β-链接素、诱导型一氧化氮合酶与环氧合酶-２在鼻咽癌中的表达及临床意义

目的　观察β 链接素（β-ｃａｔ）、诱导型一氧化氮合酶（ｉＮＯＳ）和环氧合酶 ２（ＣＯＸ-２）在鼻咽癌（ＮＰＣ）中的表达情况,探讨三者的表达及其联合表达在ＮＰＣ发生、发展、侵袭和转移过程中的可能作用。方法　采用免疫组织化学染色法观察５０例ＮＰＣ石蜡标本和１５例正常鼻咽组织中β-ｃａｔ、ｉＮＯＳ和ＣＯＸ-２的蛋白表达情况。结果　正常鼻咽组织中ｉＮＯＳ、ＣＯＸ-２未见表达,而β-ｃａｔ胞膜表达。ＮＰＣ中,所有病例β-ｃａｔ胞质均呈阳性表达,与正常组比较,差异有统计学意义（χ^２＝２４.２０７,Ｐ＝０.０００）。β-ｃａｔ胞膜表达明显降低,与正常黏膜组比较,差异有统计学意义（χ^２ ＝２４.２６５,Ｐ＝０.０００）;ｉＮＯＳ表达阳性３７例（χ^２＝２５.３７１,Ｐ＝０.０００）,ＣＯＸ-２表达阳性３３例（χ^２＝２０.１０９,Ｐ＝０.０００）,与正常组比较,差异有统计学意义。胞质内β-ｃａｔ、ｉＮＯＳ、ＣＯＸ-２的表达在不同临床分期及有无淋巴结转移之间差异有统计学意义。三者胞质的表达强度均呈正相关（Ｐ＜０.０１）。结论　胞质内β-ｃａｔ、ｉＮＯＳ和ＣＯＸ-２的过度表达与ＮＰＣ的发生、发展、浸润和转移相关;胞质内β-ｃａｔ、ｉＮＯＳ与ＣＯＸ-２的表达强度呈正相关,能同时针对三者起作用的化疗药物具有更好的抗瘤效应或放疗增敏效应。     

TRAF1在鼻咽癌及癌旁组织中的表达

目的：研究鼻咽癌组织ＥＢ病毒ＬＭＰ１与ＴＲＡＦ１（ｔｕｍｏｒ ｎｅｃｒｏｓｉｓ ｆａｃｔｏｒ ｒｅｃｅｐｔｏｒ－ａｓｓｏｃｉａｔｅｄ ｆａｃｔｏｒ１）表达的关系,以探讨ＬＭＰ１可能促进ＴＲＡＦ１表达的作用。方法：应用ＬＭＰ１和ＴＲＡＦ１抗体对３０例鼻咽癌和１２例慢性炎症鼻咽粘膜石蜡标本,以ＳＰ免疫组织化学技术检测ＬＭＰ１及ＴＲＡＦ１的表达。结果：３０例鼻咽癌中１６例是ＬＭＰ１阳性（５３．３％）,     

鼻咽癌组织中FHIT基因异常表达的研究

目的：检测正常鼻咽上皮和鼻咽癌组织中ＦＨＩＴ基因的异常表达,探讨ＦＨＩＴ基因与鼻咽癌发病的关系。方法：采用巢式ＲＴ－ＰＣＲ（ｎｅｓｔｅｄ ＲＴ－ＰＣＲ）技术对２８例鼻咽癌组织和１０例正常鼻咽上皮组织进行ＦＨＩＴ基因检测,并随机选择２例异常者进行ＤＮＡ测序分析。结果：１０例正常鼻咽上皮组织未发现ＦＨＩＴ转录本异常,１２例（４２．９％）鼻咽癌组织存在ＦＨＩＴ异常转录本。２例经测序分析发现其中１例缺失外     

