HU-331: a cannabinoid quinone, with uncommon cytotoxic properties and low toxicity

The oxidation of cannabis constituents has given rise to their corresponding quinones, which have been identified as cytotoxic agents. Out of these molecules the quinone of cannabidiol--the most abundant non-psychoactive cannabinoid in Cannabis sativa--has shown the highest cytotoxicity. This compound was named HU-331 and it exerts antiangiogenic properties, induces apoptosis to endothelial cells and inhibits topoisomerase II in nanomolar concentrations. Unlike other quinones, it is not cardiotoxic and does not induce the formation of free radicals. A comparative in vivo study in mice has shown HU-331 to be less toxic and more effective than the commonly used doxorubicin. This review summarises the properties of HU-331 and compares it with doxorubicin and other topoisomerase II inhibitors.     

Angiogenesis: new targets for the development of anticancer chemotherapies

Angiogenesis is the process by which new blood vessels are formed from preexisting microvasculature. To ensure an adequate blood supply, tumor cells release angiogenic factors that are capable of promoting nearby blood vessels to extend vascular branches to the tumor. In addition, larger tumors have been shown to release angiogeneic inhibitory factors that prevent blood vessels from sending branches to smaller, more distant tumors that compete for oxygen and nutrients. Angiogenesis is a complex multistep biochemical process, and offers several potential molecular targets for non-cytotoxic anticancer therapies. Strategies for exploiting tumor angiogenesis for novel cancer drug discovery include: (i) inhibition of proteolytic enzymes that breakdown the extracellular matrix surrounding existing capillaries; (ii) inhibition of endothelial cell migration; (iii) inhibition of endothelial cell proliferation; (iv) enhancement of tumor endothelial cell apoptosis. There is also a host of miscellaneous agents that inhibit angiogenesis for which the specific mechanisms are not clear. Several methods have been developed for measuring antiangiogenic activity both in vitro and in vivo. Although there has been intensive research efforts focused at the phenomena of angiogenesis, as well as the search for antiangiogenic agents for more than two decades, many questions remain unanswered with regard to the overall biochemical mechanisms of the angiogenesis process and the potential therapeutic utility of angiogenic inhibitors. Nevertheless potent angiogenic inhibitors capable of blocking tumor growth have been discovered, and appear to have potential for development into novel anticancer therapeutics. However there are still hurdles to be overcome before these inhibitors become mainstream therapies.     

Inhibition of angiogenesis by a monoclonal antibody to kininogen as well as by kininostatin which block proangiogenic high molecular weight kininogen

High molecular weight kininogen (HK) exhibits two activities with respect to angiogenesis after cleavage by plasma kallikrein. Cleaved HK (HKa) and its cell-binding domain 5 (D5), kininostatin, are potent antiangiogenic polypeptides. They inhibit endothelial cell migration, proliferation and tube formation. HKa and D5 inhibit angiogenesis in the chicken chorioallantoic membrane (CAM) assay. D5 stimulates apoptosis and interferes with the cell cycle. In contrast, intact HK is proangiogenic by liberating bradykinin. A monoclonal antibody to HK can inhibit angiogenesis in the CAM assay, human colon carcinoma growing as a xenograft in nude mice, and murine hybridomas growing in syngeneic hosts. Not only are the tumors decreased in volume and weight to isotype controls but the mean vascular density is decreased. Thus, both D5 and its constituent peptide and monoclonal antibody have potential for inhibiting angiogenesis and tumor growth in human therapy.     

TNP-470对裸鼠肺癌骨转移瘤生长的影响

目的:建立裸鼠肺癌骨转移模型,探讨TNP-470作为血管抑制剂对肺癌骨转移的形成及生长的影响。方法:将24只肺癌骨转移裸鼠随机分成三组:第一组隔日予以生理盐水,腹腔注射;第二组隔日腹腔注射3%乙醇;第三组隔日予以TNP-47030mg/kg腹腔注射。30天后处死,检测血清碱性磷酸酶、血管内皮生长因子(VEGF)和肿瘤微血管密度(MVD),HE染色后光镜下观察各组肿瘤组织,流式细胞仪检测肿瘤细胞凋亡率。结果:TNP-470组肿瘤的生长明显受到抑制,肿瘤组织中的MVD与对照组比较显著降低,抑瘤率为36.5%,凋亡指数上升,血清碱性磷酸酶下降。结论:TNP-470能够明显抑制裸鼠肺癌骨转移瘤的生长和新生血管形成。     

