In vivo videomicroscopy reveals differential effects of the vascular-targeting agent ZD6126 and the anti-angiogenic agent ZD6474 on vascular function in a liver metastasis model

Metastases require a functional blood supply for progressive growth. Thus, therapies that target metastatic vasculature have potential clinical utility. The effects of the vascular-targeting agent (VTA), ZD6126, and the anti-angiogenic agent, ZD6474, on vascular development and function within metastases were compared in an experimental liver metastasis model. Ras-transformed PAP2 fibroblasts were injected into the mesenteric veins of SCID mice to produce a control liver metastasis burden of 40% at 14 days. Mice given a single dose of ZD6126 (200 mg/kg, i.p.) on day 13 were examined 24 h later. Histology revealed a significant reduction in metastatic burden, associated with extensive tumor necrosis, increased tumor cell apoptosis and a reduction in tumor-associated vasculature. In vivo videomicroscopy (IVVM) revealed disrupted, non-functional vascular channels within metastases, with no blood flow. Mice given ZD6474 on days 4 to 10 (50 mg/kg daily, oral gavage) were examined on day 11. Histology revealed a lower metastatic burden, significant reductions in metastasis size and vasculature, and a significant increase in tumor cell apoptosis. IVVM revealed extensive reductions in vascularity and blood flow within metastases. Neither ZD6126 nor ZD6474 treatment affected surrounding normal liver tissue. This study shows that both agents can reduce experimental liver metastasis with no apparent effect on normal vasculature. However, these reductions were attained through distinct effects on the metastatic vasculature. Understanding differences in the modes of action of VTAs and anti-angiogenic agents will be important in optimizing their clinical application and in developing appropriate combination strategies.     

A phase I Study with oral SU5416 in patients with advanced solid tumors: A drug inducing its clearance

Summary Vascular endothelial growth factor (VEGF) is a potent stimulant of angiogenesis. SU5416, is a small molecule tyrosine kinase inhibitor, and a potent inhibitor of VEGF- mediated Flk-1 receptor signaling. Intravenous agent SU5416 has shown evidence of biological activity against a variety of tumor types. The current intravenous dosing regimen is not optimal for long-term administration, which is needed for optimal efficacy. The aim of this study was to evaluate the safety profile and pharmacokinetics of a Nanocrystal Colloidal Dispersion^TM (NCD) SU5416 formulation in humans. Patients with advanced and/or metastatic solid organ tumors were included in the trial; various SU5416 regimens were tested for tolerability, safety and were evaluated concerning pharmacokinetics. The results of this study indicate that induction of clearance after oral dosing of NCD SU5416 in humans occurs and is greater than following IV administration. It has been confirmed that SU5416 is a high clearance compound, also as an oral NCD formulation. The NCD formulation was well tolerated, but no effective drug serum levels could be achieved. These data help to understand the ADME (Absorption, Distribution, Metabolism, Excretion) properties of indoline chemical class compounds. The lessons learned should be applied in the development of next generation indoline anti-angiogenic and anti-tumor compounds.     

Cartilage-derived anti-tumor factor (CATF)

Cartilage-derived anti-tumor factor (CATF) inhibits the proliferation and DNA synthesis of bovine pulmonary artery endothelial (BPAE) cells in culture (Takigawa, M.et al. Cell. Biol. Inn. Rep., 9, 619–625, 1985). In the present study, we partially purified CATF by monitoring inhibition of DNA synthesis in BPAE cells and tested the effects of the purified materials on the growth of solid tumors and tumor-induced angiogenesis. Crude CATF (CATF_20–300k), the fraction of 20 k to 300 k daltons, separated by ultrafiltration was further separated into three fractions by ultrafiltration. The fraction of 100 k to 300 k daltons (CATF_100–300k) caused slightly more inhibition than CATF_20–300k of DNA synthesis in BPAE cells. On the other hand, the fraction of 20 k to 50 k daltons had only a slight effect, and the fraction of 50 k to 100 k had even less effect on DNA synthesis in BPAE cells. CATF_100–300k caused slightly more inhibition than CATF_20–300k of the growth of solid tumors of B16 melanoma, while the fraction of 20 k to 100 k daltons did not inhibit the growth of tumors at all. CATF_100–300k also inhibited B16 melanoma-induced angiogenesis in chick embryo chorioallantoic membranes (CAM), whereas the fraction of 20 k to 100 k daltons had little effect on the angiogenesis. CATF_100–300k was further purified by DEAE-Sepharose CL-6B chromatography. The main peak with activity on DNA synthesis in BPAE cells was eluted with 0.3 to 0.35 M NaCl at pH 8.0. The activity of this peak on DNA synthesis in BPAE cells was about 70 fold that of CATF_100–300k. The purified CATF also inhibited the growth of B16 melanoma and B16 melanoma-induced angiogenesis in CAM. On the other hand, the inactive fraction on DNA synthesis in BPAE cells obtained by DEAE-Sepharose chromatography was also inactive in inhibiting the growth of B16 melanoma and B16 melanoma-induced angiogenesis in CAM. These findings strongly suggest that CATF is an anionic macromolecule(s) and has anti-angiogenic activity, thereby inhibiting the growth of solid tumors.     

