新型酪氨酸激酶抑制剂研究进展

20世纪末,小分子酪氨酸激酶抑制剂伊马替尼（IM）的研制成功使慢性粒细胞白血病（CML）的治疗迈出了革命性一步。然而,随着时问的推移和临床应用范围的扩大,其耐药现象也逐渐凸现,尤其在CML加速期和急变期病例,已成为影响IM疗效的新问题,这就促使了新型酪氨酸激酶抑制剂的问世。     

表皮生长因子受体酪氨酸激酶抑制剂的研究进展

表皮生长因子受体（epidermal growth factor receptor，EGFR）在细胞的信号转导、细胞增殖和分化中发挥着重要的作用，对多种肿瘤的发生和发展也具有重要影响，抑制该受体活性可以有效抑制肿瘤的生长。以此为靶点的抗肿瘤药物的开发，在多种肿瘤治疗中取得了令人鼓舞的疗效。     

表皮生长因子受体酪氨酸激酶抑制剂的研究进展

表皮生长因子受体(epidermal growth factor receptor,EGFR)在细胞的信号转导、细胞增殖和分化中发挥着重要的作用,对多种肿瘤的发生和发展也具有重要影响,抑制该受体活性可以有效抑制肿瘤的生长。以此为靶点的抗肿瘤药物的开发,在多种肿瘤治疗中取得了令人鼓舞的疗效。     

大肠癌组织c-Met和VEGF表达及其与微血管密度关系的初步研究

目的:探讨大肠癌组织c-Met和血管内皮生长因子(VEGF)的表达以及两者与肿瘤血管生成的关系及其临床病理学意义。方法:选取经病理确诊的51例大肠腺癌手术切除组织标本,免疫组化SP法检测c-Met和VEGF的表达及微血管密度(MVD)。结果:大肠癌组织中c-Met和VEGF的阳性表达率分别为72.55%(37/51)和52.94%(27/51);与Dukes分期密切相关,P<0.05。大肠癌组织c-Met、VEGF均为阳性时MVD值为37.94±7.53,单一阳性时分别为30.67±1.45和23.82±7.45,均为阴性时MVD值最小,为13.64±5.33。大肠癌组织中c-Met和VEGF的表达呈显著正相关,rs=0.614,P<0.05。结论:c-Met和VEGF在大肠癌发生、发展和转移过程中起重要作用,并与肿瘤血管生成相关。     

表皮生长因子受体酪氨酸激酶抑制剂ZD1839的研究进展

在过去的几十年中 ,人们一直怀着极大的兴趣研发新药来提高实体瘤的治疗效果。然而 ,传统的细胞毒药物选择性低 ,毒副作用大 ,容易产生耐药性。近 10多年来 ,随着分子肿瘤学的发展以及对肿瘤与宿主之间复杂关系的深入研究 ,发现了某些与肿瘤发生、发展、浸润及转移有关的重要环     

肾细胞癌分子靶向治疗进展

针对血管内皮生长因子受体和表皮生长因子受体信号传导通路发展的低分子量多靶点酪氨酸激酶抑制剂、抗血管生成单克隆抗体、哺乳动物雷帕霉素靶蛋白抑制剂等分子靶向药物二线治疗肾细胞癌有延长无进展生存优势；一线治疗在无进展生存期及总生存期方面优于传统细胞因子治疗。分子靶向药物联合应用及与细胞因子或传统化疗药物的联合应用正在研究中。     

表皮生长因子受体酪氨酸激酶抑制剂耐药机制研究进展

含有表皮生长因子受体突变的非小细胞肺癌患者中70％～80％对表皮生长因子受体酪氨酸激酶抑制剂吉非替尼和厄洛替尼敏感,但最终仍会出现耐药导致肿瘤进展。表皮生长因子受体酪氨酸激酶抑制剂耐药分为原发耐药和继发耐药,继发耐药机制主要包括表皮生长因子受体二次突变（T790M）、HER2及HER3的代偿作用、MET扩增、胰岛素样生长因子受体结合蛋白缺失及哺乳动物雷帕霉素靶蛋白信号通路活化。     

表皮生长因子受体酪氨酸激酶抑制剂耐药机制研究进展

0引言基础研究和临床实验已经证实,抗表皮生长因子受体(epidermal growth factor receptor,EGFR,又称HER-1或cerbB-1)疗法能提高传统的化疗药物的作用效果,并在某些患者身上取得了部分反应率和疾病稳定的疗效。然而大多数患者并不能从这一疗法中获益,究其原因是这些患者最终都表现为对抗EGFR疗法产生耐药。本文拟就表皮生长因子受体酪氨酸激酶抑制剂的耐药机制及研究进展作一综述,为临床治疗提供理论依据。     

