RESUMO
Hypomagnesemia commonly occurs as a side effect of panitumumab treatment. In severe cases, temporary discontinuation or dose reduction of panitumumab may be necessary. Proton pump inhibitors (PPIs) are reportedly potential risk factors for hypomagnesemia. We conducted a multicenter study to assess the impact of PPIs on the risk of grade 3-4 hypomagnesemia in patients with metastatic colorectal cancer (mCRC) receiving panitumumab. We adjusted for potential bias using a propensity score-matched analysis and retrospectively reviewed the medical records of patients. Hypomagnesemia severity was graded according to the Common Terminology Criteria for Adverse Events, version 5.0. A total of 165 patients were enrolled in this study. The incidence of grade 3-4 hypomagnesemia was significantly higher in the PPI group than in the non-PPI group, both before (20.0% [30/60] vs. 8.0% [8/105], p = 0.026) and after propensity score matching (16.2% [6/37] vs. 0% [0/37], p = 0.025). In the propensity score-matched cohort, the risk of grade 3-4 hypomagnesemia was significantly higher in the PPI group (odds ratio, 2.19; 95% confidence interval, 1.69-2.84; p = 0.025). These findings suggest that concomitant use of PPIs significantly increases the risk of grade 3-4 hypomagnesemia in patients with mCRC receiving panitumumab. Therefore, close monitoring of these patients is imperative.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Humanos , Panitumumabe/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Estudos Retrospectivos , Magnésio/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/patologiaRESUMO
XLGα(olf) is an extra large transcriptional variant of the heterotrimeric G protein, Gα(olf), which we previously reported to be localized in the Golgi apparatus and interacted with Rab3A and Rab8A through its N-terminal region. However, many physiological functions of XLGα(olf) remain to be elucidated. In this study, performance of yeast two-hybrid screening with XLGα(olf) allowed isolation of COP9 signalosome subunit 5 (CSN5), known to regulate the p27(Kip1) protein level through a proteasome dependent pathway. Co-immunoprecipitation experiments followed by Western blotting also showed association of CSN5 with XLGα(olf) linked to down-regulation of p27(Kip1). Gene silencing of endogenous CSN5 by siRNA attenuated the XLGα(olf)-mediated down-regulation, which was also demonstrated to require CDK2. Both knock down of CDK2 and the treatment with a CDK2 inhibitor reversed the reduction of p27(Kip1) due to XLGα(olf). Our findings provide important clues to understanding physiological functions of XLGα(olf).
Assuntos
Quinase 2 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/biossíntese , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeo Hidrolases/metabolismo , Complexo do Signalossomo COP9 , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Regulação para Baixo , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Inativação Gênica , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeo Hidrolases/genética , RNA Interferente Pequeno/genética , Técnicas do Sistema de Duplo-HíbridoRESUMO
Age-related androgen depletion is known to be a risk factor for various diseases, such as osteoporosis and sarcopenia. Furthermore, recent studies have demonstrated that age-related androgen depletion results in accumulation of ß-amyloid protein and thereby acts as a risk factor for the development of Alzheimer's disease. Supplemental androgen therapy has been shown to be efficacious in treating osteoporosis and sarcopenia. In addition, studies in animals have demonstrated that androgens can play a protective role against Alzheimer's disease. However, androgen therapy is not used routinely for these indications, because of side effects. Selective androgen receptor modulators (SARMs) are a new class of compounds. SARMs maintain the beneficial effects of androgens on bone and muscle while reducing unwanted side effects. NEP28 is a new SARM exhibiting high selectivity for androgen receptor. To investigate the pharmacological effects of NEP28, we compared the effects on muscle, prostate, and brain with mice that were androgen depleted by orchidectomy and then treated with either placebo, NEP28, dihydrotestosterone, or methyltestosterone. We demonstrated that NEP28 showed tissue-selective effect equivalent to or higher than existing SARMs. In addition, the administration of NEP28 increased the activity of neprilysin, a known Aß-degrading enzyme. These results indicate that SARM is efficacious for the treatment of not only osteoporosis and sarcopenia, but also Alzheimer's disease.