Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three patients with advanced renal-cell cancer were treated with sunitinib 50 mg daily for 4 weeks followed by a rest period of 2 weeks because of progressive disease. The first patient developed stomatitis and a painful blister on his foot. Complaints disappeared after temporary discontinuation of treatment. Re-treatment at a lower dosage was successful until disease progression. The second patient developed skin discolouration, fatigue, fever and diarrhoea. After treatment was interrupted shortly, these symptoms disappeared and sunitinib was recommenced at a lower dosage. The patient went on to develop stomatitis, thrombocytopenia and hypertension (treated with amlodipine). She subsequently had hand-foot syndrome. She died due to brain metastases. In the third patient symptoms of disease returned during the rest period, because of which he received a reduced dosage of sunitinib on a continuous base. He developed diarrhoea which disappeared after a short interruption of the drug. Sunitinib has been approved for the treatment of advanced renal-cell cancer and imatinib-resistant gastro-intestinal stromal tumours. This novel targeting molecule is a tyrosine-kinase inhibitor of vascular endothelial growth-factor receptors, platelet-derived growth-factor receptors and c-Kit. It can induce adverse events that differ from those observed in treatment with conventional cytotoxic agents. The adverse effects are reduced by lowering the dosage and in the rest period within the treatment cycle.
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PMID:[Adverse effects of the tyrosine-kinase inhibitor sunitinib, a new drug for the treatment of advanced renal-cell cancer]. 1755 72

Sorafenib is an orally available multikinase inhibitor active on vascular endothelial growth factor receptor-2 and -3, platelet-derived growth factor receptor-beta, B-RAF, C-RAF, flt3 and C-Kit. Phase I studies showed its activity on renal cell carcinoma (RCC) and other neoplasms and identified the schedule of 400 mg (two tablets) b.i.d. as better tolerated and potentially active. The original design selected for the principal phase II trial, randomization discontinuation trial, showed the particular activity profile of this drug: low objective response rates but significant increases in progression-free survival [PFS, which frequently translate in increased overall survival (OS)]. A pattern of response completely agrees with an antiangiogenic (cytostatic) agent. The potential efficacy of sorafenib was confirmed in immunotherapy-refractory advanced RCC cases by 'TARGETs', the largest randomized double-blind study ever carried out in kidney cancer. With a doubled PFS, a trend in OS and a modest toxicity profile, mainly grade 1-2 skin toxicity and diarrhea, sorafenib has been recently approved from the Food and Drug Administration and European Agency for the Evaluation of Medicinal Products for the second-line treatment of advanced RCC. Numerous trials are ongoing to test new schedules and drug combinations, while promising results were recently achieved also in hepatocellular carcinoma. With drugs such as sorafenib, angiogenesis could become an Achilles's heel for RCC.
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PMID:Protein kinase inhibitors in the treatment of renal cell carcinoma: sorafenib. 1759 26

Treatments for metastatic renal cell carcinoma (MRCC) are limited. RCCs frequently overexpress epithelial growth factor receptor and express c-Kit and platelet-derived growth factor receptor-beta. Combination of interferon with tyrosine kinase inhibitors of epithelial growth factor receptor [gefitinib (Iressa)] or c-Kit and platelet-derived growth factor receptor-beta [imatinib (Gleevec)] was evaluated for efficacy and safety. Patients with MRCC received 12-week cycles of interferon [3 million units (MU) subcutaneously thrice in week 1 and 6 MU thrice weekly thereafter] and either gefitinib (500 mg daily) or imatinib (600 mg daily). The gefitinib/imatinib dose was reduced as needed owing to toxicity. The primary endpoint was objective tumor response. Secondary endpoints were time to tumor progression, overall survival, and safety. Seventeen patients were enrolled. Most had clear cell [36% (6/17)] or papillary [36% (6/17)] tumors. Most (n=14) were treated on the gefitinib arm, including two patients who crossed over from the imatinib arm after experiencing disease progression. Objective tumor responses were evaluable in 14 patients (82%). Of these 14, partial responses occurred in three (21%), stable disease in seven (50%), and progressive disease in four (29%). The most frequent treatment-related adverse events were skin rash, flu-like symptoms, and fatigue (both treatment arms); diarrhea (gefitinib arm only); and thrombocytopenia and leukopenia (imatinib arm only). Median time to tumor progression (range) for patients on the gefitinib arm only was 4.27 (1.13-15.97) months and median overall survival (range) was 11.42+ (1.13-29.07+) months. Combination of gefitinib with interferon safely delays progression of refractory MRCC. Further studies in this setting are warranted.
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PMID:Interferon-alpha in combination with either imatinib (Gleevec) or gefitinib (Iressa) in metastatic renal cell carcinoma: a phase II trial. 1841 19