酪氨酸激酶抑制剂在抗肿瘤领域的研究进展

酪氨酸蛋白激酶是多种肿瘤最常见的生长因子受体，是信号转导过程中的首要关键步骤。通过阻断酪氨酸激酶可破坏肿瘤细胞的信号传递，从而达到治疗肿瘤的目的。近年来，有关酪氨酸激酶抑制剂的研究非常活跃，出现了诸如C225，C11033，PKI-166，OSI-774，ZDl839，STl571等一批新药。OSI-774和ZDl839已使难治性非小细胞肺癌患者的病情减缓。C225可提高化、放疗的疗效，STl571在慢性粒细胞性白血病和胃肠间质性肿瘤治疗中取得了突破性进展。酪氨酸激酶抑制剂已成为抗肿瘤疗法中的一个新的有希望的侯选药物。     

表皮生长因子受体-酪氨酸激酶抑制剂的耐药机制

表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKI）在非小细胞肺癌（NSCLC）中的耐药越来越常见,主要包括原发性耐药与继发性耐药,其中原发性耐药主要与EGFR基因突变有关,继发性耐主要与T790M、MET等基因相关。     

Both antiangiogenesis- and angiogenesis-independent effects are responsible for hepatocellular carcinoma growth arrest by tyrosine kinase inhibitor PTK787/ZK222584

Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis of hepatocellular carcinoma. Inhibition of VEGF receptors could theoretically reduce angiogenesis and tumor growth in hepatocellular carcinoma, but this remains to be proven with an experimental study. This study examined the angiogenesis-dependent and angiogenesis-independent activities of PTK787/ZK222584 (PTK787), a tyrosine kinase inhibitor of VEGF receptors, in nude mice bearing human hepatocellular carcinoma xenografts. The in vitro effects of PTK787 on proliferation, apoptosis, and cell cycle distribution in human hepatocellular carcinoma cell lines were also studied. Oral administration of PTK787 resulted in a significant reduction in tumor volume and microvessel formation of hepatocellular carcinoma xenografts in nude mice. PTK787 inhibited tumor cell proliferation in a dose-dependent manner and also induced tumor cells to undergo apoptosis both in vivo and in vitro. The proapoptotic response was associated with down-regulation of Bcl-2 and Bcl-x(L) expression and induction of cleavage of caspase-3. In addition, PTK787 induced growth arrest in hepatocellular carcinoma cells, which was associated with G1 arrest and partial G2-M block. This effect correlated with an increase in p21(WAF1/ CIP1) (p21) and p27KIP1 (p27) protein expression. In conclusion, this study showed that PTK787 is a potent inhibitor of tumor growth in hepatocellular carcinoma by both antiangiogenic effect and direct effects on tumor cell proliferation and apoptosis. Our data suggest that blockage of VEGF receptors may provide an effective therapeutic approach for human hepatocellular carcinoma.     

Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma

BACKGROUND:

This study determined the maximum tolerated dose (MTD) and dose‐limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients.

METHODS:

All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme‐inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice‐a‐day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed.

RESULTS:

A total of 37 recurrent patients, 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice‐a‐day. DLTs were hematologic, gastrointestinal, renal, and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures.

CONCLUSIONS:

Vatalanib doses up to 1000 mg twice‐a‐day combined with imatinib and hydroxyurea were well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and platelet‐derived growth factor, respectively, were safe among recurrent malignant glioma patients and may enhance antiangiogenesis activity. Cancer 2009. © 2009 American Cancer Society.     

The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment

Our prior studies show that multiple myeloma (MM) cell lines and patient cells express high-affinity vascular endothelial growth factor (VEGF) receptor (VEGFR) Flt-1 but not Flk-1/KDR. Moreover, these studies have shown that VEGF induces proliferation and migration of MM cells, and we have begun to delineate the signaling cascades mediating those sequelae. In this study, we examined the activity of PTK787/ZK 222584 (PTK787), a molecule designed to bind specifically to the tyrosine kinase domain of VEGFR and inhibit angiogenesis. We show that PTK787 acts both directly on MM cells and in the bone marrow microenvironment. Specifically, PTK787 (1-5 micro M) inhibits proliferation of MM cells by 50%, as assayed by [(3)H]thymidine uptake. This effect of PTK787 is dose dependent in both MM cell lines and patient cells that are both sensitive and resistant to conventional therapy. PTK787 enhances the inhibitory effect of dexamethasone on growth of MM cells and can overcome the protective effect of interleukin 6 (IL-6) against dexamethasone-induced apoptosis. PTK787 (1 micro M) also blocks VEGF-induced migration of MM cells across an extracellular matrix. Importantly, PTK787 also inhibits the increased MM cell proliferation and increased IL-6 and VEGF secretion in cultures of MM cells adherent to bone marrow stem cells. These findings therefore demonstrate that PTK787 both acts directly on MM cells and inhibits paracrine IL-6-mediated MM cell growth in the bone marrow milieu. The demonstrated anti-MM activity of PTK787, coupled with its antiangiogenic effects, provides the framework for clinical trials of this agent to overcome drug resistance and improve outcome in MM.     

Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] combined with ionizing radiation on endothelial cells and tumour growth.

