Combination of thalidomide and cisplatin in an head and neck squamous cell carcinomas model results in an enhanced antiangiogenic activity in vitro and in vivo

• Published in: International journal of cancer Vol. 121; no. 8; pp. 1697 - 1704
• Main Authors: Vasvari, Gergely P., Dyckhoff, Gerhard, Kashfi, Farzaneh, Lemke, Britt, Lohr, Jennifer, Helmke, Burkhard M., Schirrmacher, Volker, Plinkert, Peter K., Beckhove, Philipp, Herold‐Mende, Christel C.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.10.2007; Wiley-Liss
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; antiangiogenic therapy; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Carcinoma, Squamous Cell - blood supply; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Cell Movement - drug effects; Cell Proliferation - drug effects; cisplatin; Cisplatin - administration & dosage; Disease Models, Animal; Drug Synergism; Female; Germ-Free Life; Head and Neck Neoplasms - blood supply; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - pathology; head and neck squamous cell carcinoma; Immunohistochemistry; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Microcirculation - drug effects; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; thalidomide; Thalidomide - administration & dosage; Tumors; Antineoplastic agent; Drug combination; antiangiogenic therapy; Malignant tumor; In vitro; Biological activity; Cisplatin; In vivo; Alkylating agent; Cancerology; Treatment; ENT disease; Head and neck squamous cell carcinoma; Head and neck cancer; Models; Antiangiogenic agent; Thalidomide; Platinum II Complexes
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.22867

Thalidomide is an immunomodulatory, antiangiogenic drug. Although there is evidence that it might be more effective in combination with chemotherapy the exact mechanism of action is unclear. Therefore, we investigated its effect in combination with metronomically applied cisplatin in a xenotransplant mouse model characteristic for advanced head and neck squamous cell carcinomas, its possible synergistic action in vitro, and which tumor‐derived factors might be targeted by thalidomide. Although thalidomide alone was ineffective, a combined treatment with low‐dose cisplatin inhibited significant tumor growth, proliferation and angiogenesis in vivo as well as migration and tube formation of endothelial cells in vitro. Noteworthy, the latter effect was enhanced after coapplication of cisplatin in nontoxic doses. An inhibitory effect on tumor cell migration was also observed suggesting a direct antitumor effect. Although thalidomide alone did not influence cell proliferation, it augmented antiproliferative response after cisplatin application emphasizing the idea of a potentiated effect when both drugs are combined. Furthermore, we could show that antiangiogenic effects of thalidomide are related to tumor‐cell derived factors including vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor and Il‐8 some known and with, granulocyte colony stimulating growth factor and granulocyte macrophage colony stimulating growth factor, some new target molecules of thalidomide. Altogether, our findings reveal new insights into thalidomide‐mediated antitumor and antiangiogenic effects and its interaction with cytostatic drugs. © 2007 Wiley‐Liss, Inc.