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Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation.Oncogene Jul 2019Inhibitors of Vascular Endothelial Growth Factor target both tumor vasculature and cancer cells that have hijacked VEGF Receptors (VEGFRs) signaling for tumor...
Inhibitors of Vascular Endothelial Growth Factor target both tumor vasculature and cancer cells that have hijacked VEGF Receptors (VEGFRs) signaling for tumor growth-promoting activities. It is important to get precise insight in the specificity of cell responses to these antiangiogenic drugs to maximize their efficiency and minimize off-target systemic toxicity. Here we report that Axitinib, an inhibitor of VEGFRs currently in use as a second line treatment for advanced renal cell carcinoma, promotes senescence of human endothelial cells in vitro. A one-hour pulse of Axitinib is sufficient for triggering cell senescence. Mechanistically, this requires oxidative stress-dependent activation of the Ataxia Telangiectasia Mutated (ATM) kinase. Axitinib-mediated senescence promoting action is prevented by short-term treatment with antioxidants or ATM inhibitors, which conversely fail to prevent senescence induced by the DNA-damaging drug doxorubicin. Coherently, induction of oxidative stress-related genes distinguishes the response of endothelial cells to Axitinib from that to doxorubicin. Importantly, an Axitinib pulse causes cell senescence in glioblastoma cells. However, neither antioxidants nor ATM inhibitors can reverse this phenotype. Thus, antioxidants may selectively protect endothelial cells from Axitinib by decreasing systemic toxicity and maintaining a functional vascularization necessary for efficient delivery of chemotherapeutic drugs within the tumor mass.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antioxidants; Ataxia Telangiectasia Mutated Proteins; Axitinib; Cellular Senescence; Endothelial Cells; Enzyme Activation; Human Umbilical Vein Endothelial Cells; Humans; Neovascularization, Pathologic; Protein Kinase Inhibitors; Reactive Oxygen Species
PubMed: 30967634
DOI: 10.1038/s41388-019-0798-2 -
Drugs of Today (Barcelona, Spain : 1998) Oct 2012Axitinib is a small-molecule protein-tyrosine kinase receptor inhibitor specifically targeting this family of receptors, in addition to platelet-derived growth factor... (Review)
Review
Axitinib is a small-molecule protein-tyrosine kinase receptor inhibitor specifically targeting this family of receptors, in addition to platelet-derived growth factor receptor and proto-oncogene c-Kit. Improved knowledge of kidney cancer development, and specifically mutations in the VHL gene, has supported the targeting of angiogenesis pathways. Axitinib is the most recently approved agent for use in metastatic renal cell carcinoma. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical activity of this agent, and describe its place in the current treatment of renal cell carcinoma.
Topics: Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Mas
PubMed: 23110259
DOI: 10.1358/dot.2012.48.10.1860768 -
Clinical Genitourinary Cancer Aug 2022There are known correlations between axitinib exposure and treatment response. The aim of the article was to study relationships between the axitinib steady-state trough...
INTRODUCTION
There are known correlations between axitinib exposure and treatment response. The aim of the article was to study relationships between the axitinib steady-state trough concentration and the treatment efficacy and toxicity.
PATIENTS AND METHODS
35 patients (24 men and 11 women), treated or initiating treatment with axitinib, were included in the study over the period 2016-2019. Blood samples were collected following 2 weeks of treatment (in patients who initiated the therapy) and at the end of Cycles 1, 2, and 3 thereafter (in the entire study population). For concentration measurements, high-performance liquid chromatography - mass spectrometry (HPLC-MS) was applied. Treatment efficacy was assessed according to the RECIST 1.1 criteria. Therapy toxicity was evaluated according to the CTCAE criteria.
RESULTS
A statistically significant relationship between the first measured axitinib trough concentration (C) value and treatment response (P = .004) as well as the median progression-free survival (mPFS) (P = .003) was observed. The association between axitinib C and the median overall survival (mOS) was not statistically significant (P = .142). A statistically significant relationship was observed between the mean trough concentration from 3-month observation (C) and treatment response (P = .008) as well as mPFS (P = .001), without a significant relationship for mOS (P = .097). At least grade 3 adverse reactions were meaningfully associated with C (P = .012) and C (P = .003).
CONCLUSION
There are significant relationships between axitinib C and treatment response, PFS, and grade ≥ 3 toxicity. The data collected may be used to determine indications for axitinib therapy monitoring based on C measurements.
Topics: Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Progression-Free Survival; Treatment Outcome
PubMed: 35428585
DOI: 10.1016/j.clgc.2022.03.006 -
Scientific Reports May 2023To investigate the therapeutic effects of axitinib, a tyrosine kinase inhibitor, in an interstitial cystitis (IC) rat model. IC patients with or without Hunner lesion...
