Mini reviewSunitinib: A VEGF and PDGF receptor protein kinase and angiogenesis inhibitor
Section snippets
The VEGF and PDGF family of ligands and receptors
The ligands for the VEGF and PDGF receptor families, all of which are polypeptide dimers, and their respective receptors are listed in Table 1. VEGFR2 is the predominant mediator of VEGF-stimulated endothelial cell migration, proliferation, survival, and enhanced vascular permeability that occur during vasculogenesis and angiogenesis. VEGF was originally described as a vascular permeability factor [2]. Although, many first messengers including cytokines and growth factors participate in
Therapeutic inhibition of VEGF action
When experimental tumors reach a size of 0.2–2.0 mm in diameter, they become hypoxic and limited in size in the absence of angiogenesis [2]. There are more than two dozen endogenous pro-angiogenic factors and more than two dozen endogenous anti-angiogenic factors. In order to increase in size, tumors undergo an angiogenic switch where the action of pro-angiogenic factors predominates, resulting in angiogenesis and tumor progression [3]. Neoplastic growth thus requires new blood vessel formation,
Sunitinib disease targets
Primary and metastatic renal cell cancers are vascular neoplasms that are resistant to traditional cytotoxic chemotherapy and radiation therapy [24]. Motzer and co-workers studied the response of patients with renal cell cancer that had metastasized to other organs and that failed to respond to interleukin-2 treatment [24]. These patients were treated in 6-week cycles with sunitinib (50 mg/day by mouth) for 4 weeks and no drug for 2 weeks. During the treatment phase, they found that the minimum,
Oral bioavailability of sunitinib
Sunitinib satisfies Lipinski’s four “rules of five” as criteria for oral bioavailability [28]. The four properties are common characteristics found in most orally effective drugs that are in use today. The rules derive their name because the relevant limitations are multiples of 5. The first criterion is that a compound should have no more that five hydrogen bond donors (OH and NH groups); sunitinib has three. The second criterion is that the drug should have no more than 10 hydrogen bond
Epilogue
Imatinib and sunitinib target selective protein kinases. For example, imatinib inhibits Abl (a non-receptor protein-tyrosine kinase), Arg (Abl-related gene), Kit (the stem cell factor receptor), and PDGFR (α and β) [6]. Sunitinib, which is a potent inhibitor of eight protein-tyrosine kinases (Table 2), is also a multi-targeted drug. A perceived advantage of targeting protein kinases over traditional cytotoxic therapy is greater specificity toward the tumor cells with fewer side effects. This
Acknowledgments
I thank Dr. Jack D. Herbert and the staff of the Health Sciences Library at the University of North Carolina at Chapel Hill for their assistance in preparing this review.
References (29)
- et al.
Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis
Cell
(1996) - et al.
PDGF receptors as cancer drug targets
Cancer Cell
(2003) PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma
Cytokine Growth Factor Rev.
(2004)Structure and regulation of Kit protein-tyrosine kinase—the stem cell factor receptor
Biochem. Biophys. Res. Commun.
(2005)- et al.
Analysis of c-kit expression in small cell lung cancer: prevalence and prognostic implications
Lung Cancer
(2006) - et al.
Colony-stimulating factor-1 in immunity and inflammation
Curr. Opin. Immunol.
(2006) Therapeutic targeting of the tumor microenvironment
Cancer Cell
(2005)- et al.
Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy
Biochem. Biophys. Res. Commun.
(2005) - et al.
Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis
Biochim. Biophys. Acta
(2004) - et al.
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
Adv. Drug Deliv. Rev.
(2001)
The protein kinase complement of the human genome
Science
Vascular endothelial growth factor (VEGF) signaling during tumor progression
Crit. Rev. Oncol. Hematol.
The role of FLT3 in haematopoietic malignancies
Nat. Rev. Cancer
Tumor angiogenesis: therapeutic implications
N. Engl. J. Med.
Cited by (339)
Novel spiroindoline quinazolinedione derivatives as anticancer agents and potential FLT3 kinase inhibitors
2023, Bioorganic and Medicinal ChemistryRecent Developments on Synthesis Strategies, SAR Studies and Biological Activities of β-Carboline Derivatives – An Update
2022, Journal of Molecular Structure