• Title, Summary, Keyword: tyrosine kinase inhibitor

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Management of Severe Fatigue Induced by Tyrosine Kinase Inhibitor in Radioiodine Refractory Thyroid Cancer (방사성요오드 불응성 갑상선암에서 티로신키나아제 억제제 투여로 유발된 중증 피로감의 관리)

  • Ahn, Byeong-Cheol
    • International journal of thyroidology
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    • v.11 no.2
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    • pp.75-77
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    • 2018
  • Tyrosine kinase inhibitor is known to prolong progression free survival in radioiodine refractory thyroid cancer patients. Fatigue/asthenia/malaise is one of most common adverse events by the tyrosine kinase inhibitor treatment, and management of the adverse event is important to keep the drug medication longer which is essential for the survival benefit. In the case report, a radioiodine refractory thyroid cancer patient receiving tyrosine kinase inhibitor experienced severe fatigue, and a pathologic fracture of right humerus occurred by slipping down which was tightly linked with the adverse event of the drug. The pathologic fracture was surgically well managed and the adverse event was well controlled by supportive managements combined with dose reduction of the tyrosine kinase inhibitor. The drug administration to the patient was kept more than 1 year without progression of the disease.

Mechanisms of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance and Strategies to Overcome Resistance in Lung Adenocarcinoma

  • Chang, Yoon Soo;Choi, Chang-Min;Lee, Jae Cheol
    • Tuberculosis and Respiratory Diseases
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    • v.79 no.4
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    • pp.248-256
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    • 2016
  • Somatic mutations that lead to hyperactivation of epidermal growth factor receptor (EGFR) signaling are detected in approximately 50% of lung adenocarcinoma in people from the Far East population and tyrosine kinase inhibitors are now the standard first line treatment for advanced disease. They have led to a doubling of progression-free survival and an increase in overall survival by more than 2 years. However, emergence of resistant clones has become the primary cause for treatment failure, and has created a new challenge in the daily management of patients with EGFR mutations. Identification of mechanisms leading to inhibitor resistance has led to new therapeutic modalities, some of which have now been adapted for patients with unsuccessful tyrosine kinase inhibitor treatment. In this review, we describe mechanisms of tyrosine kinase inhibitor resistance and the available strategies to overcoming resistance.

Management of Bleeding Induced by Tyrosine Kinase Inhibitor in Radioiodine Refractory Thyroid Cancer (방사성요오드 불응성 갑상선암에서 티로신키나아제 억제제 투여로 유발된 출혈 이상 반응 관리)

  • Shin, Dong Yeob
    • International journal of thyroidology
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    • v.11 no.2
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    • pp.71-74
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    • 2018
  • Adverse events such as hemoptysis and gastrointestinal hemorrhage during tyrosine kinase inhibitor treatment are relatively rare, but the severity of the bleeding can be higher than other common adverse events. It is necessary to educate patients about its possibility so that they can be found early. In this case report of radioiodine refractory thyroid cancer patient, hemoptysis and gastrointestinal bleeding has occurred following lenvatinib administration. Drug interruption and dose modification and dose interruption were required in addition to management for bleeding itself. It is necessary to confirm the high risk of bleeding before the administration of tyrosine kinase inhibitors, and to appropriately control the follow-up interval and drug dosage accordingly.

Regulation of $Ca_v3.2Ca^{2+}$ Channel Activity by Protein Tyrosine Phosphorylation

  • Huh, Sung-Un;Kang, Ho-Won;Park, Jin-Yong;Lee, Jung-Ha
    • Journal of Microbiology and Biotechnology
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    • v.18 no.2
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    • pp.365-368
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    • 2008
  • Calcium entry through $Ca_v3.2Ca^{2+}$ channels plays essential roles for various physiological events including thalamic oscillation, muscle contraction, hormone secretion, and sperm acrosomal reaction. In this study, we examined how protein tyrosine phosphatases or protein tyrosine kinases affect $Ca_v3.2Ca^{2+}$ channels reconstituted in Xenopus oocytes. We found that $Ca_v3.2$ channel activity was reduced by 25% in response to phenylarsine oxide (tyrosine phosphatase inhibitor), whereas it was augmented by 19% in response to Tyr A47 or herbimycin A (tyrosine kinase inhibitors). However, other biophysical properties of $Ca_v3.2$ currents were not significantly changed by the drugs. These results imply that $Ca_v3.2$ channel activity is capable of being increased by activation of tyrosine phosphatases, but is decreased by activation of tyrosine kinases.

