The effects of the oral, pan-VEGF-R kinase inhibitor CEP-7055 and chemotherapy in orthotopic models of glioblastoma and colon carcinoma in mice

Abstract

CEP-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 clinical 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, respectively, 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 versus 192 days, respectively; P V 0.02). Reductions in neurologic dysfunction, brain edema, hemorrhage, and intratumoral microvessel density (CD34 staining) were observed 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. Â 5 days), and to a lesser degree with oxaliplatin (10 mg/kg/dose i.v.), showed reductions 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 preclinical orthotopic glioma and colon carcinoma models and lend support for the use of these treatment regimens in a clinical setting in patients with glioblastoma and colon carcinoma.

The synthesized 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one (CHM-1) promoted G2/M arrest through inhibition of CDK1 and induced apoptosis through the mitochondrial-dependent pathway in CT-26 murine colorectal adenocarcinoma cells

“…The colon, liver and spleen samples were isolated and weighed individually for histopathology. The total tumor volume in each animal was estimated according to the formula: total tumor volume (mm 3 ) = L 9 W 2 /2, where L is the length and W is the width [19].…”

Molecular Pathogenesis of Lymphangioleiomyomatosis

“…In support of this assertion is the recent finding in a series of surgical and autopsy cases of LAM, that VEGF-C is overexpressed in LAM lesions and is associated with the excessive growth of lymphatics in the lesions (121). A variety of small molecule and antibody inhibitors of VEGF pathways have been developed and some are in clinical trials (126)(127)(128).…”

Projection of Exposure and Efficacious Dose Prior to First-in-Human Studies: How Successful Have We Been?

“…Animal disease models are commonly used in many therapeutic areas, as part of target validation, which allows one to study drug behavior in vivo. In oncology, for example, nude mice transplanted with human xenografts are routinely used to assess the in vivo efficacy of anti-tumor agents (12,13). In immunology, rodents with arthritis, induced by agents such as collagen or adjuvant, are also common (14)(15)(16).…”