Targeting kinases is central to drug-based cancer therapy but remains challenging because the drugs often lack specificity, which may cause toxic side effects. Modulating side effects is difficult because kinases are evolutionarily and hence structurally related. The lack of specificity of the anticancer drug imatinib enables it to be used to treat chronic myeloid leukemia, where its target is the Bcr-Abl kinase, as well as a proportion of gastrointestinal stromal tumors (GISTs), where its target is the C-Kit kinase. However, imatinib also has cardiotoxic effects traceable to its impact on the C-Abl kinase. Motivated by this finding, we made a modification to imatinib that hampers Bcr-Abl inhibition; refocuses the impact on the C-Kit kinase; and promotes inhibition of an additional target, JNK, a change that is required to reinforce prevention of cardiotoxicity. We established the molecular blueprint for target discrimination in vitro using spectrophotometric and colorimetric assays and through a phage-displayed kinase screening library. We demonstrated controlled inhibitory impact on C-Kit kinase in human cell lines and established the therapeutic impact of the engineered compound in a novel GIST mouse model, revealing a marked reduction of cardiotoxicity. These findings identify the reengineered imatinib as an agent to treat GISTs with curbed side effects and reveal a bottom-up approach to control drug specificity.

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Between 1984 and 2002, pulmonary metastases were detected in 42 (4%) out of 1,023 patients with differentiated thyroid carcinoma (DTC) in our department. The age at diagnosis ranged from 6 to 77 years. Lung metastases were diagnosed by both increased thyroglobulin (Tg) levels and positive uptake of iodine-131 on scans, and/or positive radiological findings. The primary tumours were histologically classified as papillary (30 patients), follicular (nine patients) and poorly differentiated (two tall cell, one insular carcinoma). The duration of follow-up ranged from 24 to 228 months. The end-results of the (131)I therapy were evaluated. The treatment of choice was (131)I therapy of metastases after total thyroidectomy plus lymph node dissection (if lymph node metastases were present). Applied single and total (131)I activities were 1.8-10.4 GBq and 5.5-43.7 GBq, respectively. Lung metastases were present at the time of diagnosis in 30 patients and developed during the follow-up period in the remaining 12. Twelve patients with extensive metastases died of thyroid carcinoma and another died due to secondary malignancy (malignant mesothelioma). Ten patients with lung metastases remain completely free of disease and are probably cured, while another seven were stable at the time of study. Three- and five-year survival rates were 86% (36/42) and 76% (32/42), respectively. To define the diagnostic value of high-resolution computed tomography (HRCT) and identify the distinctive features of lung metastases from DTC, 22 patients were further examined with HRCT within 2 weeks of the initial diagnosis of lung metastases and the results were compared with chest X-ray findings. HRCT detected metastases in 10 out of 14 patients with a normal chest X-ray and confirmed metastases in all patients with positive (n=5) and suspicious (n=3) chest X-ray. HRCT did not show any abnormalities in four patients with positive lung uptake on (131)I whole-body images. Stage of disease, existence of distance metastases other than to the lung, and HRCT characteristics were significant prognostic variables. Lung metastases from DTC can be cured with (131)I therapy in a considerable number of patients, especially when they are not associated with other distant metastases; they should therefore be treated at an early stage. HRCT clearly improved diagnostic ability in the evaluation of lung metastases compared with chest X-ray and should be the primary method when radiological correlation is needed. The main, and new, finding of the study is that HRCT not only improves diagnostic ability but is also of prognostic value.

ABSTRACT:The aim of this study is preparation and characterization of alginate/chitosan sponges including a model antibiotic (i.e., ciprofloxacin) to use in wound and/or burn treatment. Sponges were prepared firstly by the gelation of sodium alginate followed by lyophilization, crosslinking with calcium chloride, and finally coating with chitosan. Sponges were characterized with respect to morphology, water uptake, in vitro drug release behavior, and antimicrobial activity. Investigated and evaluated parameters in all of these studies were selected as the concentration of calcium chloride, alginate viscosity, drug content, and molecular weight of chitosan. Drug release and water uptake were found to be greatly influenced by these parameters. Water uptake and drug release rate were decreased by increasing the crosslinking density, chitosan molecular weight, and alginate viscosity. In the antimicrobial tests, it was obtained that the antimicrobial activity is directly proportional with the release rates and water uptake. Morphological studies showed a highly porous structure with interconnected pores.