In vivo antitumor effect of ascorbic acid, lysine, proline and green tea extract on human prostate cancer PC-3 xenografts in nude mice: evaluation of tumor growth and immunohistochemistry

BACKGROUND: Matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), Ki 67 (proliferative protein) and constituents of ECM play a critical role in angiogenesis, and are crucial in neoplastic invasion and metastasis. Based on the antitumor properties of certain nutrients, we investigated the effect of a diet containing lysine, proline, arginine, ascorbic acid and green tea extract on the growth of tumors induced by implanting human prostate cancer PC-3 cells in athymic nude mice and on the expression of MMPs, VEGF, Ki 67 and fibronectin in these tumors, as well as the production of mucin (by PAS staining). MATERIALS AND METHODS: Male nude mice (n =12) were inoculated with 3x10(6) prostate cancer PC-3 cells and randomly divided into two groups; Group A was fed a regular diet and Group B was fed a regular diet supplemented with 0.5% of the nutrient mixture (NM). Four weeks later, tumors were excised, weighed and processed for histology. RESULTS: The results showed inhibition of tumor growth in Group B. Histological studies revealed inhibition of MMP-9 and VEGF secretion and mitosis in Group B tissues. CONCLUSION: Nutrient supplementation strongly suppressed the growth of tumors without any adverse effects in nude mice, suggesting strong potential as an anticancer agent.     

Delivery of soluble VEGF receptor 1 (sFlt1) by gene electrotransfer as a new antiangiogenic cancer therapy

Since tumor growth is highly dependent on the formation of new blood vessels, angiogenesis inhibitors have become important players in anticancer treatments. Although less cytotoxic than conventional chemotherapy, most of the available antiangiogenic agents may provoke severe adverse effects which can limit their use. The design of new antiangiogenic strategies therefore requires integrating an early evaluation of possible interference with quiescent endothelial cells and nontumor angiogenesis. Here, we describe such a novel antiangiogenic approach based on the in vivo delivery by gene electrotransfer of a negative regulator of angiogenesis, namely, sFlt1. We found that this soluble variant of the vascular endothelial growth factor receptor 1 (Flt1, also known as VEGFR1), which acts as a VEGF trap, differentially influences tumor and postischemic hind limb angiogenesis in mice. sFlt1 gene electrotransfer in tibial cranial muscle leads to high sFlt1 protein expression and secretion, leading to a significant delay in the growth of syngeneic tumors but not altering the revascularization of ischemic peripheral tissue. The higher sensitivity of tumor-bearing animals toward sFlt1 trapping effects (vs ischemia-recovering animals) might be explained by a distinct pattern of VEGF release, as shown by VEGF measurements in plasma and tissue. In conclusion, our data support sFlt1 gene electrotransfer as a novel and safe modality to target VEGF-driven tumor angiogenesis and to maintain unaltered the recovery potential of ischemic tissues.     

Inhibition of in vivo angiogenesis by N-beta-alanyl-5-S-glutathionyl-3,4-dihydroxyphenylalanine

N-beta-alanyl-5-S-glutathionyl-3,4-dihydroxyphenylalanine (5-S-GAD), an antibacterial substance isolated from the flesh fly, inhibits human tumor growth in the nude mice model; however, the mechanism of its action is unclear. The in vivo antitumor effect includes the inhibition of tumor cell proliferation and suppression of angiogenesis. Angiogenesis is essential for tumor growth in vivo. In this study, we examined whether 5-S-GAD inhibits tumor cell-induced angiogenesis by performing the mouse dorsal air sac assay. We found that intraperitoneal administration of 5-S-GAD inhibited the angiogenesis induced by S180 mouse sarcoma cells. Furthermore, 5-S-GAD also inhibited vascular endothelial growth factor-induced angiogenesis in the Matrigel plug assay and embryonic angiogenesis in the chick embryo chorioallantoic membrane assay. However, 5-S-GAD did not show any effect on the proliferation, migration, and tube formation of vascular endothelial cells. These results provide the first evidence that a bioactive substance derived from the flesh fly has antiangiogenic activity in vivo, although the mechanisms involved could not be explained.     