Receptor activated tyrosine kinases such as c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (Gleevec) and are expressed on AML blasts. Marrow stromal cells and monocytes express KIT ligand, M-CSF and PDGF and are therefore capable of activating survival pathways in these leukemic cells. Given the synergy in vitro between Ara-C and imatinib mesylate on AML cell growth inhibition, we initiated a Phase I study combining CLAG+imatinib mesylate in AML patients. Patients with relapsed, refractory AML or CML myeloid blast crisis were eligible to receive Cladribine 5mg/m(2) days 3-7, Cytarabine 2gm/m(2) days 3-7, G-CSF 300mcg days 2-7, and escalating doses of imatinib mesylate given on days 1-15. The level 1 Gleevec dose was 400mg, while level 2 was 600mg and the level 3 dose 800mg. A total of 16 patients were enrolled, 15 AML and 1 CML myeloid blast crisis. The dose escalation occurred as planned and there was no clear evidence of added toxicity due to imatinib mesylate. One patient with an extensive cardiac history died of cardiac causes on day 1 of therapy however no other deaths occurred within 30 days of starting therapy. One patient had a Grade 3 skin rash at dose level 2. The most common toxicities encountered during induction therapy were nausea, vomiting, rash and diarrhea that were transient and/or reversible. At the 800mg dose 1 patient developed a decline in cardiac ejection fraction on day 20 who later died of sepsis, so this was considered a dose limiting toxicity. Of 16 evaluable patients 11 achieved a hypocellular marrow after initial induction with 1 additional patient achieving a hypocellular marrow following a second course of the same regimen. Four patients (25%) achieved a complete morphologic response with normal cytogenetics, 2 patients (12.5%) achieved a complete morphologic response only and 1 patient had a complete response in the bone marrow but incomplete blood count recovery. The overall response rate was 43.8%. The median overall survival was 175 days (95% CI 16.24-333.76) and the median relapse free survival was 76 days. The addition of imatinib mesylate to CLAG was well tolerated with acceptable toxicities and response rates comparable to other salvage regimens. To assess the efficacy of imatinib mesylate in combination with CLAG, a larger phase II trial is now planned.
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PMID:Phase I study of cladribine, cytarabine (Ara-C), granulocyte colony stimulating factor (G-CSF) (CLAG Regimen) and simultaneous escalating doses of imatinib mesylate (Gleevec) in relapsed/refractory AML. 1857 21

Giardia lamblia is the most common protozoan isolated from the gastrointestinal tract. Giardiasis affects predominantly children and young adults, and its usual symptoms are abdominal pain, diarrhea, and malabsorption. Interestingly, the intestinal mucosa may appear unremarkable even in clinically severe giardiasis. In addition, the protozoan Giardia lamblia is notorious for its inconspicuous appearance in hematoxylin and eosin sections. Moreover, it can still be missed even with the use of special stains such as Giemsa or trichrome. In the present study, we investigated the immunoreactivity of Giardia lamblia to c-kit in duodenal mucosal biopsies. Giardia lamblia trophozoites were immunoreactive for c-kit in all of the study group cases (n = 14) and in none of the control group cases (n = 10). Thus, c-kit immunostain is a very sensitive method for the demonstration of Giardia lamblia. Moreover, the protozoan attains a conspicuous and unique appearance, whether it floats freely in the lumen between the duodenal villi, adheres to the mucosal surface, or is located in the cytoplasm of the epithelial cells. We recommend performing c-kit immunostain in every duodenal biopsy with clinical or pathologic suspicion of giardiasis.
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PMID:C-kit (CD117) immunostain is useful for the diagnosis of Giardia lamblia in duodenal biopsies. 1952 4

