However, one group recently reported the acquisition of functional human embryonic stem cells-derived thymic organoids in NOD- scid Il2rg − / − mice, providing valuable clues about the maturation process of engrafted human T cells (Sun et al., 2013). These disadvantages might impede further application of this humanized mouse model. Moreover, these mice also show low and variable levels of T-cell-dependent antibody responses (Shultz et al., 2007). For example, NOD- scid Il2rg − / − mice lack appropriate MHC molecules for T-cell selection in the thymus and some human-specific cytokines required for engrafted human cell development and survival. Combined, these immunodeficiency advantages make NOD- scid Il2rg − / − mice excellent recipients to carry out in vivo studies of human cells, tissues and organs, especially for generating humanized mouse models, which can provide insights into in vivo human biology and be utilized in many pre-clinical research fields.Īlthough the NOD- scid Il2rg − / − mice are highly immunodeficient and humanization on these mice has proved to be a powerful and valuable model to in vivo study of human disease, there are still some obvious defects in their application for generating humanized mice. Moreover, the Il2rg − / − targeted mutation completely deletes the interleukin 2 receptor gamma chain (Il2rg), a common component of many cytokines involved in immune function such as IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, making these mice extremely deficient in NK cells which enables xenotransplantation of human cells (Cao et al., 1995). The immunodeficient non-obese diabetic (NOD) genetic background contributes to deficiency in innate immunity with impaired dendritic cell function and macrophage activity (Shultz et al., 1995), and the Prkdc scid mutation leads to elimination of adaptive immunity by loss-of-function of the Prkdc gene, whichĮncodes a protein critical for V(D)J recombination in T and B lymphocyte maturation (Blunt et al., 1995). One significant breakthrough in generating humanized mice was the development of NOD- scid Il2rg − / − mice, which are double homozygous for the severe combined immunodeficiency (SCID) mutation and interleukin-2Rg ( Il-2Rg) allelic mutation (gamma c null) (Ito et al., 2002). To further enhance our understanding of human hematopoiesis, innate immunity, infectious diseases, cancer biology and regenerative medicine. These results will guide the optimization of dosing regimen for further development of letrozole for HGG treatment.īlood brain barrier Drug–drug interactions Letrozole Pharmacokinetics Temozolomide.For decades, the stem cell field has pursued the development of humanized mice For instance, peak plasma and brain ECF TMZ levels when given alone were 14.7 ± 1.1 and 4.6 ± 0.6 µg/ml, respectively, and 12.6 ± 2.4 and 3.4 ± 0.8 µg/ml, respectively, when given with letrozole. In the drug interaction study, no PK changes were evident when TMZ and letrozole were given in combination. The elimination half-life was 2.6 h with minimal accumulation following multiple dosing. In NSG mice, peak plasma and brain tissue letrozole concentrations (C max) were 3-4 and 0.8-0.9 µg/ml, respectively. Drug levels were measured employing HPLC and PK analysis was conducted using Phoenix WinNonlin ®. Intracerebral microdialysis was performed for brain extracellular fluid (ECF) collection simultaneously with venous blood sampling. Letrozole and TMZ interaction study employed jugular vein-cannulated rats (three groups TMZ alone, letrozole alone and TMZ + letrozole). Brain tissue and blood samples were collected over 24 h. NSG mice were administered letrozole (8 mg/kg i.p) as a single or multiple dose (b.i.d, 10 days). Furthermore, we evaluated the potential PK interactions between letrozole and temozolomide (TMZ) in Sprague-Dawley rats. To facilitate optimal dosing for such studies, we evaluated the plasma and brain pharmacokinetics (PK) of letrozole in NOD-scid gamma (NSG) mice, which are frequently employed for assessing efficacy against patient-derived tumor cells. The aromatase inhibitor, letrozole, is being investigated in experimental animal models as a novel treatment for high-grade gliomas (HGGs).
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