Targeting tissue factor-expressing tumor angiogenesis and tumors with EF24 conjugated to factor VIIa

Tissue factor (TF) is aberrantly expressed on tumor vascular endothelial cells (VECs) and on cancer cells in many malignant tumors, but not on normal VECs, making it a promising target for cancer therapy. As a transmembrane receptor for coagulation factor VIIa (fVIIa), TF forms a high-affinity complex with its cognate ligand, which is subsequently internalized through receptor-mediated endocytosis. Accordingly, we developed a method for selectively delivering EF24, a potent synthetic curcumin analog, to TF-expressing tumor vasculature and tumors using fVIIa as a drug carrier. EF24 was chemically conjugated to fVIIa through a tripeptide-chloromethyl ketone. After binding to TF-expressing targets by fVIIa, EF24 will be endocytosed along with the drug carrier and will exert its cytotoxicity. Our results showed that the conjugate inhibits vascular endothelial growth factor-induced angiogenesis in a rabbit cornea model and in a Matrigel model in athymic nude mice. The conjugate-induced apoptosis in tumor cells and significantly reduced tumor size in human breast cancer xenografts in athymic nude mice as compared with the unconjugated EF24. By conjugating potent drugs to fVIIa, this targeted drug delivery system has the potential to enhance therapeutic efficacy, while reducing toxic side effects. It may also prove to be useful for treating drug-resistant tumors and micro-metastases in addition to primary tumors.     

血管生成抑制剂联合分化诱导剂治疗结肠癌的实验研究

目的通过建立人LOVO细胞结肠癌裸鼠皮下移植瘤模型,研究血管生成抑制剂（TNP-470）联合分化诱导剂（RA）抗结肠癌生长的效应,二者是否具有协同效果。方法建立人LOVO细胞结肠癌裸鼠皮下移植瘤模型,模型建立后分组治疗,按治疗方式分为对照组、TNP-470组、RA组和联合组（TNP-470＋RA）至治疗结束时处死裸鼠,测量皮下移植瘤重量,计算抑瘤率;检测肿瘤组织结肠癌细胞凋亡指数（AI）。结果裸鼠皮下移植瘤瘤重、抑瘤率,联合组和对照组及TNP-470组、RA组比较差异均有统计学意义（P〈0.05）,且TNP-470组、RA组和对照组之间差异亦有统计学意义（P〈0.05）。治疗组与对照组癌细胞AI比较,差异有统计学意义（P〈0.05）;且联合组与RA组和TNP-470组癌细胞的AI比较,差异也有统计学意义（P〈0.05）。结论血管生成抑制剂TNP-470与分化诱导剂RA联合治疗结肠癌裸鼠皮下移植瘤比TNP-470或RA单药治疗具有更强的抑瘤作用,TNP-470通过抑制肿瘤血管生成,切断肿瘤细胞的血供和营养供给,抑制结肠癌裸鼠皮下移植瘤的生长;而RA通过诱导肿瘤细胞凋亡,降低VEGF的表达抑制肿瘤的生长,二者联和应用,抗肿瘤效应明显增强。     

肿瘤分子靶向药物阿帕替尼的临床研究进展

肿瘤血管新生是癌症的标志之一,阻断血管内皮细胞生长因子信号通路进而抑制肿瘤血管新生已成为靶向治疗的新方案。阿帕替尼是一种新型小分子血管内皮生长因子-2受体酪氨酸激酶抑制剂。研究证明,阿帕替尼对胃癌、非小细胞肺癌、乳腺癌和肝癌等多种恶性肿瘤有显著的抑制作用。本文对该药的结构、机制、药动学和临床试验等进行总结,为更好的指导临床应用提供建议。     

Angiogenesis and angiogenesis inhibitors: a new potential anticancer therapeutic strategy

