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Jones-Bolin Susan , Zhao Hugh , Hunter Kathryn , Klein-Szanto Andres , Ruggeri Bruce
The effects of the oral, pan-VEGF-R kinase inhibitor CEP-7055 and chemotherapy in orthotopic models of glioblastoma and colon carcinoma in mice
Molecular Cancer Therapeutics. 2006 ;5(7) :1744-1753
PMID: AN 2006:771727
AbstractCEP-7055, a fully synthetic, orally active N,N-dimethylglycine ester of CEP-5214, a C3-(isopropylmethoxy)-fused pyrrolocarbazole with potent pan-vascular endothelial growth factor receptor (VEGFR) kinase inhibitory activity, has recently completed phase I clin. trials in cancer patients. These studies evaluated the antitumor efficacy of CEP-7055 using orthotopic models of glioblastoma and colon carcinoma in combination with temozolomide, and irinotecan and oxaliplatin, resp., for their effects on primary and metastatic tumor burden and median survival. Chronic administration of CEP-7055 (23.8 mg/kg/dose) and temozolomide resulted in improvement of median survival of nude mice bearing orthotopic human glioblastoma xenografts compared with temozolomide alone (261 vs. 192 days, resp.; P ? 0.02). Redns. in neurol. dysfunction, brain edema, hemorrhage, and intratumoral microvessel d. (CD34 staining) were obsd. in glioma-bearing mice receiving CEP-7055 alone, temozolomide alone, and the combination of CEP-7055 and temozolomide relative to vehicle and to temozolomide monotherapy. The administration of CEP-7055 in combination with irinotecan (20 mg/kg/dose i.p. x 5 days), and to a lesser degree with oxaliplatin (10 mg/kg/dose i.v.), showed redns. on primary colon carcinoma and hepatic metastatic burden in the CT-26 tumor model relative to that achieved by irinotecan and oxaliplatin monotherapy. These data show the significant efficacy and tolerability of optimal efficacious doses of CEP-7055 when given in combination with temozolomide and irinotecan relative to monotherapy with these cytotoxic agents in preclin. orthotopic glioma and colon carcinoma models and lend support for the use of these treatment regimens in a clin. setting in patients with glioblastoma and colon carcinoma. [Mol Cancer Ther 2006;5(7):1744-53]. [on SciFinder (R)]
Notes1 Pharmacology Oncology Research, Cephalon, Inc., West Chester,Fox Chase Cancer Center,Philadelphia,PA,USA. Journal 1535-7163 written in English.