Growth inhibition of orthotopic anaplastic thyroid carcinoma xenografts in nude mice by PTK787/ZK222584 and CPT-11

Abstract

Background: A preclinical evaluation of CPT‐1 (Camptosar, irinotecan) and PTK787/ZK222584, a Vascular Endothelial Growth Factor Receptor (VEGFR‐2) tyrosine kinase inhibitor, as therapeutic agents against Anaplastic Thyroid Carcinoma (ATC) was performed in vitro and in an orthotopic model of ATC in nude mice. Methods: The cytotoxic and cytostatic effects of CPT‐11 on ATC cell lines were evaluated. The antitumor effects of CPT‐11 in combination with PTK787/ZK222584 on orthotopic ATC xenografts in nude mice were also studied. Results: CPT‐11 demonstrated significant antiproliferative effects on ATC cell lines. In vivo, PTK787/ZK222584, CPT‐11 and the two agents together produced 61%, 82% and 89% decrease in tumor growth, respectively. The differences in tumor volume between CPT‐11 and CPT‐11 + PTK787/ZK222584 groups were not statistically significant. PTK787/ZK222584 inhibited the phosphorylation of VEGFR‐2 on tumor endothelium and decrease the tumor microvessel density. Conclusions: The camptothecin class of chemotherapeutic agents and antiangiogenic agents such as PTK787/ZK222584 warrant further study as novel therapeutic agents against ATC.