索拉非尼不良反应对其疗效的预测价值

《肝脏病学》(Hepatology)杂志2011年刊登了一项有关索拉非尼治疗中期肝细胞癌的前瞻性队列研究。这项研究发现那些在大于70%的疗程中主要采用半剂量治疗的患者中位生存时间长于全剂量治疗的患者。这一现象引起了我们的关注,并对此做了进一步的分析。我们认为,索拉非尼药物不良反应具有预测其疗效的价值。     

HIF,hypoxia and the role of angiogenesis in non-small cell lung cancer

Importance of the field: The role of angiogenesis in the initiation and progression of NSCLC and the molecular alterations leading to the growth of tumor vasculature are areas of great interest and recent therapeutic success.

Areas covered in this review: VEGF and its receptors play critical roles in the development of tumor vasculature and can be targeted by agents such as bevacizumab in the treatment of NSCLC. Furthermore, tumor hypoxia and the expression of the hypoxia-inducible factor (HIF) family of proteins are also linked to poorer survival in these patients. Recent studies using genetically engineered mouse models expressing stabilized HIF validate the importance of HIF in the evolution of NSCLC and demonstrate genetically that HIF is involved in NSCLC.

What the reader will gain: An overview of the key pathways and mediators of tumor angiogenesis, their relevance to the pathogenesis of NSCLC, and an update on the current status of angiogenesis inhibitors in NSCLC.

Take home message: Angiogenesis is a key mediator of NSCLC progression. Several antiangiogenic strategies are in clinical use and under development. While candidate predictive biomarkers of response to antiangiogenic therapy exist, they await independent and prospective validation.     

Sorafenib in non-small cell lung cancer

ISIS 2302 is a 20 base phosphorothioate oligodeoxynucleotide (ODN) that inhibits intercellular adhesion molecule 1 (ICAM-1) expression through an antisense mechanism. Murine and rat analogues have been effective at doses of 0.06 - 10 mg/kg in a spectrum of models of human inflammatory diseases and allograft transplantation, and ISIS 2302 inhibits the upregulation of ICAM-1 expression in a variety of human cells in vitro. In animals, including primates, plasma distribution half-life ranges from 30 - 60 min, but tissue elimination half-lives range from 1 - 5 days, and the compound is metabolised as other nucleic acids. In a Phase I iv. study, the pharmacokinetic behaviour of ISIS 2302 was similar to that in other primates, and single and multiple every other day doses from 0.06 - 2 mg/kg infused over 2 h were well-tolerated. Phase IIa studies have been completed in Crohn’s disease, rheumatoid arthritis, and psoriasis, and a combined Phase I/II renal allograft acute rejection prophylaxis study has just completed enrolment. In these studies, ISIS 2302, 0.5 - 2 mg/kg, or placebo was administered iv. every 2 - 3 days over 14 - 26 days (7 - 13 infusions) to 17 - 52 patients, with follow up for 6 months. In the Crohn’s study, evidence of highly durable (5+ month) remission-inducing and steroid-sparing properties were demonstrated, without clinically important adverse events. A 300-patient, pivotal quality trial investigating the steroid-sparing and remission-inducing qualities of ISIS 2302 in patients with steroid-dependent Crohn’s disease is completely enrolled, with results expected in the first half of 2000. Modest efficacy and excellent tolerability were demonstrated in the psoriasis and rheumatoid arthritis trials. A Phase IIa trial of a topical formulation in patients with psoriasis is expected to commence in late 1999, as is a trial of an enema formulation in distal ulcerative colitis. Administration by nebulisation for asthma is undergoing preclinical evaluation. Execution of future plans in organ transplantation will await the results of the ongoing Phase I/II trial.     

Optimizing treatment for patients with metastatic renal cell carcinoma in the central and Eastern European region

Introduction: Belarus, Bulgaria, Croatia, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Republic of Moldova, Romania, Russian Federation, Serbia, Slovakia, Slovenia and the Ukraine represent a collection of Central and Eastern European (CEE) countries in which the epidemiology and treatment of cancer varies greatly between and within countries. Current challenges include non-adherence to current treatment guidelines, restrictions in access and reimbursement for new therapies, and a lack of basic oncology programs. Metastatic renal cell carcinoma (mRCC) is a malignancy with historically poor prognosis. In CEE countries, the incidence and mortality rates of mRCC are among the highest in the world. Fortunately, mRCC represents a cancer for which a number of new targeted therapies have recently demonstrated benefit, resulting in new evidence-based treatment guidelines. Incorporating these mRCC treatment recommendations into the routine care of patients with mRCC in CEE countries would represent a major step forward for cancer care in this region.

