PF-00477736 Mediates Checkpoint Kinase 1 Signaling Pathway and Potentiates Docetaxel-Induced Efficacy in Xenografts

Abstract

Purpose: Checkpoint kinase 1 (Chk1) plays a critical role in the activation of mitotic spindle checkpoint and DNA damage checkpoint. We examined the preclinical use of the Chk1 inhibitor PF-00477736 as a docetaxel-sensitizing agent. Specifically, we investigated the correlation between PF-00477736^mediated modulation of biomarkers and the sensitization of docetaxel efficacy. Experimental Design: In vitro and in vivo studies using COLO205 and other cell lines were done to assess PF-00477736^induced enhancement of docetaxel efficacy and effects on associated biomarkers. Conclusions: Docetaxel triggers mitotic spindle checkpoint activation at low concentrations and activates both the DNA damage checkpoint and the spindle checkpoint at high concentrations. In combination with docetaxel, PF-00477736 abrogates the mitotic checkpoint, as well as the DNA damage checkpoint, and results in sensitization to docetaxel. Chk1inhibitor PF-00477736 offers a therapeutic potential for the enhancement of taxane therapy.

Gemcitabine and CHK1 Inhibition Potentiate EGFR-Directed Radioimmunotherapy against Pancreatic Ductal Adenocarcinoma

“…Therefore, we examined the in vivo tolerability of the dual and triple combinations. Because we and others (21) have found that concurrent treatment was effective, we administered CHK1i concurrently with gemcitabine instead of a 24-hour delay (7). Dosing schedules of 50 mg/kg gemcitabine and 15 mg/kg (7.5 mg/kg twice daily, b.i.d.)…”

[18F]FLT–PET Imaging Does Not Always “Light Up” Proliferating Tumor Cells

“…FLT-PET and CT imaging was done using a microPET Focus F220 scanner (Siemens Medical Solutions) and a GE eXplore microCT scanner (GE Healthcare), respectively, as described previously (21). Tumor-bearing mice were anesthetized and administered 250 mCi (1-2 mg/kg) of […”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…Other selective Chk1 inhibitors were also shown to abrogate the S-phase delay induced by topoisomerase inhibitors (Chen et al, 2006;Tse et al, 2007) and to potentiate the cytotoxicity of g-radiation in p53-deficient cells (Chen et al, 2006). These effects were associated with increased mitotic entry, induction of DSB and apoptosis, as well as marked inhibition of proliferation (Chen et al, 2006;Tse et al, 2007;Blasina et al, 2008;Zhang et al, 2009). The synergy between replication stress inducers and Chk1 inhibitors was translated into a dose-dependent increase in tumor growth delay in vivo (Tse et al, 2007;Blasina et al, 2008;Zhang et al, 2009).…”

“…These effects were associated with increased mitotic entry, induction of DSB and apoptosis, as well as marked inhibition of proliferation (Chen et al, 2006;Tse et al, 2007;Blasina et al, 2008;Zhang et al, 2009). The synergy between replication stress inducers and Chk1 inhibitors was translated into a dose-dependent increase in tumor growth delay in vivo (Tse et al, 2007;Blasina et al, 2008;Zhang et al, 2009).…”