Saturday, September 28, 2013
The experience of PA 824 against clinical isolates as well as MDR strains
This differential regulation of cytokine activity, and specially IL 6 activity, offers the basis for lenalidomide altering the bone-marrow BIX01294 microenvironment in which the aberrant expression of pro-inflammatory cytokines is very important for the development and survival of MM cells. More over, inhibition of VEGF by lenalidomide might change the bone marrow microvasculature, thereby making the tumor micro-environment less favorable for MM cell growth, migration, and survival. VEGF inhibition likely occurs via the PI3K/Akt signaling pathway, which normally becomes phosphorylated in a reaction to VEGF stimulation. Lenalidomide is up to 2,000 times more potent than thalidomide in stimulating the expansion of T cells and up to times more potent at improving the release of IL 2 and interferon.
This T cell costimulatory activity suggests that lenalidomide has the capacity to become an adjuvant to advertise type 1 cell mediated antitumor Plastid immune responses involving equally CD4 T helper cells and CD8 cytotoxic T cells. The power of lenalidomide to boost activator protein 1 and NF B action in antigen primed T cells has been proposed as a T cell costimulatory system, which might not just overcome T cell anergy, but also potentiates any non T cell receptor mediated signaling. As well as improving the adaptive immune response, there is also evidence that lenalidomide can enhance innate immunity and natural killer cell mediated lysis of MM cells specifically via its effects on IL 2 production by T cells. Lenalidomide continues to be demonstrated to directly potentiate apoptosis of MM cells via several pathways.
Included in these are inhibition of expression of the mobile inhibitor of apoptosis protein 2, Daclatasvir potentiation of those activities of other apoptosis inducers such as TNF related apoptosisinducing ligand, enhanced sensitivity to Fas induction, and increased caspase 8 activation. Caspase 8, an integrated part of Fas mediated apoptosis, is sharply up-regulated by lenalidomide. 63 In addition, dexamethasone activates caspase 9 suggesting the two drugs in combination produce double indicators with the capacity of increased cell death. Lenalidomide has been related to direct anti-proliferative action against MM cells in the absence of immune cells or proapoptotic systems by inducing G1 growth arrest. Essentially, lenalidomide inhibits the proliferation of malignant T cells while protecting normal CD34 progenitor cells.
The various mechanisms of action of lenalidomide are summarized in Figure 4. Scientific evidence for lenalidomide in MM Newly identified disease Lenalidomide isn't yet accepted for use in patients with previously untreated disease. Nevertheless, several clinical studies have reported promising response and survival benefits in this group of individuals.
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