Effect of long term imatinib on bone in adults with chronic myelogenous leukemia and gastrointestinal stromal tumors

Berman, Ellin; Girotra, Monica; Cheng, Catherine; Chanel, Suzanne; Maki, Robert G.; Shelat, Meenakshi; Strauss, H. William; Fleisher, Martin; Heller, Glenn; Farooki, Azeez

doi:10.1016/j.leukres.2013.02.005

Cited by 27 publications

(20 citation statements)

References 27 publications

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“…In subsequent prospective investigation, imatinibtreated patients have also been confirmed to manifest a decrease in calcium levels with an associated increase in PTH levels (secondary hyperparathyroidism; O'Sullivan et al 2009). Another prospective investigation by our group has also shown secondary hyperparathyroidism by and large unrelated to vitamin D deficiency or chronic renal insufficiency (Berman et al 2013).…”

Section: Imatinibmentioning

confidence: 75%

“…Recent 2-year prospective BMD data has demonstrated that w50% of these patients develop decreases in BMD at the femoral neck and/or total hip, while maintaining stability at the lumbar spine; the distal radius was not evaluated (median duration of imatinib 31 months; range 1-71 months; Berman et al 2013). Similarly, another group has shown a site-specific decrease in BMD at the femoral neck 24 months after initiation of imatinib, albeit with an associated increase in trabecular bone volume (Vandyke et al 2012).…”

Section: Imatinibmentioning

confidence: 99%

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Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

Alemán¹,

Farooki²,

Girotra³

2014

Endocrine-Related Cancer

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Tyrosine kinase inhibitors (TKIs) are at the forefront of molecular-targeted therapies for cancer. With the advent of imatinib for the treatment of chronic myelogenous leukemia, a new wave of small-molecule therapeutics redefined the oncologic treatment to become chronically administered medications with tolerable side-effect profiles compared with cytotoxic agents. Effects on bone mineral metabolism were observed during early imatinib treatment, in the form of hypophosphatemia with increased urinary phosphorus excretion. This finding led to detailed investigations of off-target effects responsible for changes in bone cell maturation, activity, and impact on bone mass. Subsequently, another BCR-Abl inhibitor (dasatinib), vascular endothelial growth factor (VEGF) inhibitors (sorafenib and sunitinib) as well as rearranged during transfection (RET) inhibitors (vandetanib and cabozantinib) were developed. Inhibition of bone resorption appears to be a class effect and is likely contributed by TKI effects on the hematopoietic and mesenchymal stem cells. As long-term, prospective, clinical outcomes data accumulate on these targeted therapies, the full extent of off-target side effects on bone health will need to be considered along with the significant benefits of tyrosine kinase inhibition in oncologic treatment. Key Words" bone " calcium " metastasis " parathyroid hormone " tyrosine kinase inhibitor

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Section: Imatinibmentioning

confidence: 75%

Section: Imatinibmentioning

confidence: 99%

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

Alemán¹,

Farooki²,

Girotra³

2014

Endocrine-Related Cancer

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“…A recent clinical study has linked long-term treatment with ABL/ ARG kinase inhibitors to a reduction in the osteocalcin levels in cancer patients (20). This clinical finding may be related to mouse genetic studies showing that ABL kinase plays a role in bone morphogenetic protein (BMP) signaling to promote osteoblast expan-sion and differentiation (21,22).…”

Section: Patient Tolerance Of Abl/arg Kinase Inhibitorsmentioning

confidence: 96%

The Capable ABL: What Is Its Biological Function?

Wang

2014

Molecular and Cellular Biology

163

175

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The mammalian ABL1 gene encodes the ubiquitously expressed nonreceptor tyrosine kinase ABL. In response to growth factors, cytokines, cell adhesion, DNA damage, oxidative stress, and other signals, ABL is activated to stimulate cell proliferation or differentiation, survival or death, retraction, or migration. ABL also regulates specialized functions such as antigen receptor signaling in lymphocytes, synapse formation in neurons, and bacterial adhesion to intestinal epithelial cells. Although discovered as the proto-oncogene from which the Abelson leukemia virus derived its Gag-v-Abl oncogene, recent results have linked ABL kinase activation to neuronal degeneration. This body of knowledge on ABL seems confusing because it does not fit the one-geneone-function paradigm. Without question, ABL capabilities are encoded by its gene sequence and that molecular blueprint designs this kinase to be regulated by subcellular location-dependent interactions with inhibitors and substrate activators. Furthermore, ABL shuttles between the nucleus and the cytoplasm where it binds DNA and actin-two biopolymers with fundamental roles in almost all biological processes. Taken together, the cumulated results from analyses of ABL structure-function, ABL mutant mouse phenotypes, and ABL substrates suggest that this tyrosine kinase does not have its own agenda but that, instead, it has evolved to serve a variety of tissue-specific and context-dependent biological functions.

