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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Effect of Cell Cycle Inhibition on Cisplatin-Induced Cytotoxicity

Department of Medicine, Committee on Cancer Biology and Cancer Research Center (M.L.F., M.E.D.) and Department of Health Studies, (K.K.), University of Chicago, Chicago, Illinois; Northern Institute for Cancer Research (D.R.N., R.J.G., R.D., L.-Z.W., N.J.C.), University of Newcastle, Newcastle upon Tyne, United Kingdom; University of Pittsburgh Cancer Institute (E.G.Z., M.J.E.), Pittsburgh, Pennsylvania; and Laboratory of Comparative Carcinogenesis (R.C.M.), National Cancer Institute at Frederick, Frederick, Maryland

Pharmacological inhibitors of cyclin-dependent kinase (CDK)2 are currently in preclinical and clinical development. The purpose of our work was to evaluate a series of guanine derivatives for their ability to inhibit CDK2, affect cell cycle progression, and enhance the cytotoxic and apoptotic effects of cisplatin. A panel of guanine derivatives, including O⁶-benzylguanine (O⁶-BG), S⁶-benzyl-6-thioguanine (S⁶-BG), S⁶-[(cyclohexyl)methyl]-6-thioguanine (S⁶-CMG), O⁶-[(cyclohexyl)methyl]guanine (O⁶-CMG), O⁶-benzyl-9-methylguanine (9-CH₃-BG), O⁶-[(cyclohexyl)methyl]-9-methyl-guanine (9-CH₃-CMG), and 7-benzylguanine (N7-BG), exhibited varying degrees of CDK2 inhibition with O⁶-CMG being the most potent and 9-CH₃-BG, 9-CH₃-CMG, and N7-BG the least potent compounds. Treatment with S⁶-CMG and O⁶-CMG significantly decreased the percentage of cells in S phase. In SQ20b and SCC61 head and neck cancer cell lines, the most potent CDK2 inhibitor, O⁶-CMG, was also the most effective at enhancing cisplatin-induced cytotoxicity and apoptosis. Cisplatin-induced DNA platination increased in SQ20b cells pretreated with S⁶-BG, S⁶-CMG, and O⁶-CMG. Treatment with both O⁶-BG and trichostatin A, an indirect cell cycle inhibitor, demonstrated additive effects on cisplatin-induced cytotoxicity. In summary, we have identified a group of guanine derivatives that were effective modulators of cisplatin-induced cytotoxicity and apoptosis.

Address correspondence to: Dr. M. Eileen Dolan, University of Chicago, 5841 S. Maryland Ave., Box MC2115, Chicago, IL 60637. E-mail: edolan{at}medicine.bsd.uchicago.edu

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