Since in most tumors multiple signaling pathways are involved,many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases.The most important tyrosine kinase families in the d...Since in most tumors multiple signaling pathways are involved,many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases.The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL,SCR,platelet derived growth factor,vascular endothelial growth factor receptor and epidermal growth factor receptor families.Both multi-kinase inhibitors and singlekinase inhibitors have advantages and disadvantages,which are related to potential resistance mechanisms,pharmacokinetics,selectivity and tumor environment.In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist.Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor.Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity,while differences in gene expression exist between tumor and stromal cells.Considering these aspects,one type of inhibitor can generally not be preferred above the other,but will depend on the specific genetic constitution of the patient and the tumor,allowing personalized therapy.The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered(epi)genetics of the tumor.This strategy might result in treatment by a single multi kinase inhibitor for one patient,but in treatment by a couple of single kinase inhibitors for other patients.展开更多
Objective： Aging is associated with the development of diseases because of immunosuppression and altered functioning of the neuroendocrine system. The medicinal properties of Morinda citrifolia L. have been widely ex...Objective： Aging is associated with the development of diseases because of immunosuppression and altered functioning of the neuroendocrine system. The medicinal properties of Morinda citrifolia L. have been widely exploited for the treatment of age-associated diseases. This study aims to investigate the in vitro and in vivo effects of noni（M. citrifolia） fruit juice（NFJ） on neuro-immunomodulation in the lymph node lymphocytes of F344 rats.Methods： Lymphocytes isolated from axillary and inguinal lymph nodes of young（3–4 months） and old（18–21 months） rats were treated in vitro with different concentrations（0.0001%, 0.01%, and 1%） of NFJ for a period of 24 h. In the in vivo study, old（16–17 months） male F344 rats were treated with 5 mL/kg body weight of 5%, 10% and 20% of NFJ, twice a day, by oral gavage, and lymph node lymphocytes were isolated after 60 d. Concanavalin A（Con A）-induced lymphocyte proliferation, interleukin-2（IL-2）and interferon-γ（IFN-γ） production and expression of intracellular markers, such as phosphoextracellular signal-regulated kinase（p-ERK1/2）, phospho-γ AMP response element-binding protein,phospho-protein kinase B（p-Akt）, phospho-tyrosine hydroxylase（p-TH）, phospho-nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor-α（p-IκB-α） and phospho-nuclear factor-κB（p-NF-κB p65 and p50） were examined in the lymphocytes of lymph nodes.Results： NFJ increased Con A-induced lymphocyte proliferation, IL-2 and IFN-γ production, and p-ERK1/2 expression both in vitro and in vivo. In in vivo NFJ-treated old rats, lymph node lymphocytes showed increased expression of p-TH and Akt, nitric oxide production and decreased expression of p-NF-κB p65 and p50.Conclusion： These results suggest that the immunostimulatory properties of NFJ are facilitated through intracellular signaling pathways involving ERK1/2, Akt and NF-κB.展开更多
文摘Since in most tumors multiple signaling pathways are involved,many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases.The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL,SCR,platelet derived growth factor,vascular endothelial growth factor receptor and epidermal growth factor receptor families.Both multi-kinase inhibitors and singlekinase inhibitors have advantages and disadvantages,which are related to potential resistance mechanisms,pharmacokinetics,selectivity and tumor environment.In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist.Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor.Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity,while differences in gene expression exist between tumor and stromal cells.Considering these aspects,one type of inhibitor can generally not be preferred above the other,but will depend on the specific genetic constitution of the patient and the tumor,allowing personalized therapy.The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered(epi)genetics of the tumor.This strategy might result in treatment by a single multi kinase inhibitor for one patient,but in treatment by a couple of single kinase inhibitors for other patients.
基金supported by a research grant(FFEP-CRP-08-002)from World Noni Research Foundation,Chennai,India
文摘Objective： Aging is associated with the development of diseases because of immunosuppression and altered functioning of the neuroendocrine system. The medicinal properties of Morinda citrifolia L. have been widely exploited for the treatment of age-associated diseases. This study aims to investigate the in vitro and in vivo effects of noni（M. citrifolia） fruit juice（NFJ） on neuro-immunomodulation in the lymph node lymphocytes of F344 rats.Methods： Lymphocytes isolated from axillary and inguinal lymph nodes of young（3–4 months） and old（18–21 months） rats were treated in vitro with different concentrations（0.0001%, 0.01%, and 1%） of NFJ for a period of 24 h. In the in vivo study, old（16–17 months） male F344 rats were treated with 5 mL/kg body weight of 5%, 10% and 20% of NFJ, twice a day, by oral gavage, and lymph node lymphocytes were isolated after 60 d. Concanavalin A（Con A）-induced lymphocyte proliferation, interleukin-2（IL-2）and interferon-γ（IFN-γ） production and expression of intracellular markers, such as phosphoextracellular signal-regulated kinase（p-ERK1/2）, phospho-γ AMP response element-binding protein,phospho-protein kinase B（p-Akt）, phospho-tyrosine hydroxylase（p-TH）, phospho-nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor-α（p-IκB-α） and phospho-nuclear factor-κB（p-NF-κB p65 and p50） were examined in the lymphocytes of lymph nodes.Results： NFJ increased Con A-induced lymphocyte proliferation, IL-2 and IFN-γ production, and p-ERK1/2 expression both in vitro and in vivo. In in vivo NFJ-treated old rats, lymph node lymphocytes showed increased expression of p-TH and Akt, nitric oxide production and decreased expression of p-NF-κB p65 and p50.Conclusion： These results suggest that the immunostimulatory properties of NFJ are facilitated through intracellular signaling pathways involving ERK1/2, Akt and NF-κB.