To investigate the therapeutic effects of axitinib, a tyrosine kinase inhibitor, in an interstitial cystitis (IC) rat model. IC patients with or without Hunner lesion and non-IC controls were enrolled (n = 5/group). Bladder tissues were stained with vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR-2), platelet-derived growth factor (PDGF), and PDGF receptor B (PDGFR-B). The IC group showed extensive VEGFR-2 and PDGFR-B staining compared with controls. Next, ten-week-old female Sprague Dawley rats were divided into three groups (n = 10/group): sham, hydrochloride (HCl), and axitinib groups. One week after HCl instillation (day 0), the axitinib group received oral axitinib (1 mg/kg) for five consecutive days and pain was evaluated daily. Bladder function, histology and genetics were evaluated on day 7. The pain threshold significantly improved 3 days after axitinib administration. Axitinib decreased non-voiding contraction and increased the micturition interval and micturition volume and alleviated urothelial denudation, angiogenesis, mast cell infiltration, and fibrosis. HCl instillation increased the expression of tyrosine kinase receptors, including VEGFR-2 and PDGFR-B; axitinib administration inhibited their expression. Oral administration of axitinib improved pain, voiding profiles, and urothelial integrity by inhibiting angiogenesis in IC rat model. Axitinib may have potential therapeutic efficacy in IC patients.
Topics: Female; Animals; Rats; Rats, Sprague-Dawley; Axitinib; Cystitis, Interstitial; Tyrosine Kinase Inhibitors; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor A; Protein Kinase Inhibitors; Hydrochloric Acid; Pain
PubMed: 37221266
DOI: 10.1038/s41598-023-35178-5 -
Chinese Clinical Oncology Oct 2019
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Female; Humans; Male; Neoplasm Metastasis
PubMed: 31280574
DOI: 10.21037/cco.2019.04.05 -
Radiation Oncology (London, England) Jan 2021To investigate maximum tolerated dose (MTD) of axitinib, a selective vascular endothelial growth factor receptor 1-3 inhibitor, in combination with radiotherapy (RT) for...
BACKGROUND
To investigate maximum tolerated dose (MTD) of axitinib, a selective vascular endothelial growth factor receptor 1-3 inhibitor, in combination with radiotherapy (RT) for advanced hepatocellular carcinoma (HCC).
METHODS
This phase I study followed the rule of traditional 3 + 3 design. Major eligibility included: (1) patients with advanced HCC unsuitable for surgery, radiofrequency ablation or transarterial chemoembolization, or who failed after prior local-regional treatment; (2) failure on sorafenib or no grant for sorafenib from health insurance system. Eligible patients with advanced HCC received axitinib for total 8 weeks during and after RT. Three cohorts with axitinib dose escalation were planned: 1 mg twice daily (level I), 2 mg twice daily (level II) and 3 mg twice daily (level III). The prescribed doses of RT ranged from 37.5 to 67.5 Gy in 15 fractions to liver tumor(s) and were determined based on an upper limit of mean liver dose of 18 Gy (intended isotoxic RT for normal liver). The primary endpoint was MTD of axitinib in combination with RT. The secondary endpoints included overall response rate (ORR), RT in-field response rate, acute and late toxicities, overall survival (OS) and progression free survival (PFS).
RESULTS
Total nine eligible patients received axitinib dose levels of 1 mg twice daily (n = 3), 2 mg twice daily (n = 3) and 3 mg twice daily (n = 3). Dose-limiting toxicity (DLT) did not occur in the 3 cohorts; the MTD was defined as 3 mg twice daily in this study. ORR was 66.7%, including 3 complete responses and 3 partial responses, at 3 months after treatment initiation. With a median follow-up of 16.6 months, median OS was not reached, 1-year OS was 66.7%, and median PFS was 7.4 months.
CONCLUSIONS
Axitinib in combination with RT for advanced HCC was well tolerated with an axitinib MTD of 3 mg twice daily in this study. The outcome analysis should be interpreted with caution due to the small total cohort. Trial registration ClinicalTrials.gov (Identifier: NCT02814461), Registered June 27, 2016-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02814461.
Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Axitinib; Carcinoma, Hepatocellular; Combined Modality Therapy; Female; Humans; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged
PubMed: 33472666
DOI: 10.1186/s13014-020-01742-w -
CNS Neuroscience & Therapeutics Mar 2022Dysfunction of the blood-brain barrier (BBB) is a prominent pathological feature of glioblastoma (GBM). Vascular endothelial growth factor (VEGF) is confirmed to be...
