scholarly journals Crosstalk in Inflammation: The Interplay of Glucocorticoid Receptor-Based Mechanisms and Kinases and Phosphatases

2009 ◽  
Vol 30 (7) ◽  
pp. 830-882 ◽  
Author(s):  
Ilse M. E. Beck ◽  
Wim Vanden Berghe ◽  
Linda Vermeulen ◽  
Keith R. Yamamoto ◽  
Guy Haegeman ◽  
...  
Keyword(s):  
Side Effects ◽  
Kinase Inhibitors ◽  
Inflammatory Diseases ◽  
Therapy Resistance ◽  
Fine Tuning ◽  
Scientific World ◽  
Proinflammatory Gene ◽  
Cofactor Recruitment ◽  
Proinflammatory Gene Expression

Abstract Glucocorticoids (GCs) are steroidal ligands for the GC receptor (GR), which can function as a ligand-activated transcription factor. These steroidal ligands and derivatives thereof are the first line of treatment in a vast array of inflammatory diseases. However, due to the general surge of side effects associated with long-term use of GCs and the potential problem of GC resistance in some patients, the scientific world continues to search for a better understanding of the GC-mediated antiinflammatory mechanisms. The reversible phosphomodification of various mediators in the inflammatory process plays a key role in modulating and fine-tuning the sensitivity, longevity, and intensity of the inflammatory response. As such, the antiinflammatory GCs can modulate the activity and/or expression of various kinases and phosphatases, thus affecting the signaling efficacy toward the propagation of proinflammatory gene expression and proinflammatory gene mRNA stability. Conversely, phosphorylation of GR can affect GR ligand- and DNA-binding affinity, mobility, and cofactor recruitment, culminating in altered transactivation and transrepression capabilities of GR, and consequently leading to a modified antiinflammatory potential. Recently, new roles for kinases and phosphatases have been described in GR-based antiinflammatory mechanisms. Moreover, kinase inhibitors have become increasingly important as antiinflammatory tools, not only for research but also for therapeutic purposes. In light of these developments, we aim to illuminate the integrated interplay between GR signaling and its correlating kinases and phosphatases in the context of the clinically important combat of inflammation, giving attention to implications on GC-mediated side effects and therapy resistance.

scholarly journals Targeting Oncogenic BRAF: Past, Present, and Future

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1197 ◽  
Author(s):  
Zaman ◽  
Wu ◽  
Bivona
Keyword(s):  
Kinase Inhibitors ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
Wild Type ◽  
Braf Mutations ◽  
Molecular Alterations ◽  
Mutant Braf

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a “precision medicine” paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies.

scholarly journals Dissociated Steroids

2007 ◽  
Vol 7 ◽  
pp. 421-430 ◽  
Author(s):  
Matthew C. Catley
Keyword(s):  
Side Effects ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Therapeutic Index ◽  
Clinical Use ◽  
Response Elements ◽  
Activation Of Transcription

Glucocorticoids (GCs) are some of the most important drugs in clinical use today. They are mainly used to suppress disease-related inflammation and are widely used for the treatment of many inflammatory diseases including asthma and arthritis. However, GCs are also associated with debilitating side effects that place limitations on the long-term use of these drugs. The development of a GC with reduced side effects would allow more effective treatments for patients who require long-term suppression of inflammation. GCs exert their effects by binding and activating the GC receptor (GR). The activated receptor then binds GC response elements (GREs) in the promoter of genes, and activates transcription (transactivation) or interferes with the activation of transcription by inhibiting the transactivating function of other transcription factors, such as AP-1 and NF-ĸB (transrepression). Transrepression is believed to be responsible for the majority of the beneficial anti-inflammatory effects of GCs, whereas transactivation is believed to play a bigger role in the unwanted side effects of GCs. Compounds that can dissociate the transactivation function of GCs from the transrepression function may, therefore, have an improved therapeutic index. A number of these dissociated corticosteroids have been developed.In vitroassays using these compounds appear to show good dissociation. However,in vivo, the dissociation appears to be lost and these compounds still produce many of the side effects associated with conventional GCs. A better understanding of the molecular mechanisms behind GC-induced effects would allow the design of novel selective GR modulators with an improved therapeutic index.