Treating systemic prostate cancer: emerging drug targets and therapies

Prostate cancer is the most common cancer among men and is the second most common cause of cancer death. Although more patients are now diagnosed with localised prostate cancer since the advent of prostate specific antigen (PSA) screening, 30 - 40% will develop recurrent disease even following definitive therapy with either surgery or radiation. Patients who develop recurrent disease may be treated with androgen deprivation strategies, however within 1 - 2 years, most patients will develop androgen independent prostate cancer (AIPC). While chemotherapy has been shown to have palliative benefit in this situation, there is no evidence of prolonged survival. Given the shear numbers of patients with this disease and its inexorable progression to AIPC for which no life prolonging therapy exists, there clearly is a need for improved treatment strategies for systemic prostate cancer. Research in this area includes testing combinations of previously studied chemotherapeutic agents as well as the identification and testing of novel agents. It is these drugs that are designed to target strategic pathways to improve survival and increase quality of life in these patients. In this paper, we will not review traditional chemotherapeutic agents but discuss several key potential areas of targeted therapy for prostate cancer.     

Antibody-based tumor vascular theranostics targeting endosialin/TEM1 in a new mouse tumor vascular model

Tumor endothelial marker 1 (TEM1, endosialin) is a tumor vascular marker with significant diagnostic and therapeutic potential. However, in vivo small animal models to test affinity reagents specifically targeted to human (h)TEM1 are limited. We describe a new mouse tumor model where tumor vascular endothelial cells express hTEM1 protein. Methods: Immortalized murine endothelial cells MS1 were engineered to express hTEM1 and firefly luciferase and were inoculated in nude mice either alone, to form hemangioma-like endothelial grafts, or admixed with ID8 ovarian tumor cells, to form chimeric endothelial-tumor cell grafts. MORAb-004, a monoclonal humanized IgG₁ antibody specifically recognizing human TEM1 was evaluated for targeted theranostic applications, i.e., for its ability to affect vascular grafts expressing hTEM1 as well as being a tool for molecular positron emission tomography (PET) imaging. Results: Naked MORAb-004 treatment of mice bearing angioma grafts or chimeric endothelial-tumor grafts significantly suppressed the ability of hTEM1-positive endothelial cells, but not control endothelial cells, to form grafts and dramatically suppressed local angiogenesis. In addition, highly efficient radioiodination of MORAb-004 did not impair its affinity for hTEM1, and [¹²⁴I]-MORAb-004-PET enabled non-invasive visualization of tumors enriched with hTEM1-positive, but not hTEM1 negative vasculature with high degree of specificity and sensitivity. Conclusion: The development of a new robust endothelial graft model expressing human tumor vascular proteins will help accelerate the development of novel theranostics targeting the tumor vasculature, which exhibit affinity specifically to human targets but not their murine counterparts. Our results also demonstrate the theranostic potential of MORAb-004 as PET imaging tracer and naked antibody therapy for TEM1-positive tumor.     

阿帕替尼治疗肺巨细胞癌1例并文献复习

目的:探讨肺巨细胞癌的临床特征、诊断和治疗方法。方法:报道1例肺巨细胞癌患者的临床资料并对相关文献进行复习。对肺巨细胞癌的临床特征、影像学表现、病理学特征和治疗方法进行分析。结果:1例肺巨细胞癌患者因刺激性呛咳、左侧胸部闷痛3个月入院。胸部CT检查及病理穿刺活检明确诊断为肺巨细胞癌。采取多西他赛联合顺铂3周方案化疗,化疗2个周期后临床症状轻微好转且疗效评价稳定（SD）,化疗4个周期后疗效评价进展（PD）,口服阿帕替尼抗肿瘤血管生成治疗后疗效评价亦是PD。结论:肺巨细胞癌临床罕见,生存期短,预后差,目前无标准的治疗方法,化疗可能短暂延缓肿瘤进展,阿帕替尼抗肿瘤血管生成治疗效果可能欠佳。     

Potent antitumor effects of the conditioned medium of bone marrow-derived mesenchymal stem cells via IGFBP-4

