Antiangiogenic Characteristics Research Articles

Synergistic chemo-photothermal anticancer effect of pH-responsive curcumin loaded mesoporous silica decorated reduced graphene

Synergistic chemo-photothermal therapy is employed to treat cancer. In this work, the curcumin loaded mesoporous silica on reduced graphene oxide (Cur-mSiO2@rGO) is synthesized. The mSiO2@rGO nanocarrier combines rGO to absorb NIR radiations with mSiO2 to load the drug. The mSiO2@rGO thus functions as bimodal photothermal agent and pH-responsive drug nanocarrier. Curcumin loaded onto the nanocarrier possesses antiproliferative, antioxidant, anti-inflammatory, pro-apoptotic, and antiangiogenic characteristics. It has anticancer potential against malignancies of stomach, liver, breast, lungs, and prostate. Breast cancer (BCa) is a major health concern worldwide. Curcumin inhibits BCa by mechanisms including apoptosis, cell cycle arrest, and modulation of signaling pathways. Moreover, curcumin blocks transcription factor (NF-κB), PI3K/AKT signaling, and STAT3 protein to inhibit liver cancer cell growth and survival. Cur-mSiO2@rGO targets cancer cells with enhanced loading capacity of 92 ± 1.02 % curcumin which is specifically released in the acidic tumor environment. NIR lamp irradiation at 808 nm ablates cancer cells to demonstrate the high photothermal conversion efficiency of rGO. In vitro experiments prove that synergistic chemo-photothermal therapy effectively kills cancer cells (HepG2 and MCF-7) compared to the single chemotherapeutic treatment. The toxicity of Cur-mSiO2@rGO is analyzed in vivo by the serum biochemical analysis, and biosafety by histopathological examination of vital body organs. A 1000 mg/kg specific dose of Cur-mSiO2@rGO shows no toxic effect on mice organs. Additionally, the in vivo studies confirm that Cur-mSiO2@rGO with NIR reduces tumor growth. Therefore, the multifunctional Cur-mSiO2@rGO can be a safe chemopreventive nanocarrier in tumor management and cancer photothermal therapy.

AZGP1 deficiency promotes angiogenesis in prostate cancer

BackgroundLoss of AZGP1 expression is a biomarker associated with progression to castration resistance, development of metastasis, and poor disease-specific survival in prostate cancer. However, high expression of AZGP1 cells in prostate cancer has been reported to increase proliferation and invasion. The exact role of AZGP1 in prostate cancer progression remains elusive.MethodAZGP1 knockout and overexpressing prostate cancer cells were generated using a lentiviral system. The effects of AZGP1 under- or over-expression in prostate cancer cells were evaluated by in vitro cell proliferation, migration, and invasion assays. Heterozygous AZGP1± mice were obtained from European Mouse Mutant Archive (EMMA), and prostate tissues from homozygous knockout male mice were collected at 2, 6 and 10 months for histological analysis. In vivo xenografts generated from AZGP1 under- or over-expressing prostate cancer cells were used to determine the role of AZGP1 in prostate cancer tumor growth, and subsequent proteomics analysis was conducted to elucidate the mechanisms of AZGP1 action in prostate cancer progression. AZGP1 expression and microvessel density were measured in human prostate cancer samples on a tissue microarray of 215 independent patient samples.ResultNeither the knockout nor overexpression of AZGP1 exhibited significant effects on prostate cancer cell proliferation, clonal growth, migration, or invasion in vitro. The prostates of AZGP1−/− mice initially appeared to have grossly normal morphology; however, we observed fibrosis in the periglandular stroma and higher blood vessel density in the mouse prostate by 6 months. In PC3 and DU145 mouse xenografts, over-expression of AZGP1 did not affect tumor growth. Instead, these tumors displayed decreased microvessel density compared to xenografts derived from PC3 and DU145 control cells, suggesting that AZGP1 functions to inhibit angiogenesis in prostate cancer. Proteomics profiling further indicated that, compared to control xenografts, AZGP1 overexpressing PC3 xenografts are enriched with angiogenesis pathway proteins, including YWHAZ, EPHA2, SERPINE1, and PDCD6, MMP9, GPX1, HSPB1, COL18A1, RNH1, and ANXA1. In vitro functional studies show that AZGP1 inhibits human umbilical vein endothelial cell proliferation, migration, tubular formation and branching. Additionally, tumor microarray analysis shows that AZGP1 expression is negatively correlated with blood vessel density in human prostate cancer tissues.ConclusionAZGP1 is a negative regulator of angiogenesis, such that loss of AZGP1 promotes angiogenesis in prostate cancer. AZGP1 likely exerts heterotypical effects on cells in the tumor microenvironment, such as stromal and endothelial cells. This study sheds light on the anti-angiogenic characteristics of AZGP1 in the prostate and provides a rationale to target AZGP1 to inhibit prostate cancer progression.

