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Effect of cell cycle inhibition on cisplatin-induced cytotoxicity

  1. Author:
    Fishel, M. L.
    Newell, D. R.
    Griffin, R. J.
    Davison, R.
    Wang, L. Z.
    Curtin, N. J.
    Zuhowski, E. G.
    Kasza, K.
    Egorin, M. J.
    Moschel, R. C.
    Dolan, M. E.

  2. Author Address

    Univ Chicago, Dept Med, Committee Canc Biol, Chicago, IL 60637 USA. Univ Chicago, Canc Res Ctr, Chicago, IL 60637 USA. Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. Univ Newcastle, No Inst Canc Res, Newcastle Upon Tyne, Tyne & Wear, England. Univ Pittsburgh, Pittsburgh Canc Inst, Pittsburgh, PA USA. Natl Canc Inst, Comparat Carcinogenesis Lab, Frederick, MD USA Dolan, ME, Univ Chicago, Dept Med, Committee Canc Biol, 5841 S Maryland Ave,Box MC2115, Chicago, IL 60637 USA
    1. Year: 2005
    2. Date: JAN
  2. Journal: Journal of Pharmacology and Experimental Therapeutics
    1. 312
    2. 1
    3. Pages: 206-213
  4. Type of Article: Article
  1. Abstract:

    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 O-6-benzylguanine (O-6-BG), S-6-benzyl-6-thioguanine (S-6-BG), S-6-[(cyclohexyl)methyl]-6-thioguanine (S-6-CMG), O-6-[(cyclohexyl) methyl] guanine (O-6-CMG), O-6-benzyl-9-methylguanine (9-CH3-BG), O-6-[(cyclohexyl)methyl]-9-methylguanine (9-CH3-CMG), and 7-benzylguanine (N7-BG), exhibited varying degrees of CDK2 inhibition with O-6-CMG being the most potent and 9-CH3-BG, 9-CH3-CMG, and N7-BG the least potent compounds. Treatment with S-6-CMG and O-6-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, O-6-CMG, was also the most effective at enhancing cisplatin-induced cytotoxicity and apoptosis. Cisplatin-induced DNA platination increased in SQ20b cells pretreated with S-6-BG, S-6-CMG, and O-6-CMG. Treatment with both O-6-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

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External Sources

  1. View record in Web of Science®
  2. WOS: 000225766400025

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