The vascular endothelial growth factor (VEGF) receptor is a major target for anti-angiogenesis-based cancer treatment. Here we report the treatment effect of ionizing radiation in combination with the novel orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on endothelial cell proliferation in vitro and with tumour xenografts in vivo. Combined treatment of human umbilical vein endothelial cells with increasing doses of PTK787/ZK222584 and ionizing radiation abrogated VEGF-dependent proliferation in a dose-dependent way, but inhibition of endothelial cell proliferation was not due to apoptosis induction. In vivo, a combined treatment regimen of PTK787/ZK222584 (4 x 100 mg/kg) during 4 consecutive days in combination with ionizing radiation (4 x 3 Gy) exerted a substantial tumour growth delay for radiation-resistant p53-dysfunctional tumour xenografts derived from SW480 colon adenocarcinoma cells while each treatment modality alone had only a minimal effect on tumour size and neovascularization. SW480 tumours from animals that received a combined treatment regimen, displayed not only an extended tumour growth delay but also a significant decrease in the number of microvessels in the tumour xenograft. These results support the model of a cooperative anti-tumoral effect of angiogenesis inhibitor and irradiation and show that the orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 is suitable for combination therapy with irradiation.     

Regorafenib in the treatment of malignant tumor

Regorafenib, an oral multi-kinase inhibitor, can inhabit a class of receptor tyrosine kinase, such as angiogenic, stromal, oncogenic and so on. Studies in vitro and clinical trials indicate that regorafenib has significant antitumor activity. The results of clinical trials are encouraging for the treatment of refractory solid tumors, especially for colorectal carcinoma.     

PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor of vascular endothelial growth factor (VEGF), has modest activity in myelofibrosis with myeloid metaplasia

Angiogenesis is part of the pathophysiology of myelofibrosis with myeloid metaplasia (MMM). PTK787/ZK 222584 (PTK/ZK) is a novel inhibitor of vascular endothelial growth factor receptors. Twenty-nine patients with MMM received a continuous dosing schedule of PTK/ZK doses of 500 or 750 mg twice daily (BID). Transient potentially PTK/ZK related mild nausea, vomiting, dizziness, fatigue, thrombocytopenia, or anorexia occurred in 15% of patients. Dose limiting toxicities of dyspepsia, proteinurea, and/or mucositis were observed in patients treated with 750 mg BID. One (3%) and five (17%) patients achieved complete remission and clinical improvement, respectively. PTK/ZK has modest activity in patients with MMM.     

受体型酪氨酸激酶抑制剂与肿瘤的治疗

表皮生长因子受体及血管内皮细胞生长因子受体是受体型酪氨酸蛋白激酶中两条重要的传导通路.同时阻断该两条通路有2种方法:①同时运用分别作用于两条通路的药物;②运用单一的可同时针对该两条通路的药物.已有的研究表明双靶向药物比单靶向药物具有更好的疗效.     

The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584

Chromatin remodeling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. Vascular endothelial growth factor (VEGF) and VEGF receptors represent critical molecular targets for antiangiogenesis therapy. In this study, we investigated the biological effect of the histone deacetylase inhibitor NVP-LAQ824 in combination with the VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on tumor growth and angiogenesis. We report that treatment with NVP-LAQ824 affected tumor and endothelial cells and was associated with increased histone acetylation, p21 up-regulation, and growth inhibition. In addition, NVP-LAQ824 treatment inhibited the expression of angiogenesis-related genes such as angiopoietin-2, Tie-2, and survivin in endothelial cells and down-regulated hypoxia-inducible factor 1-alpha and VEGF expression in tumor cells. Combination treatment with NVP-LAQ824 and PTK787/ZK222584 was more effective than single agents in inhibiting in vitro and in vivo VEGF-induced angiogenesis. Endothelial cell proliferation, tube formation, and invasion into the Matrigel plugs were reduced. In mouse models with established subcutaneous prostate (PC3) and orthotopic breast tumors (MDA-MB321), this combination treatment induced 80 to 85% inhibition of tumor growth without overt toxicity. These results suggest that the combination of histone deacetylase inhibitors and VEGF receptor inhibitors may target multiple pathways in tumor progression and angiogenesis and represents a novel therapeutic approach in cancer treatment.     

Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome.

PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety, tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute myeloid leukemia (AML), secondary AML, poor-prognosis de novo AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500-1000 mg orally b.i.d. Safety and pharmacokinetic data were collected. Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD). Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy.In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well tolerated and can be given in combination with chemotherapy for patients with MDS and AML.     

非小细胞肺癌表皮生长因子受体-酪氨酸激酶抑制剂的一线治疗

表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)参与的晚期非小细胞肺癌(NSCLC)一线治疗的几种模式显示出不同的结果.化疗与EGFR-TKI联合未显示生存优势,化疗序贯EGFR-TKI和EGFR-TKI单药这两种模式取得了巨大的突破,为晚期NSCLC个体化治疗开辟了新的道路.同时发现EGFR突变在晚期NSCLC靶向治疗方面有很好的疗效预测价值.