Tumor cells cannot grow as a mass above 2 to 3 mm3 because diffusion is insufficient for oxygen and glucose requirements, unless the tumor induces a blood supply. This mechanism of induction of a new blood supply from pre-existing vascular bed is called angiogenesis. Furthermore, tumor invasiveness and metastasis require neovascularization. In fact, recent published studies suggest that acquisition of the angiogenic phenotype is a common pathway for tumor progression and neovascularization is linked with other molecular steps leading to tumor progression. Angiogenic process is a complex multi-step cascade under the control of positive and negative soluble factors. A paracrine interaction occurs between tumor and endothelial cells. Angiogenesis involves: endothelial cell proliferation, migration and tubule formation with associated changes in the extra-cellular matrix, allowing subsequent new vessel growth toward the tumor. Each of the above steps may represent a target for antiangiogenic therapy. Antiangiogenesis is to be distinguished from direct targeting and destruction of tumor vasculature (vascular targeting). Inhibition of angiogenesis represents one of the more promising, new approaches, to anticancer treatment and its already in early clinical trials. This review takes into consideration: (i) the biological mechanism underlining angiogenesis process; (ii) the method to assess tumor angiogenesis activity; (iii) inhibition of angiogenesis as an anticancer therapy; (iv) the methodology for the clinical development of angiogenesis inhibitors, that should be considered biological response modifiers; (v) some angiogenesis antagonists that are in development and leader compounds that are under clinical trial.     

Perindopril: possible use in cancer therapy

Since angiogenesis is essential for the growth of any solid tumor, emerging efforts are being made to develop antiangiogenic therapy. To date, however, no antiangiogenic agent has become widely available for the clinical setting. Angiotensin I-converting enzyme (ACE) inhibitors are commonly used as antihypertensive agents and it has recently been suggested that they decrease the risk of cancer. Studies have found that an ACE inhibitor, perindopril, is a potent inhibitor of experimental tumor development and angiogenesis at a clinically comparable dose. The potent angiogenic factor, vascular endothelial growth factor (VEGF), is significantly suppressed by perindopril and also inhibits VEGF-induced tumor growth. In vitro studies showed that perindopril is not cytotoxic to either tumor cells or endothelial cells. Since perindopril is already in widespread clinical use without serious side effects, it may represent a potential new strategy for anticancer therapy.     

三氧化二砷及顺铂对乳腺癌裸鼠移植瘤生长的抑制作用

目的 了解三氧化二砷(As2O3)、顺铂(DDP)单独及联合应用对人乳腺癌裸鼠移植瘤生长的抑制作用. 方法 建立裸鼠人乳腺癌MCF-7细胞移植瘤动物模型,成瘤后动物随机分为4组,每组4只:(1)阴性对照组,(2)As2O3组,(3)DDP组,(4)As2O3 DDP组.疗程结束后,观察3 d,处死裸鼠.治疗期间观察并记录各组裸鼠移植瘤的生长情况及肿瘤体积和裸鼠体重的变化,计算肿瘤生长抑制率,用流式细胞仪法、透射电镜观察体内瘤体的细胞凋亡情况. 结果 As2O3组、DDP组和As2O3 DDP组治疗后肿瘤体积减少,与对照组相比,差异均有显著性(P＜0.01);与As2O3及DDP组单独用药组比较,As2O3 DDP联合用药组肿瘤体积明显减少(P＜0.01),抑瘤率明显增高(P＜0.01);而阴性对照组肿瘤体积增加.各组裸鼠体重无明显变化.As2O3 DDP联合用药组细胞凋亡率为36.9%,明显高于其他2组,差异有显著性(P＜0.01). 结论 As2O3与DDP联合用药比2药单独应用抑制肿瘤生长的作用更强,二者具有协同抗癌作用.     

New anticancer strategies targeting HIF-1

Hypoxia-inducible factor-1 (HIF-1), which is present at high levels in human tumors, plays crucial roles in tumor promotion by up-regulating its target genes, which are involved in anaerobic energy metabolism, angiogenesis, cell survival, cell invasion, and drug resistance. Therefore, it is apparent that the inhibition of HIF-1 activity may be a strategy for treating cancer. Recently, many efforts to develop new HIF-1-targeting agents have been made by both academic and pharmaceutical industry laboratories. The future success of these efforts will be a new class of HIF-1-targeting anticancer agents, which would improve the prognoses of many cancer patients. This review focuses on the potential of HIF-1 as a target molecule for anticancer therapy, and on possible strategies to inhibit HIF-1 activity. In addition, we introduce YC-1 as a new anti-HIF-1, anticancer agent. Although YC-1 was originally developed as a potential therapeutic agent for thrombosis and hypertension, recent studies demonstrated that YC-1 suppressed HIF-1 activity and vascular endothelial growth factor expression in cancer cells. Moreover, it halted tumor growth in immunodeficient mice without serious toxicity during the treatment period. Thus, we propose that YC-1 is a good lead compound for the development of new anti-HIF-1, anticancer agents.     

