Growth inhibition of orthotopic anaplastic thyroid carcinoma xenografts in nude mice by PTK787/ZK222584 and CPT-11.
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.
Kim
Seungwon
S
Department of Head and Neck Surgery, Unit 441, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.
Yazici
Yasemin D
YD
Barber
Samantha E
SE
Jasser
Samar A
SA
Mandal
Mahitosh
M
Bekele
B Nebiyou
BN
Myers
Jeffrey N
JN
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004359:Drug Therapy, Combination; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010793:Phthalazines / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C404768:vatalanib; D000077146:Irinotecan; D002166:Camptothecin