鼻咽癌ＫＤＲ受体信号传导相关蛋白的表达及意义*

目的　分析鼻咽癌组织中ＫＤＲ及其下游信号分子ＰＫＣ-β和ｐ-ＥＲＫ的表达,并探讨上述蛋白表达与鼻咽癌患者临床特征和生存期的关系。方法　免疫组织化学法检测１１０例鼻咽癌和３０例鼻咽良性病变石蜡切片中ＫＤＲ、ＰＫＣ-β和ｐ-ＥＲＫ的表达情况,用Ｓｐｅａｒｍａｎ法分析它们之间的相关性,Ｋａｐｌａｎ-Ｍｅｉｅｒ法计算生存情况,行Ｌｏｇ-ｒａｎｋ检验和Ｃｏｘ比例风险模型分析。结果　鼻咽癌组织中ＫＤＲ、ＰＫＣ-β和ｐ-ＥＲＫ阳性表达率分别为８８.２％（９７／１１０）、６３.６％（７０／１１０）和５１.８％（５７／１１０）,而在鼻咽良性病变阳性表达率低。鼻咽癌组织中ＫＤＲ表达与ＰＫＣ-β及ｐ-ＥＲＫ表达呈正相关（ｒ＝０.２９７,Ｐ＝０.００２;ｒ＝０.３３６,Ｐ＜０.００１）,ＰＫＣ β表达与ｐ ＥＲＫ表达呈正相关（ｒ＝０.３０１,Ｐ＝０.００１）。ＫＤＲ和ｐ-ＥＲＫ表达与原发肿瘤的侵犯范围相关（Ｐ＜００５）;ＰＫＣ β和ｐ ＥＲＫ表达与临床分期相关（Ｐ＜０.０５）;ＫＤＲ和ＰＫＣ-β表达与肿瘤局部复发或远处转移相关（Ｐ＜０.０５）。３种蛋白表达均与总生存不佳相关（Ｐ＜０.０５）。Ｃｏｘ多因素相关分析显示年龄＞５０岁为不良预后因素（Ｐ＜０.０５）。结论　ＫＤＲ及其下游信号分子ＰＫＣ-β和ｐ-ＥＲＫ在鼻咽癌中表达,与鼻咽癌患者的临床特征和预后关系密切。     

鼻咽癌组织中CAⅨ和APE表达及其临床意义

背景与目的：鼻咽癌治疗首选放射治疗,其疗效与临床分期的早晚明显相关。因此采用新的技术和方法以进一步提高早期诊断率,进而提高疗效一直是鼻咽癌临床研究的重要课题。本研究通过分析碳酸酐酶Ⅸ（CAⅨ）蛋白和无嘌呤/无嘧啶内切核酸酶（apurinic/apyrimidinic endonuclase,APE）表达与鼻咽癌患者临床特征的关系,探讨其在鼻咽癌诊断和治疗中的价值。方法：应用免疫组织化学法检测54例鼻咽癌和20例鼻咽慢性炎性组织中CAⅨ蛋白和APE蛋白的表达,并对10例鼻咽癌患者放疗前和放疗期间组织中CAⅨ蛋白和APE表达水平进行动态检测。结果：鼻咽癌组织中CAⅨ的阳性表达率显著高于鼻咽慢性炎性组织（P〈0.01）;CAⅨ阳性表达与患者的性别、年龄、T分期、有无颈淋巴结转移和临床分期均无相关性（P〉0.05）。鼻咽癌组织中APE的细胞核阳性表达率高于鼻咽慢性炎性组织,其差异具有统计学意义（P〈0.05）;APE阳性表达与患者的性别、年龄、T分期、有无颈淋巴结转移和临床分期均无关（P〉0.05）。放疗后获得肿瘤局部控制的患者,其放疗期间CAⅨ阳性表达率显著低于放疗前（P〈0.05）。鼻咽癌中CAⅨ和APE的阳性表达未见相关性（r=-0.028,P〉0.05）。结论：CAⅨ的高表达和APE细胞核内高表达可能在鼻咽癌的发生、发展中起重要作用。     

免疫组化法检测鼻咽病变组织中PCNA和P53的意义

本文报道采用免疫组化ＡＢＣ法检测了８０例鼻咽活检组织的ＰＣＮＡ和Ｐ５３蛋白表达情况，结果显示：（１）ＰＣＮＡ和Ｐ５３表达的阳性率在鼻咽癌分别为９４．２％和８４．６％，异型性改变为７０．０％和２８．８％，单纯性增生为３．９％和阴性，正常上皮均为阴性；（２）ＰＣＮＡ和Ｐ５３表达的细胞阳性强度和阳性细胞数量与鼻咽癌的组织类型无关，但ＰＣＮＡ和Ｐ５３表达的细胞阳性强度及Ｐ５３表面的阳性细胞数量与肿瘤的间变     

