SotanTM (sunitinib malate capsules)
For the treatment of small cell lung cancer (SCLC)
Ma Ning, Department of Medical Oncology, Henan Provincial People’s Hospital
Introduction
Sunitinib is a small molecule that inhibits a variety of receptor tyrosine kinases (RTKs), some of which are involved in tumor growth, pathological angiogenesis and tumor metastasis. By evaluating the inhibitory activity of sunitinib against various kinases (more than 80 kinases), it was demonstrated that sunitinib inhibits platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), type 1 colony-stimulating factor receptor (CSF-1R) and glial cell line-derived neurotrophic factor receptor (RET). Biochemical and cellular assays confirmed that sunitinib inhibited the activity of these RTKs and demonstrated an inhibitory effect of sunitinib in a cell proliferation assay. Biochemical and cellular assays demonstrated similar activity of the major metabolites to sunitinib.1
In in vivo assays in tumor models expressing receptor tyrosine kinase targets, sunitinib inhibited the phosphorylation process of multiple receptor tyrosine kinases (PDGFRβ, VEGFR2, KIT); it was shown to have the ability to inhibit tumor growth or cause tumor regression, and/or inhibit tumor metastasis in certain animal tumor models. Results from in vitro experiments have shown that sunitinib inhibits the growth of tumor cells with dysregulated expression of targeted RTKs (PDGFR, glial cell line-derived neurotrophic factor receptor, or KIT), and results from in vivo tests have shown that it inhibits PDGFRβ- and VEGFR2-dependent tumor angiogenesis.1
As of November 2007, a computer search of the published medical literature identified one article discussing sunitinib for SCLC, which is reviewed below.
Preclinical Data
Abrams et al. evaluated the KIT inhibitory activity of sunitinib in in vitro and in vivo trials, and the antitumor activity of sunitinib in an in vivo trial in a SCLC model. In in vitro assays, the SCF-stimulated KIT tyrosine phosphorylation process (a way to measure KIT kinase activity) and the SCF-stimulated ERK1/2 phosphorylation process (a downstream signaling event for KIT activation) were monitored when different concentrations of sunitinib were added to human SCLC cell lines. In addition, the effects of sunitinib on cell proliferation and apoptosis were evaluated. Human SCLC cell lines were also exposed to various growth factors and the effect of sunitinib on cell growth was evaluated when the above factors were added. The in vivo assay was an animal study performed in female mice (9-12 weeks in size). Two human SCLC cell lines (1 KIT-positive and 1 KIT-negative cell line) were injected into mice, and after tumor (~300-500 mm3) establishment, the mice were randomized to receive either of the following regimens: sunitinib 40 to 80 mg/kg/day, imatinib 160 mg/kg twice daily, or placebo. In another study, mice injected with a KIT-positive cell line were randomized to receive either: sunitinib 40 mg/kg (treatment until the end of the study); cisplatin 1.5 mg/kg intraperitoneally for the first 5 days, or a combination of sunitinib and cisplatin. Tumor growth was examined twice weekly during treatment in both studies, and mice were executed and tumors were excised at the end of treatment.2
Results from the in vitro study showed that sunitinib inhibited SCF-stimulated KIT phosphorylation levels, SCF-stimulated ERK1/2 phosphorylation, and SCF-stimulated cell proliferation in a dose-dependent manner. The dose level of sunitinib was higher when apoptosis occurred than when SCF-stimulated cell proliferation was inhibited. The concentration levels of sunitinib that inhibited cell proliferation did not cause a cytotoxic response. In the presence of multiple growth factors, little tumor growth inhibition was observed at low concentrations of sunitinib (≤1uM), however, higher concentrations of sunitinib produced dose-dependent tumor growth inhibition.2