AIMS
Dysfunction of the blood-brain barrier (BBB) is a prominent pathological feature of glioblastoma (GBM). Vascular endothelial growth factor (VEGF) is confirmed to be abnormally elevated in the pathogenesis of GBM, causing BBB pathological disruption, which further allows the leakage of neurotoxic blood-derived molecules into the central nervous system (CNS), interfering brain homeostasis and leading to poor patient outcome. Since BBB is an integral and pivotal part of the brain microenvironment, which strongly supports the occurrence and the pathological progression of GBM, here we have selected the VEGFR antagonist axitinib as a BBB functional regulator and hypothesized to regulate pathological BBB restoration for GBM effective treatment.
METHODS
The pathological BBB cell model was constructed to investigate the timeliness and dose effect of axitinib regulating pathological BBB restoration. In order to investigate the efficacy and safety of axitinib regulating pathological BBB restoration for anti-GBM treatment, the orthotropic GBM-bearing mice model was established for in vivo study, and bioluminescent imaging was used to real-time and noninvasively monitor tumor growth response in vivo, and survival time was also recorded.
RESULTS
Axitinib under non-cytotoxic dosage regulated pathological BBB restoration in a time-dependent mode, and multiple intervention of axitinib could realize a visible restoration of pathological BBB in vitro. Moreover, axitinib treatment restored pathological BBB in orthotropic GBM-bearing mice. We further confirmed that functional restoration of pathological BBB with axitinib had certain curative effect in prolonging median survival of orthotropic GBM-bearing mice at non-cytotoxic dosages in vivo.
CONCLUSION
The mechanism of axitinib involved in BBB functional regulation in the treatment of GBM is first illuminated in this report; moreover, this is the first report first referring to regulating pathological BBB functional recovery for GBM effective therapeutics. Overall, the view of regulating pathological BBB functional recovery may offer a novel sight for other CNS diseases relating to BBB permeability effective therapeutics.
Topics: Animals; Axitinib; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Mice; Tumor Microenvironment; Vascular Endothelial Growth Factor A
PubMed: 34967104
DOI: 10.1111/cns.13788 -
Oral Surgery, Oral Medicine, Oral... Nov 2017Tyrosine kinase inhibitors (TKIs) are oral chemotherapy drugs used primarily to treat leukemias, renal cell carcinomas, gastrointestinal stromal tumors, and...
Tyrosine kinase inhibitors (TKIs) are oral chemotherapy drugs used primarily to treat leukemias, renal cell carcinomas, gastrointestinal stromal tumors, and neuroendocrine tumors. Within this group, a number of drugs have already been implicated in jaw necrosis. Axitinib (Inlyta) is a novel TKI currently licensed for the treatment of renal cell carcinoma. We report the first case, to our knowledge, of jaw necrosis solely related to this medication and review the literature surrounding TKIs and their implication in osteonecrosis of the jaw.
Topics: Aged; Axitinib; Carcinoma, Renal Cell; Conservative Treatment; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Male; Maxillary Diseases; Osteonecrosis; Protein Kinase Inhibitors; Radiography, Panoramic
PubMed: 28918879
DOI: 10.1016/j.oooo.2017.08.003 -
Immunotherapy Nov 2022We report the case of a patient with metastatic renal cell carcinoma who developed Takotsubo syndrome (TTS) 6 days after starting pembrolizumab plus axitinib as... (Review)
Review
We report the case of a patient with metastatic renal cell carcinoma who developed Takotsubo syndrome (TTS) 6 days after starting pembrolizumab plus axitinib as first-line treatment. Coronary angiogram was negative for obstructive coronary artery disease and echocardiogram revealed a depressed left ventricular ejection fraction with apical akinesis. Axitinib was discontinued and myocardial contractile function fully recovered 23 days after the initial presentation. The treatment was safely resumed and granted a partial response of disease. A literature review regarding TTS in patients receiving VEGFR tyrosine kinase inhibitors and/or immune checkpoint inhibitors was performed. TTS is reported as a rare adverse event and the possible causal relationship between TTS and antineoplastic therapy is still unclear. Further research is warranted to better understand cardiotoxicity mechanisms and their management.
Topics: Humans; Axitinib; Carcinoma, Renal Cell; Takotsubo Cardiomyopathy; Stroke Volume; Kidney Neoplasms; Ventricular Function, Left
PubMed: 36408614
DOI: 10.2217/imt-2022-0013 -
Prescrire International Nov 2013In patients with advanced-stage or metastatic kidney cancer, interferon alfa, a cytokine, prolongs survival by about 4 months, and sunitinib, a tyrosine kinase...
In patients with advanced-stage or metastatic kidney cancer, interferon alfa, a cytokine, prolongs survival by about 4 months, and sunitinib, a tyrosine kinase inhibitor, by about 9 months. When interferon alfa fails, sorafenib, another tyrosine kinase inhibitor, appears to prolong survival by an additional 3 months. There is currently no treatment that prolongs survival after failure of sunitinib.
Topics: Axitinib; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors
PubMed: 24427834
DOI: No ID Found