Hydrogels of Alginate Derivative‐Encased Nanodots Featuring Carbon‐Coated Manganese Ferrite Cores with Gold Shells to Offer Antiangiogenesis with Multimodal Imaging‐Based Theranostics

AbstractThe investigation seeks to develop gold‐shelled carbon‐coated manganese ferrite nanodots enclosed within oxidized alginate polymeric hydrogels (MNF@C‐Au@OSA) to improve encapsulation efficiency, biocompatibility, and multimodal imaging capabilities. These engineered particles, MNF@C‐Au@OSA, are crafted through a hydrothermal synthesis, succeeded by the application of gold nanoparticle shelling and subsequent encapsulation within hydrogels derived from synthesized alginate derivatives, enhancing their overall appeal. Diverse characterization methodologies are employed in order to validate the multiple steps of the synthesis process. The resulting engineered nanoparticles exhibit dual‐mode (T1 and T2) magnetic resonance imaging (MRI) contrast capabilities and compatibility with computed tomography (CT) and fluorescence‐based imaging. To illustrate minimal toxicity, A375 cell lines are utilized for in vitro testing, whereas zebrafish embryos are employed for in vivo assessments. A Chorioallantoic Membrane Model (CAM) is used to establish the antiangiogenic characteristics of MNF@C‐Au@OSA, which is confirmed by histopathological observations. Taking these studies together, one can conclude that the engineered MNF@C‐Au@OSA possesses multimodal imaging capabilities and has demonstrated antiangiogenic properties, thereby establishing them as potential theranostic agents.

Angiogenesis in Lung Cancer: Understanding the Roles of Growth Factors.

Research has shown the role of growth factors in lung cancer angiogenesis. Angiogenesis promotes lung cancer progression by stimulating tumor growth, enhancing tumor invasion, contributing to metastasis, and modifying immune system responses within the tumor microenvironment. As a result, new treatment techniques based on the anti-angiogenic characteristics of compounds have been developed. These compounds selectively block the growth factors themselves, their receptors, or the downstream signaling pathways activated by these growth factors. The EGF and VEGF families are the primary targets in this approach, and several studies are being conducted to propose anti-angiogenic drugs that are increasingly suitable for the treatment of lung cancer, either as monotherapy or as combined therapy. The efficacy of the results are encouraging, but caution must be placed on the higher risk of toxicity, outlining the importance of personalized follow-up in the management of these patients.

Different clinical presentation of two pregnancy syndromes: Similar pro and antiangiogenic characteristics near delivery: Fetal growth preeclampsia

This research aimed to determine if there was a statistically significant distinction between the serum anti- but also pro-angiogenic chemical ratios among pregnant women having preeclampsia and/or fetal growth limitation, two clinical subgroups of placental ischemia syndrome. We conducted a prospective case-control study that looked at 77 singleton pregnancies and compared them with and without preeclampsia with 77 singleton pregnancies with and without healthy fetuses, matching for gestational age. All pregnant participants in the trial were analyzed to determine the presence or absence of adverse outcomes. Because once in comparison to the control group, the study participants had higher levels of obtainable endoglin dissolution and the ratio of fms-like tyrosine kinase-1 (sFlt-1) to trophoblastic growth factor. Despite the fact that experimental groups received a same quantity of placental growth factor, this was the case (PlGF). sFlt-1 to PlGF ratio as well as the PE without accompanying FGR cohort were the two areas in which the most prominent outliers were discovered. Since preeclamptic persons have the greatest sFlt-1 levels, this factor may be responsible for the development of PE in the mother due to ischemic placental disease.