E-cadherin和p16基因蛋白在鼻咽癌中的表达及意义

目的：探讨Ｅ－钙粘素（Ｅ－ｃａｄｈｅｒｉｎ）和p１６基因与鼻咽癌发生发展的关系。 方法：采用免疫组化方法检测７４例鼻咽癌组织和２０例炎性鼻咽部组织中Ｅ－ｃａｄｈｅｒｉｎ和p１６基因蛋白的表达。结果：炎性组织Ｅ－ｃａｄｈｅｒｉｎ和p１６显著高于鼻咽癌组织（Ｐ〈０．０５）；Ｅ－ｃａｄｈｅｉｎ和p１６保留表达与临床分期、病灶大小 无关（Ｐ〉０．０５），但在颈淋巴结转移组显著低于无颈淋巴结转移组（Ｐ〈０．０５）     

鼻咽癌发生发展过程中EBER1表达的研究

目的：探讨ＥＢＶ与鼻咽癌发生发展的关系及其病理学意义。方法：应用原位杂交技术检测５０例鼻咽癌石蜡切片组织中ＥＢＥＲ１的表达及分布状况。结果：正常鼻咽粘膜上皮及其单纯性增生、鳞状化生上皮ＥＢＥＲ１表达均阴性,鼻咽癌组织中表达率为９８％（４９／５０）,且在转移灶中不丢失。鼻咽异型增生上皮亦可表达ＥＢＥＲ１阳性信号（１６／２０）,结论：ＥＢＶ与鼻咽癌关系密切,ＥＢＶ可能在鼻咽上皮的恶性转化过程中起重要作用,鼻咽上皮的异型性改变尤其是ＥＢＥＲ１阳性者可认为是癌前病变,随访监测可能有利于早期发现鼻咽癌。     

Livin与Smac在鼻咽癌组织中的表达及临床意义

目的：探讨凋亡抑制因子Livin和凋亡促进因子Smac在鼻咽癌组织的表达及相关性,分析其与鼻咽癌转移复发的关系。方法：应用免疫组织化学SP法检测80例鼻咽癌组织和鼻咽慢性炎组织中Livin和Smac蛋白的表达情况。结果：80例鼻咽癌组织中Livin蛋白表达的阳性率显著高于鼻咽慢性炎组织（P=0.000）,癌组织中Smac表达的阳性率显著低于鼻咽慢性炎组织（P=0.000）。鼻咽癌组织中Livin的表达与颈淋巴结转移、远处转移、复发及临床分期密切相关（P〈0.05）;Smac的表达与T分期、颈淋巴结转移、远处转移、复发及临床分期密切相关（P〈0.05）。Livin和Smac的表达呈显著负相关（γ=-0.368,P=0.001）。结论：Livin的高表达及Smac的失活可能在鼻咽癌的发生及进展中起着重要作用。     

鼻咽癌组织中bcl—2蛋白和增殖细胞核抗原的表达及意义

应用免疫组化ＳＰ法研究４１例鼻咽癌组织中ｂｃｌ－２蛋白和增殖细胞核抗原（ＰＣＮＡ）的表达及意义。结果显示ｂｃｌ－２蛋白在鼻咽癌中出现异常高表达（阳性率为８２．９％），ｂｃｌ－２表达与组织学分级及颈淋巴结转移无显著性关系（Ｐ＞０．０５）；ＰＣＮＡ表达随肿瘤分级升高而增高，且与淋巴结转移有关。结果表明ｂｃｌ－２基因对鼻咽上皮的良恶性诊断具有重要的参考价值，ＰＣＮＡ可作为鼻咽癌恶性程度及预后判定的指标之一，同时发现ｂｃｌ－２蛋白与ＰＣＮＡ表达间无相关。     

Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: a phase II clinical trial

BACKGROUND: Imatinib inhibits the c-kit tyrosine kinase, which, accounts for its activity in gastrointestinal stromal tumors. The presence of c-kit protein expression in small cell lung carcinoma (SCLC) tumor specimens, as well as in vitro data supporting the role of c-kit in autocrine and paracrine growth stimulation specifically in SCLC, provided a rationale for studying imatinib in this disease. The authors conducted a Phase II single-institution study of imatinib in patients with recurrent SCLC whose tumor specimens expressed c-kit protein. METHODS: Patients with progressive SCLC after one or two previous chemotherapy regimens consented to have their tumor specimens screened by immunoperoxidase stain (CD117, Dako Corporation, Carpinteria, CA) for c-kit protein expression. If present, individuals were then eligible for treatment with an imatinib dose of 400 mg orally twice daily (total, 800 mg per day). RESULTS: The presence of c-kit protein was assessable in 36 of 39 (92%) tumor samples. Twenty-eight (78%) tumor samples had immunohistochemical staining for c-kit protein. Twelve patients were enrolled in the treatment portion of the current study. No responses were observed, and all patients had disease progression by Week 4. Edema, fatigue, nausea, and electrolyte abnormalities were the primary toxicities. CONCLUSIONS: Imatinib did not have antitumor activity against SCLC, even with c-kit protein present in tumor specimens. The dismal prognosis for these patients with progressive SCLC emphasized the urgent need for continued studies of new therapies in this population.     

