This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chow, L. Q.M. Articles by Eckhardt, S. G. Search for Related Content PubMed PubMed Citation Articles by Chow, L. Q.M. Articles by Eckhardt, S. G. Related Articles Related Correspondence

Sunitinib: From Rational Design to Clinical Efficacy

Laura Q.M. Chow, S. Gail Eckhardt

From the Department of Medical Oncology, University of Colorado Health Sciences Center, Aurora, CO

Address reprint requests to S. Gail Eckhardt, MD, University of Colorado Cancer Center (Fitzsimons site), PO Box 6511 Campus Box 8117, Aurora, CO 80045; e-mail: Gail.eckhardt{at}uchsc.edu

Sunitinib (SU011248) is an oral small molecular tyrosine kinase inhibitor that exhibits potent antiangiogenic and antitumor activity. Tyrosine kinase inhibitors such as SU6668 and SU5416 (semaxanib) demonstrated poor pharmacologic properties and limited efficacy; therefore, sunitinib was rationally designed and chosen for its high bioavailability and its nanomolar-range potency against the antiangiogenic receptor tyrosine kinases (RTKs)—vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). Sunitinib inhibits other tyrosine kinases including, KIT, FLT3, colony-stimulating factor 1 (CSF-1), and RET, which are involved in a number of malignancies including small-cell lung cancer, GI stromal tumors (GISTs), breast cancer, acute myelogenous leukemia, multiple endocrine neoplasia types 2A and 2B, and familial medullary thyroid carcinoma. Sunitinib demonstrated robust antitumor activity in preclinical studies resulting not only in tumor growth inhibition, but tumor regression in models of colon cancer, non–small-cell lung cancer, melanoma, renal carcinoma, and squamous cell carcinoma, which were associated with inhibition of VEGFR and PDGFR phosphorylation. Clinical activity was demonstrated in neuroendocrine, colon, and breast cancers in phase II studies, whereas definitive efficacy has been demonstrated in advanced renal cell carcinoma and in imatinib-refractory GISTs, leading to US Food and Drug Administration approval of sunitinib for treatment of these two diseases. Studies investigating sunitinib alone in various tumor types and in combination with chemotherapy are ongoing. The clinical benchmarking of this small-molecule inhibitor of members of the split-kinase domain family of RTKs will lead to additional insights regarding the biology, potential biomarkers, and clinical utility of agents that target multiple signaling pathways in tumor, stromal, and endothelial compartments.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Related Correspondence

• Sunitinib Malate and Multiple Receptor Tyrosine Kinases Inhibitors: Are They Also Novel Drugs for Chronic and Neurophatic Pain?
  Luigi Di Lorenzo
  JCO 2007 25: 2858-2859 [Full Text]
• Sunitinib Malate and Multiple Receptor Tyrosine Kinases Inhibitors: Are They Also Novel Drugs for Chronic and Neurophatic Pain?
  Luigi Di Lorenzo
  JCO 2007 25: 2858-2859 [Full Text]

This article has been cited by other articles:

				M. L. Telli, R. M. Witteles, G. A. Fisher, and S. Srinivas Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate Ann. Onc., September 1, 2008; 19(9): 1613 - 1618. [Abstract] [Full Text] [PDF]

				B. I. Rini, M. D. Michaelson, J. E. Rosenberg, R. M. Bukowski, J. A. Sosman, W. M. Stadler, T. E. Hutson, K. Margolin, C. S. Harmon, S. E. DePrimo, et al. Antitumor Activity and Biomarker Analysis of Sunitinib in Patients With Bevacizumab-Refractory Metastatic Renal Cell Carcinoma J. Clin. Oncol., August 1, 2008; 26(22): 3743 - 3748. [Abstract] [Full Text] [PDF]

				D. S. Hong, S. B. Reddy, V. G. Prieto, J. J. Wright, N. M. Tannir, P. R. Cohen, A. H. Diwan, H. L. Evans, and R. Kurzrock Multiple Squamous Cell Carcinomas of the Skin After Therapy With Sorafenib Combined With Tipifarnib Arch Dermatol, June 1, 2008; 144(6): 779 - 782. [Abstract] [Full Text] [PDF]

				T. Efferth, V. B. Konkimalla, Y.-F. Wang, A. Sauerbrey, S. Meinhardt, F. Zintl, J. Mattern, and M. Volm Prediction of Broad Spectrum Resistance of Tumors towards Anticancer Drugs Clin. Cancer Res., April 15, 2008; 14(8): 2405 - 2412. [Abstract] [Full Text] [PDF]

				S. L. Showalter, J. M. Lloyd, D. T. Glassman, and A. C. Berger Extra-Gastrointestinal Stromal Tumor of the Pancreas: Case Report and a Review of the Literature Arch Surg, March 1, 2008; 143(3): 305 - 308. [Abstract] [Full Text] [PDF]

				M. Azizi, A. Chedid, and S. Oudard Home Blood-Pressure Monitoring in Patients Receiving Sunitinib N. Engl. J. Med., January 3, 2008; 358(1): 95 - 97. [Full Text] [PDF]

				P. Suwattee, S. Chow, B. C. Berg, and E. M. Warshaw Sunitinib: A Cause of Bullous Palmoplantar Erythrodysesthesia, Periungual Erythema, and Mucositis Arch Dermatol, January 1, 2008; 144(1): 123 - 125. [Full Text] [PDF]

				P. J. Saylor and T. R. Reid Tumor Lysis Syndrome After Treatment of a Gastrointestinal Stromal Tumor With the Oral Tyrosine Kinase Inhibitor Sunitinib J. Clin. Oncol., August 10, 2007; 25(23): 3544 - 3546. [Full Text] [PDF]

				L. Di Lorenzo Sunitinib Malate and Multiple Receptor Tyrosine Kinases Inhibitors: Are They Also Novel Drugs for Chronic and Neurophatic Pain? J. Clin. Oncol., July 1, 2007; 25(19): 2858 - 2859. [Full Text] [PDF]

				L. Q.M. Chow and S. G. Eckhardt In Reply J. Clin. Oncol., July 1, 2007; 25(19): 2859 - 2861. [Full Text] [PDF]