scholarly journals Sorafenib therapy decreases the clearance of thyrotropin

2013 ◽  
Vol 168 (2) ◽  
pp. 163-167 ◽  
Author(s):  
Herman Verloop ◽  
Johannes W A Smit ◽  
Olaf M Dekkers
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Standard Dose ◽  
Thyroid Tissue ◽  
Area Under The Curve ◽  
Differentiated Thyroid Carcinoma ◽  
Sorafenib Treatment ◽  
Sorafenib Therapy ◽  
Before And After

ObjectiveThyroid function abnormalities are common during treatment with tyrosine kinase inhibitors such as sorafenib. Suggested causes are direct effects on thyroid tissue and increased extrathyroidal metabolism of serum thyroxine and 3,5,3-triiodothyronine. We postulated that tyrosine kinase inhibitors may affect the peripheral metabolism of TSH as well. The effect of sorafenib on TSH clearance was studied.DesignIn a study of athyreotic patients on TSH suppression therapy, TSH concentrations were measured after recombinant human TSH (rhTSH) injections before and after 26 weeks of sorafenib therapy.MethodsBefore and after the last week of sorafenib therapy, 20 patients with progressive differentiated thyroid carcinoma received a standard dose regimen of two injections 0.9 mg rhTSH on two consecutive days. TSH concentrations were measured 48 h (TSH48 h) and 96 h (TSH96 h) after the first rhTSH injection. The area under the curve (TSH-AUC), reflecting TSH content between 48 and 96 h following rhTSH administration, was calculated.ResultsTSH48 h levels (120.5 mU/l before vs 146.3 mU/l after; P=0.029), TSH96 h levels (22.0 mU/l before vs 35.5 mU/l after; P=0.001), and TSH-AUC (142.7 vs 186.8 mU/l; P=0.001) were significantly higher after sorafenib treatment. Higher sorafenib doses were associated with increased changes in TSH96 h and TSH-AUC. In two patients, TSH levels after sorafenib therapy exceeded 200 mU/l.ConclusionsSorafenib therapy is accompanied by higher rhTSH levels, probably due to a decreased TSH clearance. Further studies are recommended to clarify whether a decreased clearance of TSH is sorafenib specific.

scholarly journals Questions and Controversies in the Clinical Application of Tyrosine Kinase Inhibitors to Treat Patients with Radioiodine-Refractory Differentiated Thyroid Carcinoma: Expert Perspectives

2021 ◽  
Vol 53 (03) ◽  
pp. 149-160
Author(s):  
Frederik A. Verburg ◽  
Holger Amthauer ◽  
Ina Binse ◽  
Ingo Brink ◽  
Andreas Buck ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Performance Status ◽  
Progression Free Survival ◽  
Placebo Treatment ◽  
Differentiated Thyroid Carcinoma ◽  
Future Research ◽  
Prospective Comparison

AbstractNotwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.

scholarly journals FLT3 tyrosine kinase inhibitors synergize with BCL-2 inhibition to eliminate FLT3/ITD acute leukemia cells through BIM activation

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ruiqi Zhu ◽  
Li Li ◽  
Bao Nguyen ◽  
Jaesung Seo ◽  
Min Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Selective Inhibitor ◽  
Leukemia Cells ◽  
Sorafenib Treatment ◽  
Limited Success ◽  
Pathway Inhibition

AbstractTyrosine kinase inhibitors (TKIs) targeting FLT3 have shown activity but when used alone have achieved limited success in clinical trials, suggesting the need for combination with other drugs. We investigated the combination of FLT3 TKIs (Gilteritinib or Sorafenib), with Venetoclax, a BCL-2 selective inhibitor (BCL-2i), on FLT3/ITD leukemia cells. The combination of a FLT3 TKI and a BCL-2i synergistically reduced cell proliferation and enhanced apoptosis/cell death in FLT3/ITD cell lines and primary AML samples. Venetoclax also re-sensitized FLT3 TKI-resistant cells to Gilteritinib or Sorafenib treatment, mediated through MAPK pathway inhibition. Gilteritinib treatment alone dissociated BIM from MCL-1 but increased the binding of BIM to BCL-2. Venetoclax treatment enhanced the binding of BIM to MCL-1 but dissociated BIM from BCL-2. Treatment with the drugs together resulted in dissociation of BIM from both BCL-2 and MCL-1, with an increased binding of BIM to the cell death mediator BAX, leading to increased apoptosis. These findings suggest that Venetoclax mitigates the unintended pro-survival effects of FLT3 TKI mainly through the dissociation of BIM and BCL-2 and also decreased BIM expression. This study provides evidence that the addition of BCL-2i enhances the effect of FLT3 TKI therapy in FLT3/ITD AML treatment.

scholarly journals Tyrosine-kinase inhibitors to treat radioiodine-refracted, metastatic, or recurred and progressive differentiated thyroid carcinoma [Review]

2016 ◽  
Vol 63 (7) ◽  
pp. 597-602 ◽  
Author(s):  
Yasuhiro Ito ◽  
Shinichi Suzuki ◽  
Ken-ichi Ito ◽  
Tsuneo Imai ◽  
Takahiro Okamoto ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Differentiated Thyroid Carcinoma

scholarly journals Adaptation of human iPSC-derived cardiomyocytes to tyrosine kinase inhibitors reduces acute cardiotoxicity via metabolic reprogramming