Pharmacokinetic and clinical phase II trial of imatinib in patients with impaired liver function and advanced hepatocellular carcinoma

OBJECTIVES: No effective chemotherapy for advanced hepatocellular carcinoma (HCC) exists. Expression of the platelet-derived growth factor receptor (PDGFR) has been demonstrated in HCC, which may derive from hepatic stem cells that express c-kit. The aim of this trial was to evaluate imatinib, a tyrosine kinase inhibitor of PDGFR and c-kit, in patients with advanced HCC and impaired liver function. PATIENTS AND METHODS: Patients were treated with 400-600 mg imatinib daily. Immunohistochemical staining was performed for PDGFR and c-kit. Response was assessed by CT scans every 8 weeks. For pharmacokinetics studies, 74 plasma samples were assessed. RESULTS: Of the 17 patients enrolled in the study, 15 were evaluable for response. Only 1 tumor was positive for PDGFR and none was positive for c-kit. Grade 3/4 neutropenia occurred in 2 patients (1 had neutropenic fever). There was no objective response, and 5 (33%) patients had stable disease. Median time to treatment failure was 1.8 months in the whole study cohort and 3.7 months in the patients with stable disease. Patients treated with 400 mg imatinib did not significantly differ in pharmacokinetics from patients with chronic myelogenous leukemia (CML). CONCLUSION: In this small group of patients with advanced, mostly PDGFR- and c-kit-negative HCC, imatinib showed no therapeutic effect. In contrast to CML patients, the pharmacokinetics of imatinib were not significantly affected by impaired liver function.     

Imatinib mesylate in patients with adenoid cystic cancers of the salivary glands expressing c-kit: a Princess Margaret Hospital phase II consortium study.

PURPOSE: This study aimed to assess the antitumor activity of imatinib in adenoid cystic carcinoma (ACC) of the salivary gland expressing c-kit. A high level of c-kit expression has been identified in more than 90% of ACCs. Imatinib specifically inhibits autophosphorylation of the bcr-abl, platelet-derived growth factor receptor beta, and c-kit tyrosine kinases. PATIENTS AND METHODS: In a single-arm, two-stage, phase II clinical trial, adult patients with unresectable or metastatic ACC measurable by Response Evaluation Criteria in Solid Tumors Group criteria and expressing c-kit by immunohistochemistry were treated with imatinib 400 mg orally bid. Response was assessed every 8 weeks. RESULTS: Sixteen patients have been enrolled onto the study; 10 were female. Median age was 47 years (range, 31 to 69 years). Median Eastern Cooperative Oncology Group performance status was 1 (range, 0 to 2). Fourteen patients had lung metastases, 14 had prior radiotherapy, and six had prior chemotherapy. Toxicities occurring in at least 50% of patients included fatigue, nausea, vomiting, diarrhea, anorexia, edema, dyspnea, and/or headache, usually of mild to moderate severity. In 15 patients assessable for response, no objective responses have been observed. Nine patients had stable disease as best response. Six patients had progressive disease after two cycles. CONCLUSION: Because of the lack of activity, the study has been stopped after the first stage and additional evaluation of imatinib in this population is not warranted. Overexpression of wild-type c-kit was not sufficient for clinical benefit from imatinib in ACC. Accrual to this study was rapid for a relatively rare cancer, encouraging additional efforts to identify more effective systemic therapy for these patients.     

