No abstract

Non-invasive thermometry is pivotal to the future advances of regional hyperthermia as a cancer treatment modality. Current magnetic resonance (MR) thermometry methods suffer from poor thermal resolution due to relatively weak dependence of chemical shift of the (1)H water signal on temperature. This study evaluated the feasibility of using thulium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (TmDOTA(-)) for MR thermometry. TmDOTA(-) is non-toxic and the gadolinium complex of DOTA(4-) is widely used as a MR contrast agent. The results demonstrate that the temperature dependence of the TmDOTA(-) proton shifts are about two orders of magnitudes higher than the water proton and, thus, provide excellent accuracy and resolution. In addition, TmDOTA(-) proton shifts are insensitive to the paramagnetic complex concentration, pH, Ca(2+) or presence of plasma macromolecules and ions. Because hyperthermia is known to produce changes in tissue pH and other physiological parameters, these properties of TmDOTA(-) greatly simplify the procedures for using the lanthanide complex for MR thermometry. Application of TmDOTA(-) for measurement of temperature in a subcutaneously implanted human melanoma xenograft is demonstrated. Finally, the feasibility of imaging one of the (1)H resonances of the lanthanide complex is demonstrated in phantom experiments. Overall, TmDOTA(-) appears to be a promising probe for MR thermometry in vivo.

Non-invasive thermometry using hyperfine-shifted MR signals from paramagnetic lanthanide complexes has attracted attention recently because the chemical shifts of these complexes are many times more sensitive to temperature than the water 1H signal. Among all the lanthanide complexes examined thus far, thulium tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (TmDOTMA-) appears to be the most suitable for MR thermometry. In this paper, the feasibility of imaging the methyl 1H signal from TmDOTMA- using a frequency-selective radiofrequency excitation pulse and chemical shift-selective (CHESS) water suppression is demonstrated. A temperature imaging method using a phase-sensitive spin-echo imaging sequence was validated in phantom experiments. A comparison of regional temperature changes measured with fiber-optic probes and the temperatures calculated from the phase shift near each probe showed that the accuracy of imaging the temperature with TmDOTMA- is at least 0.1-0.2 degrees C. The feasibility of imaging temperature changes in an intact rat at 0.5-0.6 mmol/kg dose in only a few minutes is demonstrated. Similar to commonly used MRI contrast agents, the lanthanide complex does not cross the blood-brain barrier. TmDOTMA- may prove useful for temperature imaging in many biomedical applications but further studies relating to acceptable dose and signal-to-noise ratio are necessary before clinical applications.

The aim of the present study was to investigate the antiproliferative and proapoptotic actions of N-(5-benzyl-1,3-thiazol-2-yl)-3,5-dimethyl-1-benzofuran-2-carboxamide derivative (compound 5) in glioma cells in comparison with the actions of temozolomide (TMZ) and doxorubicin (Dox), used as positive controls. The antiproliferative activity of the compound 5, TMZ, and Dox on human glioblastoma U251 and human glioblastoma multiform T98G cells was measured using the MTT test. Western blot analysis, fluorescent microscopy, agarose gel retardation assay, flow cytometric analysis, and the DNA comet assay under alkaline conditions were carried out to study the effect of compound 5 on U251 cells. This compound showed ~20 times higher cytotoxicity toward U251 and T98G cells compared with the effects of TMZ and approximately two times higher activity than that of the Dox. Compound 5 induced apoptosis in U251 cells by PARP1 and caspase 3 cleavage mechanisms, also inducing an increase in the level of Bax and Bim proapoptotic proteins and a decrease in the level of phosho-ERK1/2 kinase. The cytotoxicity of compound 5 was associated with an increase in the production of the hydrogen peroxide and the formation of DNA single-strand breaks. This compound 5 did not intercalate into a DNA molecule. Thus, the novel thiazole derivative (compound 5) proved to be a potential antiglioma drug that showed much higher cytotoxic action on human glioma cells compared with the effects of TMZ and Dox. Its cytotoxicity is associated with apoptosis induction, production of the reactive oxygen species, and formation of DNA single-strand breaks without significant DNA intercalation.

The development of novel efficient substances for anticancer chemotherapy is an important problem of medicinal chemistry. Aim. To evaluate the level of cytotoxic action of novel thiazole derivatives towards tumor cell lines of different origin. Methods. Four N acylated 2-amino-5-benzyl-1,3-thiazoles (5a-d) were synthesized by reaction of 2-amino-5-R-benzyl-1,3-thiazoles with acid chlorides in the presence of triethylamine in the dioxane medium. Anticancer screening of the synthesized thiazoles was performed by the MTT assay. Results. Thiazole derivatives were shown to exert antineoplastic activity towards different types of tumor cells. The anti-glioma and anti-melanoma selectivity of these derivatives action was demonstrated. The compound 5a was found to be the most toxic for human glioblastoma U251 cells and human melanoma WM793 cells. At the same time, the created compounds possessed low toxicity towards pseudo-normal cells. Conclusion. The novel thiazole derivative 5a was the most toxic against human glioblastoma and melanoma cells. K e y w o r d s: thiazole derivatives, 2-amino-5-benzyl-1,3-thiazoles, anticancer activity, leukemia, glioblastoma, melanoma.