenic transformation yield than the
drug in air. These data are consistent with the structure-activity relationship for bioreductive drugs in that
heterocyclic-N-oxides with reactive side chains such as RB 92816 are cytotoxic and potentially carcinogenic.