Areas covered: This review discusses the unique challenges faced by the aforementioned Eastern European countries in the treatment of metastatic renal cell cancer, in an attempt to assist health-care providers in providing the best care possible for their European patients.

Expert opinion: Despite a wealth of clinical trial data supporting the use of targeted therapies for first-line treatment of mRCC, cytokine-based immunotherapy is still used in some of these European countries. With implementation and adherence to existing guidelines, treatment can be clinically and economically optimized in patients with mRCC from this region.     

分子靶向药物在肝细胞肝癌治疗中的研究进展

对于不适宜手术切除的晚期肝细胞肝癌,传统的化疗并不能改善患者的预后。分子靶向药物的出现为肝细胞肝癌的治疗提供了新的治疗手段。分子靶向药物治疗肝细胞肝癌的临床试验中,包括多靶点抑制剂、血管内皮生长抑制剂、小分子酪氨酸激酶抑制剂以及分子靶向药与化疗的联合等已经显示出了潜在的疗效和良好的发展前景。临床试验显示索拉非尼可延长肝细胞肝癌的中位无疾病进展时间至9.2个月,中位总生存至10.5个月,贝伐单抗与厄洛替尼联合治疗肝细胞肝癌延长中位总生存达68周。本文针对肝细胞肝癌使用多靶点抑制剂、血管内皮生长抑制剂等的临床研究进展进行综述。     

The combination of HTATIP2 expression and microvessel density predicts converse survival of hepatocellular carcinoma with or without sorafenib

Our previous studies have demonstrated that sorafenib can promote the dissemination of hepatocellular carcinoma (HCC) through downregulation of HTATIP2, a suppressor of tumor growth and metastasis that is associated with inhibition of angiogenesis. Here, we investigated the predictive values of the HTATIP2 level and microvessel density (MVD) with or without sorafenib administration for HCC. Three independent cohorts were included. Using tissue microarray, we assessed the relationship between HTATIP2 expression/MVD and overall survival. The results showed that high HTATIP2 expression and a low MVD value were independent protective prognostic factors after curative HCC resection (297 cases/cohort 1); however, both parameters were converted to independent negative prognostic indicators for patients with postsurgical sorafenib treatment (69/143 cases/cohort 2; P<0.05 for all). This same relationship was observed in patients that received sorafenib treatment for advanced HCC (83 cases/cohort 3; efficacy measures and survival analyses, P<0.05 for all). Moreover, the combination of HTATIP2 and MVD had better power to predict patient death and disease recurrence (P<0.001 for both). We conclude that the combination of HTATIP2 and MVD predicts the converse survival of HCC with or without sorafenib intervention. Our findings can assist in the selection of candidates for personalized treatment with sorafenib.     

吲哚脲类化合物的设计合成及其体外抗肿瘤活性研究

目的以索拉非尼为先导物,设计并合成一系列吲哚脲类化合物,并对其体外抗肿瘤活性进行初步评价。方法以5-硝基吲哚-2-甲酸为起始原料,采用BOP法合成酰胺,再将硝基还原成胺基,最后与异氰酸酯缩合,共3步反应制备目标化合物;采用MTT法评价目标化合物对4种肿瘤细胞株(MX-1、A375、HepG2、Ketr3)的生长抑制作用。结果与结论合成了28个吲哚脲类新化合物,其结构经1H-NMR和HR-MS确证。体外活性结果表明,与索拉非尼相比多数化合物选择性地作用于MX-1细胞株,显示出较强的抑制肿瘤细胞增殖的活性。其中含甲基哌啶的化合物26、30和31抑制MX-1和A375细胞生长的作用显著强于索拉非尼。尤其是化合物31抑制A375细胞增殖的作用是索拉非尼的10倍,对HepG2的抑制活性与索拉非尼相当,IC50值均达到微摩尔级水平,值得进一步研究。     

索拉非尼治疗晚期肝细胞癌的系统评价

目的 系统评价索拉非尼治疗晚期肝细胞癌的疗效与安全性.方法 计算机检索PubMed (1966～2009年)、Cochrane Library(2009年第4期)、Embase(1990～2009年)、中国期刊全文数据库(1994～2009年)、中国生物医学文献数据库(1978～2009年)、中文科技期刊数据库(198...     

