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Effect of Nucleotides and Related Compounds on Glutamine Synthetase Activity in Chick Embryo Retina: A Biochemical and Immunohistochemical Study
: The effect of a number of nucleotides and related compounds on glutamine synthetase (GS) induction in retina from 12‐day chick embryo was studied with both biochemical and immunohistochemical techniques. A number of these compounds gave rise to GS activity comparable to that induced by treatment with cortisol, which is known to give rise to precocious induction of the enzyme in this system. Of the cyclic nucleotides examined, cAMP (0.5‐1.2 × 10−3 M) gave essentially no increase in GS activity. In contrast, dibutyryl cAMP (0.8 × 10−3 M) had a more significant effect on GS activity, as did 8‐bromo‐cAMP and cGMP at the same concentration. The activity elicited by these nucleotides was generally half that obtained by treatment with 2.8 × 10−7 M‐cortisol for the same length of time, 8‐Bromo‐cGMP (0.8 × 10−3 M) had an effect comparable to the aforementioned concentration of cortisol. Since phosphodiesterase activity is minimal in the chick retina at 12 days of development, addition of isobutylmethylxanthine (1 × 10−5 M) to this system had, as would be expected, little effect on GS activity. Of the noncyclic compounds, 8‐bromoguanosine often gave rise to GS activity comparable to that obtained with cortisol. The other compounds (8‐bromo‐5′‐GMP, guanosine, adenosine, and 5′‐AMP) generally had less of an effect on GS. In general, the degree of staining in the immunohistochemical localization of GS corresponded well with the biochemical results and showed the enzyme to be present in regions consistent with the distribution of Muller cells and their processes. Thin‐layer chromatography and radioimmunoassay of the nucleotides did not show any steroid impurity in any of the compounds used in the study, even when determinations were carried out at five times the concentration of nucleotide used in the experiments
Promises of Protein Kinase Inhibitors in Recalcitrant Small-Cell Lung Cancer: Recent Scenario and Future Possibilities
SCLC is refractory to conventional therapies; targeted therapies and immunological checkpoint inhibitor (ICI) molecules have prolonged survival only marginally. In addition, ICIs help only a subgroup of SCLC patients. Different types of kinases play pivotal roles in therapeutics-driven cellular functions. Therefore, there is a significant need to understand the roles of kinases in regulating therapeutic responses, acknowledge the existing knowledge gaps, and discuss future directions for improved therapeutics for recalcitrant SCLC. Here, we extensively review the effect of dysregulated kinases in SCLC. We further discuss the pharmacological inhibitors of kinases used in targeted therapies for recalcitrant SCLC. We also describe the role of kinases in the ICI-mediated activation of antitumor immune responses. Finally, we summarize the clinical trials evaluating the potential of kinase inhibitors and ICIs. This review overviews dysregulated kinases in SCLC and summarizes their potential as targeted therapeutic agents. We also discuss their clinical efficacy in enhancing anticancer responses mediated by ICIs