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p53 Small-Molecule Inhibitor Enhances Temozolomide Cytotoxic Activity against Intracranial Glioblastoma Xenografts

¹ Brain Tumor Research Center and Departments of ² Neurological Surgery, ³ Radiation Oncology, and ⁴ Pathology, University of California San Francisco, San Francisco, California; and ⁵ Graduate Program in Molecular Neuroscience and ⁶ Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota

Requests for reprints: C. David James, Department of Neurological Surgery, University of California San Francisco, Room HSW 792, 513 Parnassus Avenue, San Francisco, CA 94143. Phone: 415-476-5876; Fax: 415-502-0613; E-mail: david.james{at}ucsf.edu.

Key Words: glioblastoma • p53 • temozolomide • xenograft

In this study, we investigated the precursor and active forms of a p53 small-molecule inhibitor for their effects on temozolomide (TMZ) antitumor activity against glioblastoma (GBM), using both in vitro and in vivo experimental approaches. Results from in vitro cell viability analysis showed that the cytotoxic activity of TMZ was substantially increased when p53 wild-type (p53^wt) GBMs were cotreated with the active form of p53 inhibitor, and this heightened cytotoxic response was accompanied by increased poly(ADP-ribose) polymerase cleavage as well as elevated cellular phospho-H2AX. Analysis of the same series of GBMs, as intracranial xenografts in athymic mice, and administering corresponding p53 inhibitor precursor, which is converted to the active compound in vivo, yielded results consistent with the in vitro analyses: TMZ + p53 inhibitor precursor cotreatment of three distinct p53^wt GBM xenografts resulted in significant enhancement of TMZ antitumor effect relative to treatment with TMZ alone, as indicated by serial bioluminescence monitoring as well as survival analysis (P < 0.001 for cotreatment survival benefit in each case). Mice receiving intracranial injection with p53^null GBM showed similar survival benefit from TMZ treatment regardless of the presence or absence of p53 inhibitor precursor. In total, our results indicate that the p53 active and precursor inhibitor pair enhances TMZ cytotoxicity in vitro and in vivo, respectively, and do so in a p53-dependent manner. [Cancer Res 2008;68(24):10034–8]