Nonclinical Safety Evaluation of Sunitinib: A Potent Inhibitor of VEGF, PDGF, KIT, FLT3, and RET Receptors

Abstract

Sunitinib malate (SUTENT) is a multitargeted receptor tyrosine kinase (RTK) inhibitor that is approved multinationally for the treatment of imatinibresistant/-intolerant gastrointestinal stromal tumor and advanced renal cell carcinoma. This paper characterizes the organ toxicity of sunitinib in SpragueDawley rats and cynomolgus monkeys, and the reversibility of any treatment-induced effects. Rats and monkeys received sunitinib (0-15 and 0-20 mg/kg/day, respectively) orally on a consecutive daily dosing schedule for thirteen weeks or on an intermittent daily dosing schedule for up to nine months. Clinical observations and laboratory parameters were recorded. Necropsy was conducted following treatment/recovery periods, and histologic examinations were performed. In rats, sunitinib was generally tolerated at 0.3 and 1.5 mg/kg/day, and findings were reversible. In monkeys, the level at which there were no observed adverse effects was 1.5 mg/kg/day, and findings were similarly reversible (except for uterine/ovarian weight changes and skin pallor). Data suggest that inhibition of multiple RTK pathways may induce pharmacologic effects on organ systems in nonclinical species. Key pharmacologic effects of sunitinib included reversible inhibition of neovascularization into the epiphyseal growth plate, and impaired corpora lutea formation and uterine development during estrus. Similar observations have been noted with this class of RTK signaling inhibitors and are consistent with pharmacologic perturbations of physiologic/angiogenic processes associated with the intended molecular targets.

SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

“…It inhibited VEGFA-induced survival with an IC 50 of 664 nmol/L, confirming its moderate activity on VEGFR-2 and had no effect on FGF2-induced proliferation. In the same experiment, sunitinib inhibited VEGFA-, VEGFA-C-, and VEGFA-D-induced survival with an IC 50 of about 5 nmol/L and, consistent with reported data (38), it had no effect on FGF2-induced survival ( Supplementary Fig. S1).…”

Growth Factors as Active Participants in Carcinogenesis: A Perspective

“…67 Sunitinib is also thought to lead to hypertension and renal dysfunction, 277 neovascularization of epiphyseal growth plate, and impaired corpora lutea formation in monkeys. 188 …”

Femoral Head Growth Plate Dysplasia and Fracture in Juvenile Rabbits Induced by Off-target Antiangiogenic Treatment

“…VEGF and FGF family receptors deliver potent angiogenic signals that promote endothelial cell survival, growth, migration, and differentiation (Cross and Claesson-Welsh 2001;Shibuya and Claesson-Welsh 2006). Inhibition with bevacizumab, sunitinib, and recentin (which inhibit the VEGF pathway) as well as PD176067 (which inhibits the FGF pathway), all induce epiphyseal growth plate dysplasia in rats and monkeys Patyna et al 2008;Wedge et al 2005;Brown et al 2005). Inhibition of angiogenesis by other classes of molecule, such as MMPs (Vu et al 1998), and vascular targeting agents (Hall, Westwood, and Wadsworth 2006) also induces growth plate dysplasia, suggesting that this change is pathognomonic for antiangiogenic treatment.…”

“…In the rodent, therefore, treatment with VEGFR inhibitors results in a constellation of toxicity characterized by incisor tooth dental dysplasia (Patyna et al 2008), ovarian atrophy (Wedge et al 2005), dose-responsive epiphyseal growth plate dysplasia (Wedge et al 2005), adrenal degeneration (Patyna et al 2008), and choroid plexus inflammation (Patyna et al 2008) as well as other less well-characterized changes.…”