Erismodegib is an orally bioavailable small molecule

by Selleckchem | Jan 07 2013

C Kit is a transmembrane receptor tyrosine kinase that binds stem cell factor SCF . CKit is encoded by the kit proto oncogene, localized to human chromosome and to mouse chromosome The c Kit SCF erismodegib interaction is critical for the survival and development of stem cells involved in hematopoiesis, in pancreas development and in melanogenesis. The c Kit gene product is expressed in several normal cell types including mast cells, the interstizial cells of Cajal and the melanocytes and epithelial cells of the breast. Alterations in c Kit expression are seen in a variety of neoplasms including mastocitosis, gastrointestinal cell tumors GISTs and germ cell tumors. After binding to the stem cell factor, c Kit begins a signal cascade that contributes to the Lenvatinib growth and differentiation of multiple hematopoietic lineages.

Previous studies have shown that c Kit is expressed in junctional components of benign compound nevi and it is frequently positive in superficial spreading melanoma early stage ; this positivity is lost in the vertical growth phase of invasive melanoma. More interestingly, a loss of c Kit TH-302 immunostaining from primary malignant melanoma to metastatic melanoma in the same patients has been reported. Malignant transformation of melanocytes is associated with changes in the expression of c Kit. Several studies have demonstrated that the progression of human melanoma is associated with the loss of expression of c Kit. These studies revealed that expression of the tyrosine kinase receptor encoded by the c Kit proto oncogene gradually declines during growth and invasion of human melanoma The explanation for the loss of c Kit expression in melanoma progression has still not been fully explained.
Since SCF plays a crucial role in melanocyte proliferation, there is an interest in the diagnostic or treatment potentials of c Kit in melanocytic lesions, especially in melanoma. Given the heterogeneous appearance of malignant melanoma, diagnostic difficulties and poor inter observer reproducibility, this study was designed to assess whether the 3-Methyladenine expression of c Kit identifies differences in melanocytic lesions, considering benign nevi, primary melanoma and metastatic melanoma. Materials and Methods A retrospective study was initiated to review the medical records of all patients with a diagnosis of benign nevus and malignant melanoma between and at the Anatomy Pathology Division, University of Cagliari, Italy.
Through a careful clinicalpathological correlation, we identified cases of pigmented lesions grouped into cases of benign nevus blue nevi, intradermal nevi, junctional nevi, cases of primary compound nevus, cases of Spitz nevus , cases of primary melanoma and cases of metastatic melanoma. Five micron paraffin sections from benign and malignant melanocytic lesions were immunostained for CD, c Kit, cod,A polyclonal rabbit anti Human CD, c Kit, DAKO, Carpinteria, CA, USA , diluted The incubation time of the primary antibody was min. Heat induced antigen retrieval was adopted min at in Tris edta pH . We used the Dako cytomation LSAB system HRP DAKO that is based on a modified labelled avidin biotin LAB technique in which a biotinylated secondary antibody forms a complex with peroxidase coniugated strepavidin molecules.
Endogenous peroxidase activity was quenched by incubating min specimens with % hydrogen peroxide. The staining was completed after incubation min with amino .ethyl carbazole AEC substrate chromogen, which resulted in a red colored precipitate at the antigen site. Slides were reviewed by two pathologists who were not aware of the clinical data, and evaluated it for both tumor cell percentage and intensity of immunoreactivity. The percentage of positive cells was recorded as negative; % of cells staining; % of cells staining; % of cells staining; and % of cells staining. Intensity was scored as negative , weak , moderate , and strong , and evaluated by comparing contiguous epidermal melanocytes and interstitial mast cells considering moderately positive contiguous melanocytes and intensely positive dermal mast cells .
The product of the percentage and the intensity score was used as the final measure of the staining. Differences in c Kit immunoreactivity in the top and in the bottom of lesions were as well evaluated. Further variables considered in the present study were: maximal dimensions of lesions, age and sex of patients.