Skeletal Effects of the Tyrosine Kinase Inhibitors Imatinib, Dasatinib, and Bosutinib in Young Rats

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4429-4429
Author(s):  
Josephine Tabea Tauer ◽  
Lorenz C. Hofbauer ◽  
Reinhold G. Erben ◽  
Meinolf Suttorp
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Cortical Thickness ◽  
Kinase Inhibitors ◽  
Standard Dose ◽  
High Dose ◽  
Time Points ◽  
Tibial Length ◽  
Skeletal Effects

Abstract Abstract 4429 Background: In patients with chronic myeloid leukemia (CML) tyrosine kinase inhibitors (TKIs) such as imatinib (IMA), dasatinib (DASA), and bosutinib (BOSU) are used to selectively inhibit the oncogenic BCR-ABL tyrosine kinase. However, these TKIs also exhibit off-target effects on other kinases (e.g. PDGFR, c-FMS) involved in the regulation of bone metabolism. In adult patients with CML, disturbances in bone structure and metabolism are observed during IMA therapy, while in pediatric patients longitudinal growth retardation represents a major concern. Here, we compared the skeletal effects of chronically administered IMA, DASA, and BOSU in young, growing rats. Methods: From age 4 weeks to age 14 weeks, groups (n=10 each) of male Wistar rats were chronically exposed via the drinking water to concentrations representing i) standard dose and ii) two-fold dose of the standard dose of IMA (i: 1 mM and ii: 2 mM), DASA (i: 50 μM and ii: 100 μM), or BOSU (i: 50 μM and ii: 100 μM). Additional groups received the high doses of the TKIs tested in an intermittent fashion over 3 consecutive days per week. Controls were left untreated. Three to four rats of each group were sacrificed after 2 weeks (prepubertal), 4 weeks (pubertal), or 10 weeks (postpubertal) of exposure, respectively. Biochemical bone markers were analyzed in serum. Bone length of femora and tibiae was determined with calipers. Trabecular (trab) and cortical (cort) bone mineral density (BMD) and cortical thickness were assessed by pQCT. Bone strength of femora was measured by a 3-point bending test. Results: Continuous exposure to IMA and DASA led to dose dependent reductions in femoral and tibial length. No such effect was observed under BOSU exposure. Intermitted exposure of all 3 TKIs tested reduced effects on femoral and tibial length. IMA and DASA lowered femoral and tibial trab BMD in prepubertal rats. At pubertal age, rats receiving high dose IMA showed reduced femoral and tibial trab BMD compared to controls, while no such effect was observed for DASA and BOSU. Postpubertally, femoral and tibial trab BMD did not differ from controls in all groups. Moreover, TKI exposure did not affect femoral or tibial cortical BMD and cortical thickness at any dose and age tested. The bone resorption marker tartrate resistant acidic phosphatase (TRACP) was reduced in rats receiving continuously high dose of IMA at all time points tested, and also in postpubertal rats receiving 50 μM and 100 μM of BOSU. The bone formation marker osteocalcin was reduced in all groups and at all time points under IMA exposure, whereas no such effect was observed for DASA and BOSU. Femoral mechanical properties did not differ from controls pre- and pubertally for all 3 TKIs tested. However, high dose IMA reduced femoral breaking strength in postpubertal rats (Fig.1). DASA or BOSU did not cause changes in biomechanical bone strength. Conclusion: The juvenile rat model is an appropriate model to examine side effects of long-term exposure of TKIs on growing bones. Compared with IMA and DASA, BOSU seems to exert a less negative effect on the bone parameters tested. Given the limited pediatric experience with TKI, regular monitoring of skeletal side effects under long-term TKI treatment is warranted. Moreover, skeletal status and fracture rates should be systematically analyzed in patients under IMA treatment. Acknowledgment: Supported by grant DFG SU122-3/1 to MS, DFG HO 1875/10-1 to LCH, and FWF I 734 to RGE. Disclosures: No relevant conflicts of interest to declare.

Anti drug antibodies monitoring in biologics use: clinical implications

2020 ◽  
Vol 15 ◽  
Author(s):  
Rim Dhahri ◽  
Selma Athimni ◽  
Maroua Slouma ◽  
Leila Metoui ◽  
Imene Gharsallah ◽  
...  
Keyword(s):  
Side Effects ◽  
Drug Monitoring ◽  
Therapeutic Response ◽  
Recent Literature ◽  
Inflammatory Diseases ◽  
Published Data ◽  
Clinical Implications ◽  
Residual Rate ◽  
Time Period