Polypharmacological Cell-Penetrating Peptides from Venomous Marine Animals Based on Immunomodulating, Antimicrobial, and Anticancer Properties.

Complex pathological diseases, such as cancer, infection, and Alzheimer's, need to be targeted by multipronged curative. Various omics technologies, with a high rate of data generation, demand artificial intelligence to translate these data into druggable targets. In this study, 82 marine venomous animal species were retrieved, and 3505 cryptic cell-penetrating peptides (CPPs) were identified in their toxins. A total of 279 safe peptides were further analyzed for antimicrobial, anticancer, and immunomodulatory characteristics. Protease-resistant CPPs with endosomal-escape ability in Hydrophis hardwickii, nuclear-localizing peptides in Scorpaena plumieri, and mitochondrial-targeting peptides from Synanceia horrida were suitable for compartmental drug delivery. A broad-spectrum S. horrida-derived antimicrobial peptide with a high binding-affinity to bacterial membranes was an antigen-presenting cell (APC) stimulator that primes cytokine release and naïve T-cell maturation simultaneously. While antibiofilm and wound-healing peptides were detected in Synanceia verrucosa, APC epitopes as universal adjuvants for antiviral vaccination were in Pterois volitans and Conus monile. Conus pennaceus-derived anticancer peptides showed antiangiogenic and IL-2-inducing properties with moderate BBB-permeation and were defined to be a tumor-homing peptide (THP) with the ability to inhibit programmed death ligand-1 (PDL-1). Isoforms of RGD-containing peptides with innate antiangiogenic characteristics were in Conus tessulatus for tumor targeting. Inhibitors of neuropilin-1 in C. pennaceus are proposed for imaging probes or therapeutic delivery. A Conus betulinus cryptic peptide, with BBB-permeation, mitochondrial-targeting, and antioxidant capacity, was a stimulator of anti-inflammatory cytokines and non-inducer of proinflammation proposed for Alzheimer's. Conclusively, we have considered the dynamic interaction of cells, their microenvironment, and proportional-orchestrating-host- immune pathways by multi-target-directed CPPs resembling single-molecule polypharmacology. This strategy might fill the therapeutic gap in complex resistant disorders and increase the candidates' clinical-translation chance.

Pleiotropic properties of statins via angiogenesis modulation in cardiovascular disease

Inhibition of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by statins is affected by inhibiting the active site of the enzyme in a competitive manner. Statins reduce plasma cholesterol by inhibiting its de novo synthesis. In addition, statins impart 'pleiotropic' activities that do not directly relate to their ability to decrease cholesterol. The proangiogenic and antiangiogenic characteristics of statins are among these pleiotropic effects. These angiogenic-modifying properties could offer new therapeutic applications. Statins stimulate or suppress angiogenesis in a biphasic manner. Whereas low doses of statin stimulate angiogenesis, high doses reduce protein prenylation and limit cell development and angiogenesis. In this review, we discuss how statins impact angiogenesis, with a particular focus on angiogenesis in stroke and cardiovascular disease (CVD).

Synthetic Approaches Towards the Total synthesis of tubulysin and its fragments: A review.

