Cathy C. Zhang, Gabriel E Troche, Zhengming Yan
May 1, 2005
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Influential Citations
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Quality indicators
Journal
Cancer Research
Abstract
4413 Deregulated cyclin-dependent kinase (CDK) activity is characterized by uncontrolled cell cycle progression, which is a hallmark of human cancer. AG-024322 is a multi-targeted (pan)-CDK inhibitor displaying potent inhibition of the cell cycle kinases CDK1, CDK2, and CDK4. In cellular assays AG-024322 inhibits phosphorylation of CDK substrates, causing induction of cell cycle arrest, broad-spectrum anti-proliferative activity and induction of apoptosis. In vivo experiments demonstrate that AG-024322 inhibits the growth of established human tumor xenografts of different origins. Significant anti-tumor efficacy was observed in 8 of the 9 tumor models tested, with tumor growth inhibition (TGI) ranging from 32% to 86.4%. In addition, the anti-tumor effects of AG-024322 are dose-dependent. At the maximum tolerated dose (MTD) of 20 mg/kg, AG-024322 causes a 65% TGI in the MV522 tumor model, 52% TGI at 1/2 of the MTD and only slight anti-tumor activity at 1/4 of the MTD. Direct evidence that AG-024322 antitumor activity correlates with modulation of the target was obtained by monitoring the phosphorylation status of the substrate Retinoblastoma (Rb) protein in tumor tissue. There is a clear dose dependent reduction in the level of phospho-Rb795, and this inhibition of Rb phosphorylation in vivo shows a strong correlation with the dose-dependent inhibition of tumor growth. In addition, treatment with AG-024322 causes dose-dependent apoptosis in tumors in vivo, as assessed by TUNEL staining of the excised tumors. Similarly, staining for Ki67, a common marker of cell proliferation, is significantly reduced after administration of AG-02322 at MTD levels. The sum of the in vivo data demonstrates that AG-024322 displays broad-spectrum anti-tumor activity and clear target modulation in vivo, as demonstrated by inhibition of Rb phosphorylation, anti-proliferative staining, and induction of apoptosis. Moreover, the extent of target modulation correlates with drug exposure in the pharmacodynamic model.