A 5-year-old female miniature dachshund presenting with persistent vomiting and diarrhea had two concurrent rare pathological conditions: systemic candidiasis and mesenteric mast cell tumor with multiorgan metastases. Neoplastic mast cells formed mass in the mesentery of the cecal-colonic region and were also found in the liver, spleen, kidneys, lungs, adrenal grands, ovaries, bone marrow and other tissues. The cells had intracytoplasmic granules with metachromasia and were immunohistochemically positive for c-kit and histamine. Granulomatous lesions with fungal organisms were present in the heart, lungs, kidneys, pancreas, subserosal and surrounding adipose tissue of the duodenum, thyroid glands and mesenteric mass, and phagocytosed organisms were detected in the liver and bone marrow. Bacteriologically and immunohistochemically, the fungi were consistent with Candida albicans.
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PMID:Systemic candidiasis and mesenteric mast cell tumor with multiple metastases in a dog. 1926 39

VEGFR and c-Kit signaling pathways may contribute to the pathophysiology of acute myeloid leukemia (AML). Thirty-five patients with AML received cediranib (RECENTIN), an oral, highly potent VEGF signaling inhibitor with c-Kit activity, at doses of < or =30 mg/day. The most common adverse events were diarrhea, hypertension and fatigue. Six patients experienced an objective response (3 each at 20 and 30 mg). Dose- and time-dependent reductions in sVEGFR-2 were observed, and there was a positive correlation between cediranib exposure and the change in plasma VEGF levels from baseline. Cediranib was generally well tolerated and showed preliminary evidence of activity as a monotherapy.
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PMID:An open-label, Phase I study of cediranib (RECENTIN) in patients with acute myeloid leukemia. 1967 89

Sunitinib is an oral multikinase inhibitor that blocks the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) alpha and beta, c-kit, and other receptors. These attributes have proven to be efficacious in the treatment of metastatic renal cell carcinoma (RCC) and unresectable gastrointestinal stromal tumors (GIST). Most side effects, including hypertension, hand-foot syndrome, and diarrhea are generally well manageable. Clinical trials are underway to determine the efficacy of sunitinib in other tumor types including metastatic breast, colorectal, and lung cancers. This chapter will detail the preclinical data leading to the results of the pivotal phase III clinical trials that have led to the widespread use of sunitinib in metastatic RCC and advanced GIST.
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PMID:Sunitinib. 2007 32

PURPOSE Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.
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PMID:Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. 2081 65

Mast cells (MCs) typically reside at barrier sites of the body, including the intestinal mucosa, and play a vital role in innate host defence. Activated MCs release a wide variety of bioactive mediators. These include preformed mediators stored in the granules (e.g. histamine and tryptase) and newly synthesised mediators (e.g. prostaglandins, leukotrienes and cytokines). MCs are present in all layers throughout the gastrointestinal (GI) tract and there is a close bi-directional connection between MCs and enteric nerves that is of vital importance in the regulation of GI functions. Some gain-of-function mutations in c-kit, encoding the tyrosine kinase- receptor for stem cell factor, are associated with the rare disease entity, systemic mastocytosis. These patients present symptoms arising from MC mediator release or infiltration. GI manifestations are common in this patient group, mainly abdominal pain and diarrhoea. Endoscopy with biopsies reveals MC infiltration in the mucosa. Other diagnostic tools include bone marrow biopsy and serum tryptase. Treatment is symptomatic with antihistamines or cromoglycate in mild cases, whereas severe cases need cytoreductive therapy that should be managed with expert haematologists. From a day-to-day clinical perspective, the important role of MCs in neuroimmune interaction has been implicated in the intestinal response to stress, in alterations of mucosal and neuromuscular function in irritable bowel syndrome or inflammatory bowel disease, and in the pathogenesis of non-erosive oesophageal reflux disease. Thus, MCs have important regulatory and protective roles in innate defence, in addition to being a potential mediator of mucosal pathophysiology in GI diseases. We need to learn how to balance the response of these volatile cells to be able to benefit from their versatility.
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PMID:Mast cells and mastocytosis. 2020 9


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