A vascular endothelial growth factor receptor-2 kinase inhibitor potentiates the activity of the conventional chemotherapeutic agents paclitaxel and doxorubicin in tumor xenograft models

Inhibition of angiogenesis may have wide use in the treatment of cancer; however, this approach alone will not cause tumor regression but may only slow the growth of solid tumors. The clinical potential of antiangiogenic agents may be increased by combining them with conventional chemotherapeutics. 4-[4-(1-Amino-1-methylethyl)phenyl]-2-[4-(2-morpholin-4-yl-ethyl)phenylamino]pyrimidine-5-carbonitrile (JNJ-17029259) represents a novel structural class of 5-cyanopyrimidines that are orally available, selective, nanomolar inhibitors of the vascular endothelial growth factor receptor-2 (VEGF-R2) and other tyrosine kinases involved in angiogenesis, such as platelet-derived growth factor receptor, fibroblast growth factor receptor, VEGF-R1, and VEGF-R3, but have little activity on other kinase families. At nanomolar levels, JNJ-17029259 blocks VEGF-stimulated mitogen-activated protein kinase signaling, proliferation/migration, and VEGF-R2 phosphorylation in human endothelial cells; inhibits the formation of vascular sprouting in the rat aortic ring model of angiogenesis; and interferes with the development of new veins and arteries in the chorioallantoic membrane assay. At higher concentrations of 1 to 3 microM, this compound shows antiproliferative activity on cells that may contribute to its antitumor effects. JNJ-17029259 delays the growth of a wide range of human tumor xenografts in nude mice when administered orally as single-agent therapy. Histological examination revealed that the tumors have evidence of reduced vascularity after treatment. In addition, JNJ-17029259 enhances the effects of the conventional chemotherapeutic drugs doxorubicin and paclitaxel in xenograft models when administered orally in combination therapy. An orally available angiogenesis inhibitor that can be used in conjunction with standard chemotherapeutic agents to augment their activity may have therapeutic benefit in stopping the progression of cancer and preventing metastasis.     

A combination of liposomal sunitinib plus liposomal irinotecan and liposome co-loaded with two drugs enhanced antitumor activity in PC12-bearing mouse

Pheochromocytomas are highly angiogenic neuroendocrine tumors. The side effects of treatment with cytotoxic agents frequently outweigh the benefits. Neuroendocrine tumors are highly angiogenic, dependent on vascular endothelial growth factor and receptor (VEGFR) activation. Sunitinib has antitumor and antiangiogenic activities that target VEGFRs. We investigated the antitumor activity of liposomal sunitinib and irinotecan alone and in combination. Liposomal sunitinib and irinotecan, and liposomes co-loaded with both drugs were prepared, and antitumor activity and biodistribution were examined in nude mice bearing PC12 tumors. Liposomal sunitinib increased in life span (ILS, 14.3%) compared with free sunitinib (?17.1% ILS) with moderate tumor growth suppression, whereas liposomal irinotecan suppressed tumor growth significantly without a survival benefit compared with free irinotecan (?21.7 and ?13.3% ILSs, respectively). The combination of liposomal sunitinib plus liposomal irinotecan, and liposomes co-loaded with both drugs, induced significant inhibition of tumor growth and increased life-span more than the combination of free drugs. Accumulation of irinotecan in tumors by the combination of the two liposomal drugs and liposomes co-loaded with both drugs was significantly increased compared with the combination of free drugs. This study provides novel formulations of sunitinib and irinotecan in combination for the treatment of pheochromocytoma.     

Acetazolamide inhibits aquaporin-1 protein expression and angiogenesis

INTRODUCTION Recently the medical remedy for malignant tumorhas been concentrated to cut off the tumor nutritionsupply such as inhibiting the angiogenesis and otheraspects[1]. Angiogenesis, the formation of new bloodvessels, is essential for tumor progression and meta-stasis. Vigorous neovascularization, or angiogenesis,has been associated with a poor prognosis for cancersarising at several primary sites[2]. The process of an-giogenesis is required for sustaining tumor growth inthe …