Cell transfer therapy using mesenchymal stem cells (MSCs) has pronounced therapeutic potential, but concerns remain about immune rejection, emboli formation, and promotion of tumor progression. Because the mode of action of MSCs highly relies on their paracrine effects through secretion of bioactive molecules, cell-free therapy using the conditioned medium (CM) of MSCs is an attractive option. However, the effects of MSC-CM on tumor progression have not been fully elucidated. Herein, we addressed this issue and investigated the possible underlying molecular mechanisms. The CM of MSCs derived from human bone marrow greatly inhibited the in vitro growth of several human tumor cell lines and the in vivo growth of the SCCVII murine squamous cell carcinoma cell line with reduced neovascularization. Exosomes in the MSC-CM were only partially involved in the inhibitory effects. The CM contained a variety of cytokines including insulin-like growth factor binding proteins (IGFBPs). Among them, IGFBP-4 greatly inhibited the in vitro growth of these tumors and angiogenesis, and immunodepletion of IGFBP-4 from the CM significantly reversed these effects. Of note, the CM greatly reduced the phosphorylation of AKT, ERK, IGF-1 receptor beta, and p38 MAPK in a partly IGFBP4-dependent manner, possibly through its binding to IGF-1/2 and blocking the signaling. The CM depleted of IGFBP-4 also reversed the inhibitory effects on in vivo tumor growth and neovascularization. Thus, MSC-CM has potent inhibitory effects on tumor growth and neovascularization in an IGFBP4-dependent manner, suggesting that cell-free therapy using MSC-CM could be a safer promising alternative for even cancer patients.     

恩度治疗小细胞肺癌脑转移瘤瘤周水肿1例报告及文献复习

目的:探讨治疗脑转移瘤瘤周水肿的方法。方法:总结1例小细胞肺癌脑转移患者的临床资料及恩度治疗脑转移瘤瘤周水肿的效果,并对治疗脑水肿相关文献进行复习。结果:恩度抗血管生成治疗小细胞肺癌脑转移瘤瘤周水肿有很好的临床效果,能够控制脑水肿,减轻临床症状,提高生活质量。结论:恩度可以作为治疗脑转移瘤瘤周水肿的有效药物选择。     

抗血管生成药物治疗恶性脑水肿的研究进展

抗血管生成药物通过减少血管通透性和血脑屏障破坏,能有效减轻恶性脑水肿,缓解临床症状,改善患者生命质量。目前多种抗血管生成药物在治疗恶性脑水肿方面取得了积极的疗效,因此被认为是较糖皮质激素治疗恶性脑水肿更为安全、有效的治疗手段。     

奥希替尼联合贝伐珠单抗治疗伴EGFR T790M突变肺腺癌的疗效与机制研究

  目的  通过移植瘤动物实验探讨奥希替尼联合抗VEGF单克隆抗体靶向药物贝伐珠单抗的疗效及作用机制,为进一步临床试验提供理论依据。  方法  构建EGFR T790M突变的H1975人肺腺癌细胞移植瘤动物模型。实验分组:低剂量奥希替尼组、高剂量奥希替尼组、低剂量奥希替尼联合贝伐珠单抗组、高剂量奥希替尼联合贝伐珠单抗组。每组各5只小鼠,给药  方法  奥希替尼2.5 mg/kg/d或5 mg/kg/d,采用每天灌胃处理;贝伐珠单抗5 mg/kg,每周2次腹腔注射。接种后和给药期间绘制肿瘤生长曲线,给药2周后处死裸鼠,活检整个肿瘤。免疫组织化学SP法检测肿瘤HIF-1α、VEGF和微血管密度（microvessel density,MVD）。应用Western blot法检测EGFR及其下游AKT和ERK信号通路蛋白的表达。  结果  给药2周后,高剂量奥希替尼单药组较低剂量奥希替尼单药组肿瘤体积明显缩小,HIF-1α、VEGF表达率和MVD显著降低（P < 0.05）,p-EGFR、p-AKT和p-ERK表达减少（P < 0.05）。低剂量奥希替尼联合贝伐珠单抗组肿瘤体积明显小于低剂量奥希替尼单药组（P < 0.05）,上述因子均明显降低（P < 0.05）。低剂量奥希替尼联合组与高剂量奥希替尼单药组比较,肿瘤体积差异无统计学意义（P=0.178）,p-EGFR、p-AKT、p-ERK表达差异无统计学意义（P＞0.05）。高剂量奥希替尼联合组与高剂量奥希替尼单药组体积差异无统计学意义（P=0.642）。两个联合组之间,体积差异均无统计学意义（P=0.072）,上述因子表达差异均无统计学意义（P＞0.05）。  结论  贝伐珠单抗能够显著增加奥希替尼对伴EGFR T790M突变的肺腺癌移植瘤的杀伤能力。贝伐珠单抗与奥希替尼协同作用是通过降低肿瘤中VEGF表达,改善肿瘤微环境,增强抑制EGFR下游信号通路激活而实现的。