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Mechanism of Action of Bisimidazoacridones, New Drugs with Potent, Selective Activity against Colon Cancer¹

Molecular Aspects of Drug Design, Macromolecular Structure Laboratory [L. H., W. M. C., C. J. M.], Confocal Microscopy [E. A. H., J. H. R.], and Carcinogen-Modified Nucleic Acid Chemistry [G. P.], ABL-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702

Antitumor bisimidazoacridones are bifunctional DNA binders which have recently been shown to selectively target human colon carcinoma cells in vitro and in vivo and appear to be excellent candidates for clinical development. We have studied the mechanism of action of one bisimidazoacridone, WMC26, which is 1,000–10,000 times more toxic to human colon carcinoma cells (HCT116) than to melanoma cells (SKMEL2) in vitro. Plasmid DNA exposed to WMC26 showed enhanced digestion by DNase I at A-T-rich sites, suggesting alterations in DNA conformation upon drug binding. These results led us to investigate whether WMC26 was selectively toxic due to a specific recognition of DNA bends by repair excinucleases, as has been demonstrated with the DNA bisintercalator, ditercalinium. Both prokaryotic and eukaryotic cells with intact repair capacity were shown to be selectively sensitive to WMC26, strongly indicating that excision repair plays a role in its toxicity. Confocal microscopy studies utilizing fluorescence of the WMC26 chromophore showed compound localization in the perinuclear cytoplasmic area, as had been previously noted for ditercalinium, indicating that cytoplasmic DNA could be the target. This irreversible accumulation of compound was gradually followed by vacuolization of the cytoplasm and cell death. Cell cycle analysis of both lines treated with WMC26 or with ditercalinium showed that, while the latter induced HCT116 growth arrest at G₁–G₀, WMC26 also blocked the cell cycle at G₂-M; SKMEL2 cells did not undergo any changes in cell cycle as a result of either treatment. Our data show that WMC26 is 10–100 times more cytotoxic than ditercalinium in vitro. Like ditercalinium, WMC26 appears to exert its toxicity via cytoplasmic elements, through a mechanism involving excision repair processes. However, its highly selective cytotoxicity may stem from additional undefined targets in sensitive colon cancer cells.

¹ Research supported by National Cancer Institute, Department of Health and Human Services, under contract NO1-CO-46000 (A. B. L.). The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.

² To whom requests for reprints should be addressed.

Received 1/25/95. Accepted 4/ 5/95.

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