Tubulysins, linear tetrapeptides show extraordinary cytotoxicity against various cancer cells, with IC50 values in nano or picomolar range. Due to their extremely vigorous anti-proliferative and antiangiogenic characteristics, tubulysins exhibit captivating prospects in the development of anticancer drugs. This review focuses on diverse routes for the total synthesis of natural and synthetic tubulysins as well as their fragments. The purpose of this review is to present the synthetic strategies for the development of antitumor agents, tubulysins. A range of synthetic pathways adopted for the total synthesis of tubulysins and their fragments have been described in this review. Synthesis of fragments, Tuv, Tup, and Tut can be accomplished by adopting appropriate strategies such as Manganese-mediated synthesis, Ireland-Claisen rearrangement, Mukaiyama aldol reaction, and Mannich process etc. Tubulysin B, D, U, V, and N14-desacetoxytubulysin H have been prepared through Mitsunobu reaction, tert-butanesulfinamide method, Tandem reaction, aza-Barbier reaction, Evans aldol reaction, and C-H activation strategies etc. The remarkable anticancer potential of tubulysins toward a substantiate target make them prominent leads for developing novel drugs against multidrug-resistant cancers.

Single extracellular vesicle analysis in human amniotic fluid shows evidence of phenotype alterations in preeclampsia.

Amniotic fluid surrounding the developing fetus is a complex biological fluid rich in metabolically active bio‐factors. The presence of extracellular vesicles (EVs) in amniotic fluid has been mainly related to foetal urine. We here characterized EVs from term amniotic fluid in terms of surface marker expression using different orthogonal techniques. EVs appeared to be a heterogeneous population expressing markers of renal, placental, epithelial and stem cells. Moreover, we compared amniotic fluid EVs from normal pregnancies with those of preeclampsia, a hypertensive disorder affecting up to 8% of pregnancies worldwide. An increase of CD105 (endoglin) expressing EVs was observed in preeclamptic amniotic fluid by bead‐based cytofluorimetric analysis, and further confirmed using a chip‐based analysis. HLA‐G, a typical placental marker, was not co‐expressed by the majority of CD105+ EVs, in analogy with amniotic fluid stromal cell derived‐EVs. At a functional level, preeclampsia‐derived EVs, but not normal pregnancy EVs, showed an antiangiogenic effect, possibly due to the decoy effect of endoglin. Our results provide a characterization of term amniotic fluid‐EVs, supporting their origin from foetal and placental cells. In preeclampsia, the observed antiangiogenic characteristics of amniotic fluid‐EVs may reflect the hypoxic and antiangiogenic microenvironment and could possibly impact on the developing fetus or on the surrounding foetal membranes.

Elucidation of anti-proliferative and anti-angiogenic potential ofnovel imidazo[2,1-b][1,3,4]thiadiazole derivatives in Ehrlich ascites tumor model

Introduction and Aim:Synthesis of antineoplastic drugs is challenging and shrouded with possibilities of multidrug resistance and numerous side effects. Imidazo[2,1-b][1,3,4]thiadiazole moieties exhibit tremendous scope as novel anti-cancer molecules. In the present study, we synthesize and characterize a series of 5(a-e) Imidazo[2,l-b][1, 3,4]thiadiazole derivatives andevaluate them for antiproliferative properties using in vivo, in vitro , andin silicoapproach. Materials and Methods:The in vivostudies conducted using murine Ehrlich Ascites Cancer (EAC) cell model establishes that treatment with 5c reduces the tumorigenesisby promoting apoptosis inEAC-bearing mice. The cells retrieved from the control andtreatment arms of EAC cell bearing mice were used for nuclear and Giemsa staining, DNA fragmentation, RT-PCR and chorioallantoic membrane evaluations. Results:5cinduces apoptosis, plasma membrane degradation, up-regulation of apoptotic genes and anti-angiogenic characteristics. In vitro evaluation of 5cusing,various cancer cell linesagainst normal fibroblast 3T3 L1 cells confirm 5c sensitivity to MCF-7 with IC50value of 8?M. 5c exudes marked reduction in cell viability, dual nuclear staining,and long-term colony formationassays in thesecells. Conclusion:5c inhibits the growth and proliferation of cancer cells. The results of our molecular docking predictions further substantiate our claim. This study is valuable as 5c exhibitsapromising approach for the treatment of cancer and itsanti-proliferative potential can be exploited for designing novel anticancer drugs in the near future. Keywords:Imidazo[2,1-b][1,3,4]thiadiazole derivatives;NMRcytotoxicity, EAC cell;apoptosis;anti-angiogenesis.