Down-regulation of MMP-2 expression due to inhibition of receptor tyrosine kinases by imatinib and carboplatin in HNSCC

Squamous cell carcinoma of the head and neck (HNSCC) is the most common neoplasm arising in the upper aerodigestive tract. Unfortunately, the survival for this type of cancer has not improved significantly in the past 25 years. To enhance the survival rate multimodal therapy regimens have been set up. In these regimens chemotherapy plays a pivotal role in the majority of advanced cases. Transmembrane protein- tyrosine kinases (PTK) are fundamental elements of the signal transduction. In consequence, they might be promising targets for cancer therapy. Imatinib (STI 571) was originally designed to inhibit the BCR-ABL tyrosine kinase in chronic myeloid leukemia. But imatinib also has an inhibitory impact on the PTK receptor c-kit and on its PTK activity. Furthermore, growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM). The ECM is altered by matrix metalloproteinases (MMP). In this study, we incubated different HNSCC cell lines with rising concentrations of imatinib and/or carboplatin. After an incubation time of up to 10 days, we evaluated c-kit, MMP-2 and MMP-14 by ELISA techniques and immunohistochemical methods. Especially the combination of 7.5 μmol carboplatin with 30 μmol imatinib resulted in a significant decrease in MMP-2 expression in all observed cell lines (p<0.05). We did not demonstrate a significant alteration in c-kit expression by imatinib and carboplatin. We observed an increase in apoptosis in HNSCC cells by the combination of the two observed chemotherapeutic drugs. In all cell lines tested, expression of c-kit and MMP could be demonstrated. Our results indicate that MMP-2 expression was suppressed in the presence of imatinib. Thus, imatinib may exert in part its inhibitory effect on malignant cell growth via the blockage of the signal transduction of PTK receptors. Further studies are warranted, especially one keeping in mind the moderate toxicity of imatinib.     

Effects of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, on human mast cells bearing wild-type or mutated codon 816 c-kit

Most adults with systemic mastocytosis (SM) carry an activating mutation in the codon 816 of c-kit. We investigated the activity of the new tyrosine kinase inhibitor AMN107 on c-kit mutated mast cell lines and bone marrow samples from patients with SM and compared it to that of imatinib mesylate, a tyrosine kinase inhibitor effective in some patients with SM. In HMC-1(560) mast cells carrying wild-type codon 816 c-kit, AMN107 was very effective and as potent as imatinib in inhibiting cellular proliferation and inducing apoptosis (P<0.0823). By contrast, in HMC-1(560,816) cells bearing a c-kit mutation in codon 816, neither drug exerted a significant effect (P<0.0015). AMN107 was also as effective as imatinib in inhibiting phosphorylation of c-kit in HMC-1(560) cells. However, AMN107 had little effect on ex vivo survival of bone marrow mast cells with 816 c-kit mutation obtained from patients with SM. Based upon our results, AMN107 and imatinib are equipotent against mast cells with wild-type c-kit and those harboring the juxtamembrane D560G c-kit mutant but have no significant activity over the dose range tested against cells expressing the c-kit D816V mutant tyrosine kinase.     

CD117 (c-kit) expression in human hepatocellular carcinoma

AimsAlthough various methods of treatment have been tried, treatment options for advanced hepatocellular carcinoma (HCC) remain limited. Expression of the platelet-derived growth factor has been shown in HCC, which may derive from hepatic stem cells that express the c-kit proto-oncogene. Because of the promising results of imatinib and the key role played by c-kit in gastrointestinal stromal tumours and other solid tumours, the aim of this study was to determine the prevalence of c-kit (CD117) overexpression in patients with HCC.Materials and methodsA retrospective study of 258 archival specimens of subjects with histologically confirmed HCC was carried out. Expression of the c-kit proto-oncogene was evaluated by immunohistochemistry using rabbit anti-CD117 antibody A4502.ResultsThe overall percentage of positive immunohistochemical staining of HCCs was 2.3% (6/258).ConclusionsOur results suggest that CD117 is not significantly overexpressed in HCC and there seems to be no role for the use of imatinib.     

Imatinib mesylate inhibits Leydig cell tumor growth: evidence for in vitro and in vivo activity