Background: Over the years, drug monitoring-such as anti drug antibodies (ADA) dosage- has witnessed major transformations. In fact ADA are more and more used in rheumatology and gastro-enterology in monitoring chronic inflammatory diseases therapeutic response. The main purpose of those researches is to produce less immunogenic drug and in consequences to improve tolerance and efficiency, since immunogenicity of those drugs still is the main constraint to their long-term use. The aim of this review was to highlight anti-drug-antibodies potential effects on the pharmacokinetics and bioavailability of biotherapies as well as their clinical implications. Methods: For this purpose we did collect and summarize published data on pubmed using key words “Biologics, Rheumatoid Arthritis, Spondyloarthritis, Crohn disease, Anti drug antibodies, residual rate, immunogenicity, efficacy, tolerance”. The time-period selected for this study was 2000-2019. Results: Anti- Drug-antibodies do decrease pharmaco-availability of drugs and in consequences its efficiency and high risk of refractory disease and side effects. Conclusion: Recent literature is consistent with the fact that drug monitoring using ADA dosage coupled with residual drug concentration offers reliable options to comfort practitioner’ therapeutic management decisions. This is particularly interesting in failure to treatment or in side effects onset situations.

Tyrosine kinase inhibitor nilotinib induced palmoplantar erythrodysesthesia: A rare case

2022 ◽  
pp. 107815522110724
Author(s):  
Muzeyyen Aslaner Ak ◽  
Pelin Ertop Doğan ◽  
Birsen Sahip
Keyword(s):  
Side Effects ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Palmoplantar Erythrodysesthesia

Introduction Nilotinib is a second generation Tyrosine Kinase inhibitor (TKI) used in the treatment of Chronic Myeloid Leukemia (CML). The development of tyrosine kinase inhibitors has transformed chronic phase chronic myeloid leukemia from a disease with a poor prognosis to a treatable chronic disease. Long-term treatment with tyrosine kinase inhibitors means that patients must be clinically managed and monitored for years. While under Nilotinib tretament, the development of palmoplantar erythrodyesthesia is a very rare condition compared to other oncological drugs. Case report A 66-year-old male patient, who was diagnosed with chronic phase CML in 2019 had been placed under imatinib treatment . He had major molecular response loss in 2021, and was started on second generation TKI nilotinib 2  ×  400mg/day, considering his comorbidities. We present a case of a 66-year-old patient with CML who developed palmoplantar erythrodysesthesia on the 21st day starting nilotinib treatment. Conclusion It is important to manage the side effects that develop in long-term treatments. Adverse events can have a negative impact on patient compliance and quality of life and lead to poor clinical outcomes Our case is the first to develop PPE after beginning nilotinib use. We present this phenomenon to raise awareness and ignite a review of management strategies.In this case, we wanted to emphasize the importance of managing side effects.

scholarly journals A krónikus myeloid leukaemia tirozin-kináz-gátló kezelésének mellékhatásai és azok gyakorlati ellátása

2021 ◽  
Vol 162 (30) ◽  
pp. 1198-1207
Author(s):  
Gabriella Mezei ◽  
Árpád Illés ◽  
Péter Batár
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukaemia ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Healthy Population ◽  
Number Of Patients

