Purpose: To evaluate the therapeutic and biological effects of CHIR-258, an orally bioavailable, potent inhibitor of class III-V receptor tyrosine kinases, in colon cancer models. Experimental Design: The pharmacologic activity of CHIR-258 was characterized by monitoring target modulation as well as by evaluating the antitumor and antiangiogenic effects in human colon xenograft models. Results: CHIR-258 inhibits vascular endothelial growth factor receptor1/2, fibroblast growth factor receptor 1/3, and platelet-derived growth factor receptor B (PDGFRB) and shows both antitumor and antiangiogenic activities in vivo. Treatment of KM12L4a human colon cancer cells with CHIR-258 resulted in a dose-dependent inhibition of vascular endothelial growth factor receptor 1and PDGFRB phosphorylation and reduction of phosphorylated extracellular signal-regulated kinase (ERK) levels, indicating modulation of target receptors and downstream signaling. In vivo administration of CHIR-258 resulted in significant tumor growth inhibition and tumor regressions, including large, established tumors (500-1,000 mm 3 ). Immunohistochemical analysis showed a reduction of phosphorylated PDGFRB and phosphorylated ERK in tumor cells after oral dosing with CHIR-258 compared with control tumors. These changes were accompanied by decreased tumor cell proliferation rate and reduced intratumoral microvessel density. CHIR-258 inhibited the phosphorylation of PDGFRB and ERK phosphorylation in tumors within 2 hours following dosing and the inhibitory activity was sustained for >24 hours. Significant antitumor activity was observed with intermittent dosing schedules, indicating a sustained biological activity. Conclusion:These studies provide evidence that biological activity of CHIR-258 in tumors correlates with efficacy and aids in the identification of potential biomarkers of this multitargeted receptor tyrosine kinase inhibitor. CHIR-258 exhibits properties that make it a promising candidate for clinical development in a variety of solid and hematologic malignancies.

The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.

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Adriamycin has a wide spectrum of antitumour activity with dose-related cardiotoxicity as a major side effect. This cardiotoxicity has been suggested to result from the generation of oxygen free radicals. The objective of the present study was to investigate the influence of the antioxidant, butylated hydroxyanisole co-therapy on the cardiotoxicity of adriamycin, in-vivo. The aqueous solubility of butylated hydroxyanisole was enhanced by inclusion complex formation with hydroxypropyl-beta-cyclodextrin. The extent of drug-induced myocardial damage in rats was assessed using intravenous 111In-labelled antimyosin Fab and chronological changes in serum creatine kinase levels. There was a dose-related increase in myocardial antimyosin uptake in rats, which reached a plateau at an adriamycin dose of 10 mg kg-1. The antimyosin uptake at this dose (% dose g-1 = 0.1942 +/- 0.0150, n = 8) was significantly reduced by co-administration of butylated hydroxyanisole with adriamycin (10 mg kg-1 of each) to 0.1462 +/- 0.0116 (n = 5, P < 0.05). Assessment of cardiotoxicity in the rats was also performed by measuring serial changes in serum creatine kinase levels. Increasing doses of adriamycin caused an increase in serum creatine kinase levels with peak values obtained between 2 and 8 h after dosing. These values decreased upon co-administration of butylated hydroxyanisole with adriamycin at 10 mg kg-1, each and 30 mg kg-1 each by 29 and 41%, respectively. On the other hand, butylated hydroxyanisole did not inhibit the tumouricidal activity of adriamycin as investigated in-vitro using the NMU rat mammary adenocarcinoma cell-line. The significant reduction in anthracycline cardiotoxicity by butylated hydroxyanisole coadministration may result from its scavenging action on adriamycin-mediated free-radical formation or its enhancement of activity of enzymes involved in the metabolism of adriamycin.

Microparticles produced from polyisobutylcyanoacrylate (IBCA) and polyglutaraldehyde (PGA) were investigated for their relative affinity and surface characteristics using doxorubicin (DOX) as a model drug. IBCA microparticles have been reported to exhibit neutral hydrophobic surface features, whereas PGA microparticles have been shown to possess negatively charged carboxyl groups on their surface. The adsorption of DOX on the surface of these particles was studied by adding the drug to preformed microparticles. The amount of drug adsorbed was determined by centrifugation and analysis of the supernatant for the free drug by HPLC. The adsorption data was examined by Langmuir, Scatchard, and Hill equations. The results indicate that IBCA micropatricles have a higher adsorption capacity for DOX, however PGA microparticles demonstrated a higher relative affinity for the drug molecule. Additionally, both microparticles presented curvilinear Scatchard plots indicating the possibility of more than one type of binding sites for Drug Dev Ind Pharm Downloaded from informahealthcare.com by McMaster University on 11/05/14For personal use only. 760 VORA, BAPAT, AND BOROUJERDIthe drug on the surface of these particles. It appears that strong electrostatic attraction may exist between the positively charged amino group on DOX and the negatively charged carboxyl groups of PGA microparticles. Drug Dev Ind Pharm Downloaded from informahealthcare.com by McMaster University on 11/05/14 For personal use only. Drug Dev Ind Pharm Downloaded from informahealthcare.com by McMaster University on 11/05/14 For personal use only.