Leydig cell tumors are usually benign tumors of the male gonad. However, if the tumor is malignant, no effective treatments are currently available. Leydig cell tumors express platelet-derived growth factor (PDGF), kit ligand and their respective receptors, PDGFR and c-kit. We therefore evaluated the effects of imatinib mesylate (imatinib), a selective inhibitor of the c-kit and PDGFR tyrosine kinases, on the growth of rodent Leydig tumor cell lines in vivo and in vitro, and examined, in human Leydig cell tumor samples, the expression of activated PDGFR and c-kit and the mutations in exons of the c-kit gene commonly associated with solid tumors. Imatinib caused concentration-dependent decreases in the viability of Leydig tumor cell lines, which coincided with apoptosis and inhibition of proliferation and ligand-stimulated phosphorylation of c-kit and PDGFRs. Mice bearing s.c. allografts of a Leydig tumor cell line treated with imatinib p.o., had an almost complete inhibition of tumor growth, less tumor cell proliferation, increased apoptosis, and a lesser amount of tumor-associated mean vessel density compared with controls. No drug-resistant tumors appeared during imatinib treatment but tumors regrew after drug withdrawal. Human Leydig cell tumors showed an intense expression of the phosphorylated form of c-kit and a less intense expression of phosphorylated PDGFRs. No activating mutations in common regions of mutation of the c-kit gene were found. Our studies suggest that Leydig cell tumors might be a potential target for imatinib therapy.     

Lack of clinical efficacy of imatinib in metastatic melanoma

This two-centre phase-II trial aimed at investigating the efficacy of imatinib in metastasised melanoma patients in correlation to the tumour expression profile of the imatinib targets c-kit and platelet-derived growth factor receptor (PDGF-R). The primary study end point was objective response according to RECIST, secondary end points were safety, overall and progression-free survival. In all, 18 patients with treatment-refractory advanced melanoma received imatinib 800 mg day(-1). In 16 evaluable patients no objective responses could be observed. The median overall survival was 3.9 months, the median time to progression was 1.9 months. Tumour biopsy specimens were obtained from 12 patients prior to imatinib therapy and analysed for c-kit, PDGF-Ralpha and -Rbeta expression by immunohistochemistry. In four cases, cell lines established from these tumour specimens were tested for the antiproliferative effects of imatinib and for functional mutations of genes encoding the imatinib target molecules. The tumour specimens stained positive for CD117/c-kit in nine out of 12 cases (75%), for PDGF-Ralpha in seven out of 12 cases (58%) and for PDGF-Rbeta in eight out of 12 cases (67%). The melanoma cell lines showed a heterogenous expression of the imatinib target molecules without functional mutations in the corresponding amino-acid sequences. In vitro imatinib treatment of the cell lines showed no antiproliferative effect. In conclusion, this study did not reveal an efficacy of imatinib in advanced metastatic melanoma, regardless of the expression pattern of the imatinib target molecules c-kit and PDGF-R.     

Potential use of imatinib in Ewing's Sarcoma: evidence for in vitro and in vivo activity

BACKGROUND: Ewing's sarcoma cells express c-kit, a receptor tyrosine kinase, and its ligand, stem cell factor (SCF), creating a potential autocrine loop that may promote tumor survival. We thus examined whether the specific tyrosine kinase inhibitor imatinib mesylate (hereafter imatinib; formerly STI571) could inhibit the proliferation of Ewing's sarcoma cells in vitro and in vivo. METHODS: The effect of imatinib on c-kit expression and phosphorylation in Ewing's sarcoma cells was examined by immunoblotting. The effect of imatinib on cell growth and apoptosis was examined with an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay and with a morphologic test and Annexin V staining, respectively. The effect of imatinib oral therapy (every 12 hours for 5-7 days) on primary tumor growth was assessed in Ewing's sarcoma xenografts in SCID/bg mice (5 or 10 mice per group). RESULTS: All Ewing's sarcoma cell lines tested were sensitive to imatinib-mediated apoptosis with a concentration inhibiting growth by 50% (IC50) of 10-12 micro M. Imatinib inhibited SCF-mediated c-kit phosphorylation (IC50 = 0.1-0.5 microM). In the xenograft model, imatinib treatment resulted in the regression or control of primary Ewing's sarcomas. After 6 days of treatment, the mean lower extremity volume including xenograft tumor was 3744 mm3 (95% confidence interval [CI] = 3050 to 4437 mm3), 1442 mm3 (95% CI = 931 to 1758 mm3), and 346 mm3 (95% CI = 131 to 622 mm3) in mice treated with carrier alone or with imatinib at 50 mg/kg or at 100 mg/kg, respectively. CONCLUSIONS: Imatinib interferes with growth of all Ewing's sarcoma cell lines tested in vitro and in vivo. Targeted inhibition of tyrosine kinase-dependent autocrine loops, therefore, may be a viable therapeutic strategy for Ewing's sarcoma.     

Phase II trial of imatinib mesylate in patients with metastatic melanoma

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.