Összefoglaló. A krónikus myeloid leukaemia ritka, klonális őssejt eredetű betegség. A myeloid sejtsor kóros működését a 9-es és 22-es kromoszómák reciprok transzlokációja következtében kialakuló fúziós gén (BCR/ABL1) által kódolt patológiás (fokozott) aktivitású tirozin-kináz jelátviteli fehérje okozza. A tartós, gyakran élethosszig tartó BCR/ABL1 specifikus tirozin-kináz-gátló (TKI-) kezelés a betegek jelentős hányadában az egészséges populáció túlélését elérő teljes gyógyulást biztosít, melyhez folyamatos, a mindenkori szakmai ajánlásoknak megfelelő onkohematológiai ellenőrzés szükséges. Az igen hatékony TKI-kezelés mellett azonban nemkívánatos mellékhatások jelentkezhetnek, melyek – számos szervrendszert érintve – a krónikus myeloid leukaemiás beteg kezelését multidiszciplináris együttműködéssé szélesítik ki. Jelenleg Magyarországon ötféle TKI érhető el, melyek mellékhatásprofilja igen eltérő. A kezelés elindításakor, illetve terápiamódosítás esetén beteg- és kórképspecifikus szempontokat mérlegelve kell kiválasztani az adott TKI-kezelést. Tekintettel a tartós kezelés mellett elérhető kiváló túlélési eredményekre, egyre gyakoribb azoknak a krónikus myeloid leukaemiás betegeknek a száma, akiknél változó súlyosságú nemkívánatos mellékhatások jelentkeznek, melyek miatt a betegek sokszor nem a hematológus szakorvosnál jelentkeznek. A leggyakrabban észlelt szövődmények ismertetését saját beteganyagunk részletes elemzése kapcsán a mindennapi klinikai gyakorlatban is bemutatjuk. Igen fontos, hogy a társszakmák (háziorvos, belgyógyász, kardiológus, angiológus, diabetológus, tüdőgyógyász, gasztroenterológus stb.) gyakorlói is tisztában legyenek az adott TKI-kezelés lehetséges mellékhatásaival, azok megelőzésével, időben történő felismerésével és hatékony kezelésével. Szakmai közreműködésük révén így segíthetik a klinikai hematológust a megfelelő terápia megtervezésében, valamint a betegek folyamatos kezelése kapcsán gyakran szükségessé váló szakmaspecifikus gondozásában is. Orv Hetil. 2021; 162(30): 1198–1207. Summary. Chronic myeloid leukemia is a rare clonal stem cell disorder. The pathological overproduction of the myeloid cell line is caused by abnormal function of a tyrosine kinase encoded by a fusion gene (BCR/ABL1) which is formed upon a reciprocal translocation of chromosomes 9 and 22. Long-term, often lifelong treatment with BCR/ABL1-specific tyrosine kinase inhibitors provides excellent disease control and overall survival rates close to the general survival of a healthy population in a significant proportion of patients. These patients require continuous oncohematological monitoring in accordance with the current diagnostic and treatment guidelines. However, undesirable side effects may occur that extend the treatment of the patients to a multidisciplinary approach involving a number of nonhematological specialities. Currently, five types of tyrosine kinase inhibitors are available in Hungary, with very different side effect profiles. At the start of treatment or in the event of a change in therapy, patient- and leukemia-specific assessments should be taken to select the most proper tyrosine kinase inhibitors treatment. Given the excellent survival outcomes achieved with long-term tyrosine kinase inhibitor treatment, there is an increasing number of patients who might experience adverse events of different kind or severity, which often results in patients ending up in different, nonhematological medical situations. The description of the most frequently observed complications in connection with a detailed cross-sectional analysis of our own patient cohort is also presented here resembling everyday clinical practice. It is very important that practitioners of other medical professions (general practitioner, internist, cardiologist, angiologist, diabetologist, pulmonologist, gastroenterologist, etc.) should be aware of the possible side effects of specific tyrosine kinase inhibitor therapies. They can help to assist the clinical hematologist in planning the appropriate tyrosine kinase inhibitor therapy as well as in professional caretaking of these patients. Orv Hetil. 2021; 162(30): 1198–1207.

Side effects of tyrosine kinase inhibitors (TKIs) on bone remodelling

2012 ◽  
Vol 224 (03) ◽  
Author(s):  
JT Tauer ◽  
A Ulmer ◽  
LC Hofbauer ◽  
M Suttorp
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Bone Remodelling

Cutaneous ulcers following hydroxyurea therapy

Phlebologie ◽  
2004 ◽  
Vol 33 (06) ◽  
pp. 202-205 ◽  
Author(s):  
K. Hartmann ◽  
S. Nagel ◽  
T. Erichsen ◽  
E. Rabe ◽  
K. H. Grips ◽  
...  
Keyword(s):  
Side Effects ◽  
Side Effect ◽  
Antineoplastic Agent ◽  
Limited Time ◽  
Myeloproliferative Diseases ◽  
Dermatological Side Effects ◽  
Chronic Myeloproliferative Diseases ◽  
Hydroxyurea Therapy

SummaryHydroxyurea (HU) is usually a well tolerated antineoplastic agent and is commonly used in the treatment of chronic myeloproliferative diseases. Dermatological side effects are frequently seen in patients receiving longterm HU therapy. Cutaneous ulcers have been reported occasionally.We report on four patients with cutaneous ulcers whilst on long-term hydroxyurea therapy for myeloproliferative diseases. In all patients we were able to reduce the dose, or stop HU altogether and their ulcers markedly improved. Our observations suggest that cutaneous ulcers should be considered as possible side effect of long-term HU therapy and healing of the ulcers can be achieved not only by cessation of the HU treatment, but also by reducing the dose of hydroxyurea for a limited time.

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