Tyrosine Kinase is Involved in Hemin-Induced Pyresis

  • Lee, Sang-Ho;Jang, Choon-Gon;Lee, Seok-Yong
    • Archives of Pharmacal Research
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    • v.26 no.5
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    • pp.411-415
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    • 2003
  • To investigate the mechanisms involved in hemin-induced febrile response, the rectal temperature of rats were measured after intracerebroventricular (i.c.v.) injections of hemin, with or without antagonists. Hemin ($10\mu\textrm{g}$) elicited a significant febrile response, which lasted from 30 min, to more than 6 h, after its administration, but this was not the case with biliverdin (i.c.v.) and bilirubin (i.c.v.). The hemin-induced febrile response was significantly inhibited by pretreatment with an inhibitor of tyrosine kinase (genistein), but not by pretreatment with an inhibitor of protein kinase C (chelerythrine) and a scavenger of iron (deferoxamine). These results suggest that tyrosine kinase is involved in the hemin-induced febrile response.

Screening on Receptor Tyrosine Kinase Inhibitory Activity of Marine Algae-Derived Symbiotic Microorganisms (해조류 공생미생물의 Receptor Tyrosine Kinase 억제효능 검색)

  • Yun, Keum-Ja;Yang, Guohua;Feng, Zhile;Nenkep, Viviane N.;Xavier, Siwe-Noundou;Leutou, Alain S.;Kim, Gun-Do;Cho, Hee-Yeong;Choi, Hong-Dae;Son, Byeng-Wha
    • Korean Journal of Pharmacognosy
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    • v.41 no.1
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    • pp.43-47
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    • 2010
  • In order to screen new receptor tyrosine kinase inhibitor which is expected to be anticancer drug lead, we have investigated receptor tyrosine kinase inhibitory activity on the marine alga-derived symbiotic microorganisms (500 strains). The significant activities (over 70% inhibition at $10\;{\mu}g/ml$) were observed in the extracts of ten strains (Strain No.: MFA018, 019, 206, 242, 325, 335, 343, 344, 354, 356), isolated from marine red algae, five strains (Strain No.: MFA030, 126, 213, 324, 339), isolated from the brown algae, and one strain (Strain No.: MFA272), isolated from the marine green algae, respectively. Among the active strains, MFA019 and 356 showed strong receptor tyrosine kinase inhibitory activity with $IC_{50}$ values of 0.6 and $0.9\;{\mu}g/ml$, respectively.

Involvement of Src Family Tyrosine Kinase in Apoptosis of Human Neutrophils Induced by Protozoan Parasite Entamoeba histolytica

  • Sim, Seo-Bo;Yu, Jae-Ran;Lee, Young-Ah;Shin, Myeong-Heon
    • The Korean Journal of Parasitology
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    • v.48 no.4
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    • pp.285-290
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    • 2010
  • Tyrosine kinases are one of the most important regulators for intracellular signal transduction related to inflammatory responses. However, there are no reports describing the effects of tyrosine kinases on neutrophil apoptosis induced by Entamoeba histolytica, In this study, isolated human neutrophils from peripheral blood were incubated with live trophozoites in the presence or absence of tyrosine kinase inhibitors. Entamoeba-induced receptor shedding of CD16 and PS externalization in neutrophils were inhibited by pre-incubation of neutrophils with the broad-spectrum tyrosine kinase inhibitor genistein or the Src family kinase inhibitor PP2. Entamoeba-induced ROS production was also inhibited by genistein or PP2, Moreover, genistein and PP2 blocked the phosphorylation of ERK and p38 MAPK in neutrophils induced by E. histolytica. These results suggest that Src tyrosine kinases may participate in the signaling event for ROS-dependent activation of MAPKs during neutrophil apoptosis induced by E. histolytica.

Crystal Structures of Spleen Tyrosine Kinase in Complex with Two Novel 4-Aminopyrido[4,3-d] Pyrimidine Derivative Inhibitors