Pharmacokinetics and Early Tumor Response to Conventional Transarterial Chemoembolization with Sorafenib and Doxorubicin in a VX2 Rabbit Tumor Model

PurposeTo investigate the pharmacokinetics (PK) and early effects of conventional transarterial chemoembolization (TACE) using sorafenib and doxorubicin on tumor necrosis, hypoxia markers, and angiogenesis in a rabbit VX2 liver tumor model.Materials and MethodsVX2 tumor-laden New Zealand White rabbits (N = 16) were divided into 2 groups: 1 group was treated with hepatic arterial administration of ethiodized oil and doxorubicin emulsion (DOX-TACE), and the other group was treated with ethiodized oil, sorafenib, and doxorubicin emulsion (SORA-DOX-TACE). Animals were killed within 3 days of the procedure. Levels of sorafenib and doxorubicin were measured in blood, tumor, and adjacent liver using mass spectrometry. Tumor necrosis was determined by histopathological examination. Intratumoral hypoxia-inducible factor (HIF) 1α, vascular endothelial growth factor (VEGF), and microvessel density (MVD) were determined by immunohistochemistry.ResultsThe median intratumoral concentration of sorafenib in the SORA-DOX-TACE group was 17.7 μg/mL (interquartile range [IQR], 7.42–33.5 μg/mL), and its maximal plasma concentration (C_max) was 0.164 μg/mL (IQR, 0.0798–0.528 μg/mL). The intratumoral concentration and C_max of doxorubicin were similar between the groups: 4.08 μg/mL (IQR, 3.18–4.79 μg/mL) and 0.677 μg/mL (IQR, 0.315–1.23 μg/mL), respectively, in the DOX-TACE group and 1.68 μg/mL (IQR, 0.795–4.08 μg/mL) and 0.298 μg/mL (IQR, 0.241–0.64 μg/mL), respectively, in the SORA-DOX-TACE group. HIF-1α expression was increased in the SORA-DOX-TACE group than in the DOX-TACE group. Tumor volume, tumor necrosis, VEGF expression, and MVD were similar between the 2 groups.ConclusionsThe addition of sorafenib to DOX-TACE delivered to VX2 liver tumors resulted in high intratumoral and low systemic concentrations of sorafenib without altering the PK of doxorubicin.     

LY3214996 relieves acquired resistance to sorafenib in hepatocellular carcinoma cells

Background: Sorafenib, an oral multi-kinase inhibitor of rapidly accelerated fibrosarcoma; vascular endothelial growth factor receptor-2/3, platelet-derived growth factor receptor, c-Kit, and Flt-3 signaling, is approved for treatment of advanced hepatocellular carcinoma (HCC). However, the benefit of sorafenib is often diminished because of acquired resistance through the reactivation of ERK signaling in sorafenib-resistant HCC cells. In this work, we investigated whether adding LY3214996, a selective ERK1/2 inhibitor, to sorafenib would increase the anti-tumor effectiveness of sorafenib to HCC cells.Methods: The Huh7 cell line was used as a cell model for treatment with sorafenib, LY3214996, and their combination. Phosphorylation of the key kinases in the Ras/Raf/MAPK and PI3K/Akt pathways, protein expression of the cell cycle, and apoptosis migration were assessed with western blot. MTT and colony-formation assays were used to evaluate cell proliferation. Wound-healing assay was used to assess cell migration. Cell cycle and apoptosis analyses were conducted with flow cytometry.Results: LY3214996 decreased phosphorylation of the Ras/Raf/MAPK and PI3K/Akt pathways, including p-c-Raf, p-P90RSK, p-S6K and p-eIF4EBP1 activated by sorafenib, despite increased p-ERK1/2 levels. LY3214996 increased the anti-proliferation, anti-migration, cell-cycle progression, and pro-apoptotic effects of sorafenib on Huh7^R cells.Conclusions: Reactivation of ERK1/2 appears to be a molecular mechanism of acquired resistance of HCC to sorafenib. LY3214996 combined with sorafenib enhanced the anti-tumor effects of sorafenib in HCC. These findings form a theoretical basis for trial of LY3214996 combined with sorafenib as second-line treatment of sorafenib-resistant in advanced HCC.