RESUMO
CHS 828, a newly recognized pyridyl cyanoguanidine, has shown promising antitumor activity both in vitro and in vivo and is presently in early phase I clinical trial in collaboration with EORTC. In this study, the effects of CHS 828 and a series of analogues on extracellular acidification and cytotoxicity were compared with those of m-iodobenzylguanidine (MIBG) in human tumor cells. The extracellular acidification rate was measured using the Cytosensor microphysiometer, and determination of cytotoxicity and proliferation was [(14)C] performed by the fluorometric microculture cytotoxicity assay (FMCA) and measurement of [(14)C]thymidine and leucine uptake. CHS 828 significantly increased the acidification rate during the first 15-24 hr in a concentration-dependent manner. This effect was abolished by removal of glucose from the medium, substituted with 10 mM of pyruvate, indicating stimulated glycolysis as the source of the increased acidification rate. However, CHS 828 induced cytotoxicity at concentrations well below those that affected the rate of acidification; when a series of closely related pyridylguanidine analogues were tested and compared, no apparent relationship between cytotoxicity and acidification could be discerned. Furthermore, comparable increases in the acidification rate were evident in one subline with high-grade resistance to the cytotoxic actions of CHS 828. The results indicate that CHS 828 may share the inhibitory actions of MIBG on mitochondrial respiration with a subsequent increase in glycolysis and acidification rate. However, this mechanism of action appears neither necessary nor sufficient to fully explain the cytotoxic actions of CHS 828 in human tumor cells, actions which remain to be mechanistically clarified.
Assuntos
3-Iodobenzilguanidina/farmacologia , Antineoplásicos/farmacologia , Cianetos/farmacologia , Guanidinas/farmacologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Antineoplásicos/química , Cianetos/química , DNA de Neoplasias/biossíntese , DNA de Neoplasias/efeitos dos fármacos , Fluorometria , Guanidinas/química , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/efeitos dos fármacos , Células Tumorais CultivadasAssuntos
Antibióticos Antineoplásicos/síntese química , Desoxiglucose/análogos & derivados , Desoxiglucose/química , Ramnose/análogos & derivados , Ramnose/química , Desoxiglucose/síntese química , Glicosilação , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Rotação Ocular , Ramnose/síntese químicaRESUMO
The chronic and progressive nature of multiple sclerosis (MS) often excludes patients from neuropsychological treatment. At the Multiple Sclerosis Rehabilitation Hospital, Haslev, 40 patients with mild to moderate cognitive and behavioral impairment associated with MS were randomized to either specific cognitive treatment (20 pts) by direct training, compensatory strategies and neuropsychotherapy, or to non-specific, deliberately diffuse mental stimulation (20 pts). Treatment was for a mean of 46 days. The effects of treatment were evaluated by neuropsychological tests before treatment, immediately after treatment (short-term effects) and 6 months later (long-term effects). After short-term treatment, effects on cognitive measures were not convincing, but on the Beck Depression Inventory (BDI) the specific cognitive treatment group reported significantly less depression. After 6 months only this group showed an effect, since the visuo-spatial memory was improved. However, the depression ratings (BDI) were almost maintained from the short-term level. Interestingly, the non-specific treatment group rated themselves as significantly more depressed. Conclusively, it is worth while to offer specific neuropsychological treatment to MS patients with cognitive and behavioral dysfunction.