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“…De ezt a csökkenést a csontépítő osteoblastsejtek aktivitása nem követte és az erre vonatkozó klinikai megfigyelések egymásnak ellentmondóak voltak [11][12][13][14]. A tirozinkináz-gátlókkal kezelt betegeknél hypophosphataemia [5,9,12,13,15,16], hypocalcaemia [12,13,15,16], valamint hyperparathyreosis [12,13,15,16] lépett fel.…”

Section: A Két Tirozinkináz-gátló Csontanyagcserét éRintő Humán Klinunclassified

Az onkohematológiai betegségek kezelésében használt tirozinkináz-gátló imatinib és nilotinib csonthatásainak irodalmi áttekintése és a saját kutatási eredmények bemutatása

et al. 2016

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A tirozinkináz-gátlók bizonyos onkohematológiai betegségek kezelésében elterjedten használt gyógyszerek. Több klinikai tanulmány igazolta, hogy a BCR-ABL specifikus tirozinkináz-gátlók alkalmazása komplex és még nem egyértelműen azonosított módon változtatja meg a csontszövet élettani folyamatait. Mivel a kezelések egyre több beteget érintenek, illetve hosszú évtizedekig vagy akár élethosszig is tarthatnak, indokolt ezen mechanizmusok molekuláris hátterének részletesebb megismerése. A szerzők összefoglalják az imatinibbel és a nilotinibbel végzett, csontanyagcseréhez kapcsolódó alapkutatási eredményeket, humán klinikai megfigyeléseket, kiegészítve in vitro osteo blast-sejtkultúrákon végzett saját kísérleteik eredményeivel. Az összefoglalt kutatási eredmények alapján az imatinib és a nilotinib csontsejtekre gyakorolt hatása függ az alkalmazott hatóanyag-koncentrációtól, a sejtek érettségi állapotától, illetve az általuk kötött receptor-tirozinkináz útvonalak megoszlási arányától. Jelen közleményben első-ként készítettek a hazai szakirodalomban hiánypótló, átfogó irodalmi áttekintést a tirozinkináz-gátlók csontanyagcserét befolyásoló hatásaival kapcsolatban és végeztek teljes transzkriptom-analízist osteoblastokon a sejtszintű hatás-mechanizmus jobb megértését szolgálva. Orv. Hetil., 2016, 157(36), 1429-1437. Kulcsszavak: imatinib, nilotinib, osteoblast, osteoclast Literature review and presentation of our own research results regarding the effects on bone of tyrosine kinase inhibitors imatinib and nilotinib used in the treatment of oncohematological diseasesTyrosine kinase inhibitors are widely used for treatment of certain oncohematological diseases. Several clinical studies have confirmed that specific BCR-ABL tyrosine kinase inhibitors alter the physiological process of bone tissue in a complex and unclearly identified manner. Since these treatments are being given to more and more patients, and the therapy takes decades or lasts even lifelong, it is justifiable to obtain more detailed knowledge of the molecular background of these mechanisms. In this article the authors summarize preliminary research results and human clinical observations on imatinib and nilotinib which are related to bone metabolism, and present the results of their own experiments in in vitro osteoblast cultures. Based on the presented results, the effects of imatinib and nilotinib on bone cells depend on the concentration of imatinib and nilotinib, the maturation stage of the cells and the distribution ratio of receptor tyrosine kinase signaling pathways. In this study the authors firstly prepared a stop-gap, com-DOI: 10.1556/650.2016.30525 *A szerzők egyenlő arányban vettek részt a kézirat megírásában.

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Effect of long term imatinib on bone in adults with chronic myelogenous leukemia and gastrointestinal stromal tumors

Cited by 27 publications

References 27 publications

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

The Capable ABL: What Is Its Biological Function?

Az onkohematológiai betegségek kezelésében használt tirozinkináz-gátló imatinib és nilotinib csonthatásainak irodalmi áttekintése és a saját kutatási eredmények bemutatása

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