No immunohistochemical signal was present in tumors with other simple or complex deletions

vival of patients with several cancers. SCLC highly express several molecules such as c-kit, c-Met and vascular endothelial growth factor. The c-kit protooncogene encodes a 145-kDa transmembrane tyrosine kinase receptor consisting of an extracellular portion with five immunoglobulin-like domains: the first three contain a ligand binding site and the fourth and fifth domains are associated with receptor dimerization, the transmembrane portion, and the intracellular portion having kinase enzymatic activity. Stem cell factor is a ligand for c-kit and its binding leads to receptor activation and triggers the activation of downstream signal pathways involved in cell growth, differentiation and development. C-kit is implicated in the rapid cell growth observed in SCLC and thus is considered a candidate target molecule for diagnostics and therapeutics of SCLC. Imatinib, an inhibitor of c-kit-tyrosine kinase activity, is highly effective against chemotherapy-resistant gastrointestinal C-Kit Targeted Radioimmunotherapy stromal tumors . Although several preclinical studies reported that suppression of c-kit signaling inhibits SCLC cell growth, phase II imatinib trials in patients with relapsed ckit-positive SCLC reported no objective responses or sustained disease stabilization. This suggests that progression may not depend on c-kit owing to a lack of activating mutations unlike GIST, despite high c-kit expression in SCLC. Although blockade of the c-kit pathway may not have a therapeutic effect on SCLC, c-kit may be a promising target for the selective delivery of therapeutic agents such as toxins and radioisotopes to c-kit positive SCLC tumor cells by means of carriers such as antibodies. We previously reported that high levels of 111In-labeled anti-ckit antibody, 12A8, accumulated in c-kit-expressing SCLC xenografts, while its accumulation was low in normal organs. Therefore, 12A8 has the potential to be used for radioimmunotherapy by substituting c-emitting 111In with b- or a-emitting radionuclides with suitable TG100 115 nuclear properties. The concept of RIT has been realized in clinics for the treatment of non-Hodgkin B cell lymphoma, using anti-CD20 antibody labeled with 90Y or 131I. 90Y is a pure b-emitter with high energy, long particle range, an appropriate half-life 10422886 for RIT with IgG and suitable for RIT with an internalizing antibody. In the present study, we evaluated and compared the in vitro and in vivo properties of two radiolabeled anti-c-kit monoclonal antibodies, 12A8 and 67A2, and their use in experimental RIT of SCLC using 90Y-labeled antibodies. 67A2, 12A8 and 67A2 were approximately 50, 50, 300 and 450 kBq/mg, respectively. The labeling yield was approximately 80% for 111In labeling and 65% to 97% for 90Y labeling, and the radiochemical purity exceeded 96%. 67A2 was also labeled with 125I using chloramine-T for internalization assay as previously described. The specific activity of 67A2 was approximately 500 kBq/mg. In vitro assay Cell binding, competitive inhibition and internalization assays were conducted 9346307 as previously described. Briefly, in a cell binding assay, serially-diluted SY cells in PBS were incubated with the 111In-labeled antibody on ice for 60 min. After washing, the radioactivity bound to the cells was measured. The immunoreactivity of the 111In-labeled antibodies was estimated according to the method of Lindmo et al. In a competitive inhibition assay, the 111In-labeled antibody was incubated with SY cells in the prese