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¹ Department of Oncology, Faculty of Medicine, McGill University Health Centre/Montreal General Hospital, Montreal, Quebec, Canada; ² Departments of Medicine and Oncology, Lady Davis Institute of the Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada; and ³ Oncozyme Pharma, Inc., Montreal, Quebec, Canada

Requests for reprints: Terry Y-K. Chow, Department of Oncology, Faculty of Medicine, McGill University Health Centre/Montreal General Hospital, 1650 Avenue Cedar, Room 10-148, Montreal, Quebec, Canada H3G 1A4. Phone: 514-934-1934 ext. 42904; Fax: 514-934-8202. E-mail: tchow{at}po-box.mcgill.ca

DNA repair mechanisms are crucial for the maintenance of genomic stability and are emerging as potential therapeutic targets for cancer. In this study, we report that the endo-exonuclease, a protein involved in the recombination repair process of the DNA double-stranded break pathway, is overexpressed in a variety of cancer cells and could represent an effective target for developing anticancer drugs. We identify a dicationic diarylfuran, pentamidine, which has been used clinically to treat opportunistic infections and is an inhibitor of the endo-exonuclease as determined by enzyme kinetic assay. In clonogenic and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays as well as in the in vivo Lewis lung carcinoma mouse tumor model, pentamidine is shown to possess the ability to selectively kill cancer cells. The LD₅₀ of pentamidine on cancer cells maintained in vitro is correlated with the endo-exonuclease enzyme activity. Tumor cell that has been treated with pentamidine is reduced in the endo-exonuclease as compared with the untreated control. Furthermore, pentamidine synergistically potentiates the cytotoxic effect of DNA strand break and cross-link-inducing agents such as mitomycin C, etoposide, and cisplatin. In addition, we used the small interfering RNA for the mouse homologue of the endo-exonuclease to down-regulate the level of endo-exonuclease in the mouse myeloma cell line B16F10. Down-regulation of the endo-exonuclease sensitizes the cell to 5-fluorouracil. These studies suggested the endo-exonuclease enzyme as a novel potential therapeutic target for cancer.

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Received 3/ 9/04; revised 5/ 5/04; accepted 6/17/04.