Článek shrnuje použití cytokinů v terapii metastatického karcinomu ledviny od doby, kdy vzhledem k radiorezistentnímu a chemorezistentnímu chování renálního karcinomu byly prakticky jedinou systémovou terapií, až k jejich užití v dnešní době, kdy ustupují do pozadí a nahrazují je nové biologické léky, jako především tyrozinkinázové inhibitory či inhibitory mTOR. Své místo si zachovává pouze interferon-? v kombinaci s bevacizumabem (monoklonální protilátka proti VEGF), jakožto jedna z možností léčby první linie terapie mRCC. Současně se článek také zabývá mechanizmy účinků cytokinů, včetně nežádoucích, které také použití této léčby omezují., The article summarizes the use of cytokines in treating metastatic renal cell carcinoma from the time when, given the radioresistant and chemoresistant properties of renal cell carcinoma, they were virtually the only systemic therapy until present day when they give way and are being replaced with new biological agents, such as tyrosine kinase inhibitors or mTOR inhibitors. It is only interferon-? in combination with bevacizumab (a monoclonal antibody against VEGF) that has retained its position as one of the therapeutic options in the first-line treatment for mRCC. The article also deals with the mechanisms of effects of cytokines, including adverse effects that limit the use of this treatment., Michaela Zezulová, Bohuslav Melichar, and Lit.: 23
This paper reviews some of our findings which have shown the usefulness of in vitro methods in the study of hypothalamic neurones. (1) Membrane current analyses of dispersed neurones of the rat preoptic and anterior hypothalamus (POA) during thermal stimulation have revealed that warm-sensitive neurones are endowed with a non-inactivating Na+ channel having a high Qjo in the hyperthermic range (35-41 °C). (2) A brain slice study has shown that neurones in the organum vasculosum lamina terminalis (OVLT) region have much higher sensitivity to PGE2 than POA neurones. This provides further evidence of a critical role of the OVLT in translation of blood-borne cytokine signals into brain signals for fever induction. (3) Local application of IL -1/9 and IFNa altered the activity of thermosensitive (TS) neurones and glucose responsive (GR) neurones in vitro in an appropriate way to produce fever and anorexia. While the responses to IL -1/9 required the local release of prostaglandins, the responses to IFNa were found to be mediated by opioid receptor mechanisms. (4) The responses of POA TS neurones and VMH GR neurones to IL -1/9 but not those to IFNa, were reversibly blocked by aMSII, an endogenous antipyretic peptide. Thus, immune cytokines and their related neuroactive substances may affect hypothalamic TS and GR neurones thereby producing elaborately regulated changes in homeostatic functions such as thermoregulation (fever) and feeding (anorexia), which are considered as host defence responses.
We have evaluated whether the addition of either bradykinin or histamine favours the lymphatic absorption of human recombinant ¡nterferon-a2 (IFN-cq) administered by the subcutaneous route. Subcutaneous administration of IFN-a2 with bradykinin enhances IFN absorption via both capillaries and lymphatics, so that either the plasma or lymph areas under the concentration curves (ACJC) increase significantly up to 1751 ±483 and 1319±608 l(_l/ml/min respectively as compared to the respective ACJC values (613±208 and 483±213 ICJ/ml/min) obtained after IFN injection in normal saline. Since the lymph ACJC/plasma ACJC ratios remain unaltered, there is no preferential lymphatic absorption of IFN-a2 after bradykinin administration. Dual-label experiments, 125l-IFN-a2 in saline and 131l-IFN-a2 in saline containing 200 jig histamine were injected subcutaneously into the left and into the right shank of the same animal, gave similar results. The kinetics of 125l and 131l acid-soluble radioactivity confirm that histamine favours both plasmatic and lymphatic absorption.