Oncogenic potential of bifunctional bioreductive drugs.
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.
Hei
T K
TK
Center for Radiological Research, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
Liu
S X
SX
Hall
E J
EJ
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001388:Aziridines / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D045563:Indolequinones; D007211:Indoles / Q000633:toxicity*; D051379:Mice; D008809:Mice, Inbred C3H; D016685:Mitomycin / Q000633:toxicity*; D010084:Oxidation-Reduction; D011719:Pyrazines / Q000633:toxicity*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D007211:Indoles; D011719:Pyrazines; C087409:RB 90740; D016685:Mitomycin; C060817:apaziquone