  • Lee, Sang Jae;Choi, Jang-Sik;Bong, Seoung Min;Hwang, Hae-Jun;Lee, Jaesang;Song, Ho-Juhn;Lee, Jaekyoo;Kim, Jung-Ho;Koh, Jong Sung;Lee, Byung Il
    • Molecules and Cells
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    • v.41 no.6
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    • pp.545-552
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    • 2018
  • Spleen tyrosine kinase (SYK) is a cytosolic non-receptor protein tyrosine kinase. Because SYK mediates key receptor signaling pathways involving the B cell receptor and Fc receptors, SYK is an attractive target for autoimmune disease and cancer treatments. To date, representative oral SYK inhibitors, including fostamatinib (R406 or R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659, have been assessed in clinical trials. Here, we report the crystal structures of SYK in complex with two newly developed inhibitors possessing 4-aminopyrido[4,3-D]pyrimidine moieties (SKI-G-618 and SKI-O-85). One SYK inhibitor (SKI-G-618) exhibited moderate inhibitory activity against SYK, whereas the other inhibitor (SKI-O-85) exhibited a low inhibitory profile against SYK. Binding mode analysis indicates that a highly potent SYK inhibitor might be developed by modifying and optimizing the functional groups that interact with Leu377, Gly378, and Val385 in the G-loop and the nearby region in SYK. In agreement with our structural analysis, one of our SYK inhibitor (SKI-G-618) shows strong inhibitory activities on the ${\beta}$-hexosaminidase release and phosphorylation of SYK/Vav in RBL-2H3 cells. Taken together, our findings have important implications for the design of high affinity SYK inhibitors.

Effects of Protein Kinase Inhibitors on Melanin Production in B16 Melanoma Cells Stimulated via Cyclic AMP-dependent Pathway (B16 Melanoma 세포에서 Protein Kinase 억제제들이 Cyclic AMP 경로를 통한 멜라닌 생성에 미치는 영향)

  • 차상복;조남영;윤미연;임혜원;김경원;박영미;이지윤;이진희;김창종
    • YAKHAK HOEJI
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    • v.47 no.1
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    • pp.31-36
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    • 2003
  • To investigate the effect of protein kinase on melanin production via cAMP-dependent pathway, we measured the melanin amount and tyrosinase activity in B16 melanoma cells stimulated by alpha-melanocyte stimulating hormone (MSH), forskolin and 8-Br-cAMP. MSH, forskolin and 8-Br-cAMP significantly increased both melanin production and tyrosinase activity in B16 cells. Melanin production and tyrosinase activity by MSH are significantly inhibited by cyclic AMP-dependent protein kinase inhibitor (KT5720) and protein kinase C down-regulation treated with PMA. Bisindolmaleimide (1$\mu$M), protein kinase C inhibitor, significantly inhibited melanin production and tyrosinase activity stimulated by MSH, forskolin and 8-Br-cAMP with the following order of potency: MSH>forskolin>8-Br-cAMP. Tyrosine kinase inhibitor, genistein and DHC, significantly inhibited both, but the inhibitory effect was more potent in 8-Br-cAMP-stimulated B16 cells than MSH-stimulated cells. NFkB inhibitor (parthenolide) significantly inhibited melanin production and tyrosinase activity. Neither melanin production nor tyrosinase activity induced by MSH, forskolin and 8-Br-cAMP were affected by KN-62 (calmodulin-dependent protein kinase II inhibitor), PD098059 (mitogen-activated protein kinase inhibitor, MAPKK) and worthmannin (phosphatidylinositol 3-kinase inhibitor). These results suggest that both protein kinase C and tyrosine kinase are involved in melanin production by cyclic AMP-dependent pathway and NFkB pathway may play an important role in cyclic AMP-dependent melanin production in B16 melanoma cells.

The Involvement of Protein Kinase C and Tyrosine Kinase in Vanadate-induced Contraction

  • Sim, Sang-Soo;Kim, Chang-Jong
    • Archives of Pharmacal Research
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    • v.21 no.3
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    • pp.315-319
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    • 1998
  • Gastric smooth muscle of cats was used to investigate the involvement of protein kinase in vanadate-induced contraction. Vanadate caused a contraction of cat gastric smooth muscle in a dose-dependent manner. Vanadate-induced contraction was totally inhibited by 2 mM EGTA and 1.5 mM $LACI_3$ and significantly inhibited by $10\mu$M verapamil and $1\mu$M nifedipine, suggesting that vanadate-induced contraction is dependent on the extracellular $Ca^{2+}$ concentration, and the influx of extracellular $Ca^{2+}$ was mediated through voltage-dependent $Ca^{2+}$ channel. Both protein kinase C inhibitor and tyrosine kinase inhibitor significantly inhibited the vanadate-induced contraction and the combined inhibitory effect of two protein kinase inhibitors was greater than that of each one. But calmodulin antagonists did not have any influence on the vanadate-induced contraction. On the other hand, both forskolin ($1\mu$M) and sodium nitroprusside ($1\mu$M) significantly inhibited vanadate-induced contraction. Therefore, these results suggest that both protein kinase C and tyrosino kinase are involved in the vanadate-induced contraction which required the influx of extracellular $Ca^{2+}$ in cat gastric smooth muscle, and that the contractile mechanism of vanadate may be different from that of agonist binding to its specific receptor.

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