2018 ◽  
Author(s):  
Huan Wang ◽  
Robert P. Sheehan ◽  
Adam C. Palmer ◽  
Robert A. Everley ◽  
Sarah A. Boswell ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Aerobic Glycolysis ◽  
Cardiac Metabolism ◽  
Metabolic Reprogramming ◽  
Negative Consequences ◽  
Adaptive Responses ◽  
Sorafenib Treatment ◽  
Human Cardiomyocytes

SUMMARYTyrosine kinase inhibitors (TKIs) are widely used to treat solid tumors but can be cardiotoxic. The molecular basis for this toxicity and its relationship to therapeutic mechanisms remain unclear; we therefore undertook a systems-level analysis of human cardiomyocytes exposed to four TKIs. Cardiomyocytes (CMs) differentiated from human induced pluripotent stem cells (hiPSCs) were exposed to sunitinib, sorafenib, lapatinib or erlotinib and responses assessed by functional assays, microscopy, RNA sequencing and mass spectrometry (GEO GSE114686; PRIDE PXD012043). TKIs have diverse effects on hiPSC-CMs distinct from inhibition of tyrosine-kinase mediated signal transduction; cardiac metabolism is particularly sensitive. Following Sorafenib treatment, oxidative phosphorylation is down-regulated, resulting in a profound defect in mitochondrial energetics. Cells adapt by upregulating aerobic glycolysis. Adaptation makes cells less acutely sensitive to Sorafenib, but may have long-term negative consequences. Thus, cardiomyocytes exhibit adaptive responses to anti-cancer drugs conceptually similar to those previously shown in tumors to mediate drug resistance.

Tyrosine kinase inhibitors in differentiated thyroid carcinoma: a review of the clinical evidence

2011 ◽  
Vol 1 (2) ◽  
pp. 241-253 ◽  
Author(s):  
Hendrieke C Hoftijzer ◽  
Ellen Kapiteijn ◽  
Tatiana Schneider ◽  
Guido C Hovens ◽  
Hans Morreau ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Clinical Evidence ◽  
Kinase Inhibitors ◽  
Differentiated Thyroid Carcinoma

Effects of Tyrosine Kinase Inhibitors On Spermatogenesis and Pituitary Gonadal Axis in Males with Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1688-1688 ◽  
Author(s):  
Mohamed A. Yassin ◽  
Ashraf T Soliman ◽  
Ahmed S Elawa ◽  
Hanadi Rafii El-Ayoubi ◽  
Vincenzo Desanctis
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Sperm Count ◽  
Myelogenous Leukemia ◽  
Sperm Parameters ◽  
Semen Parameters ◽  
Normal Morphology ◽  
Before And After

Abstract Abstract 1688 Objective: The introduction of several classes of targeted therapeutics for the treatment of chronic myelogenous leukemia (CML) raises the question of whether male fertility is affected and the degree of this affection, if any, among the different generations of tyrosine kinase inhibitors. When two drugs are equally effective, the drug with less toxic effect on fertility is favorable. Our aims were to evaluate semen parameters and pituitary gonadal function before and 4 months after starting tyrosine kinase inhibitors (TKI) namely, Dasatinib, Nilotinib, and Imatinib in patients with CML. Design: Prospective study. Setting, Patients, Interventions: We studied the effect of TKIs' first generation (Imatinib) and second generation ( Dasatinib and nilotinib) on semen parameters, endocrine functions in 20 euogonadal male patients with CML, and capacity to ejaculate, aged from 35 to 51 years. They were receiving either Imatinib, Dasatinib or Nilotinib as upfront therapy. We studied gonadotrophins (LH and FSH) and testosterone (T) secretion and evaluated sperm parameters before and after four months of using these TKIs. Main Outcome Measures and Results: Four months after starting TKIs there were significant decreases in serum testosterone, LH, FSH concentrations. The total sperm count, total and rapid progressive sperm motility, and % sperms with normal morphology decreased significantly versus before treatment. (table 1). After 4 months of therapy, Dasatinib effects on sperm count (SC), volume(SV), all sperm motilities and % of sperms with normal morphology(%NM) were significantly less harmful compared to Imatinib and Nilotinib. (Table 2). Significant correlations were found between serum T concentrations and semen parameters before and after TKIs therapy including SC ( r = 0.658 and r = 0.73 respectively, p < 0.001), rapid progressive motility (r = 0.675 and r = 0.758 respectively p < 0.001), and the % NM(r = 0.752 and r = 0.834 respectively, p < 0.001). After TKIs therapy, LH were correlated significantly with T concentrations ( r = 0.434, p < 0.001) and SV and SC (r = 0.439 and r = 0.376 respectively, p: 0.01). Conclusion: Our study suggests that in patients with CML TKIs are associated with significant decrease of sperm parameters and decreased concentrations of serum T, LH, FSH. These potentially toxic effects on spermatogenesis are less prominent in patients treated with Dasatinib compared to Imatinib and Nilotinib. The mechanisms and pathways for these effects need further human and/or experimental studies. Disclosures: Yassin: Hamad medical corporation MRC: Employment, Research Funding. Soliman:Hamad medical corporation MRC: Employment, Research Funding. Elawa:Hamad medical corporation MRC: Employment, Research Funding.

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