An Update on the Role of Dietary Phytochemicals in Human Skin Cancer: New Insights into Molecular Mechanisms.

Human skin is continuously subjected to environmental stresses, as well as extrinsic and intrinsic noxious agents. Although skin adopts various molecular mechanisms to maintain homeostasis, excessive and repeated stresses can overwhelm these systems, leading to serious cutaneous damage, including both melanoma and non-melanoma skin cancers. Phytochemicals present in the diet possess the desirable effects of protecting the skin from damaging free radicals as well as other benefits. Dietary phytochemicals appear to be effective in preventing skin cancer and are inexpensive, widely available, and well tolerated. Multiple in vitro and in vivo studies have demonstrated the significant anti-inflammatory, antioxidant, and anti-angiogenic characteristics of dietary phytochemicals against skin malignancy. Moreover, dietary phytochemicals affect multiple important cellular processes including cell cycle, angiogenesis, and metastasis to control skin cancer progression. Herein, we discuss the advantages of key dietary phytochemicals in whole fruits and vegetables, their bioavailability, and underlying molecular mechanisms for preventing skin cancer. Current challenges and future prospects for research are also reviewed. To date, most of the chemoprevention investigations have been conducted preclinically, and additional clinical trials are required to conform and validate the preclinical results in humans.

Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues.

Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenic pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort. We recently designed and synthesized a new class of compounds, consisting of both tetrafluorinated thalidomide analogues (Gu973 and Gu998) and tetrafluorobenzamides (Gu1029 and Gu992). In this study, we demonstrate the antiangiogenic properties of these newly synthesized compounds. We examined the specific antiangiogenic characteristics in vitro using rat aortic rings with carboxyamidotriazole as a positive control. In addition, further in vitro efficacy was evaluated using human umbilical vein endothelial cells (HUVEC) and PC3 cells treated with 5 and 10 μmol/L doses of each compound. All compounds were seen to reduce microvessel outgrowth in rat aortic rings as well as to inhibit HUVECs to a greater extent, at lower concentrations than previously tested thalidomide analogs. The antiangiogenic properties of the compounds were also examined in vivo in fli1:EGFP zebrafish embryos, where all compounds were seen to inhibit the extent of outgrowth of newly developing blood vessels. In addition, Gu1029 and Gu973 reduced the anti-inflammatory response in mpo:GFP zebrafish embryos, whereas Gu998 and Gu992 showed no difference. The compounds' antitumor effects were also explored in vivo using the human prostate cancer PC3 xenograft model. All four compounds were also screened in vivo in chicken embryos to investigate their teratogenic potential. This study establishes these novel thalidomide analogues as a promising immunomodulatory class with anticancer effects that warrant further development to characterize their mechanisms of action.

Surgical implantation of steroids with antiangiogenic characteristics for treating neovascular age-related macular degeneration

Neovascular age-related macular degeneration (AMD) is associated with rapid vision loss due to choroidal neovascularization (CNV), leakage, and scarring. Steroids have gained attention in their role for the treatment of neovascular AMD for their antiangiogenic and anti-inflammatory properties. This review aims to examine effects of steroids with antiangiogenic properties in the treatment of neovascular AMD. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 11), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2012), EMBASE (January 1980 to November 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to November 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 21 November 2012. We included randomized controlled clinical trials of intra- and peri-ocular antiangiogenic steroids in people diagnosed with neovascular AMD. Two authors independently screened abstracts and full-text articles, assessed risk of bias in the included trials, and extracted data. We did not conduct a meta-analysis. We included three trials after screening a total of 1503 abstracts and 21 full-text articles. The three trials included a total of 809 participants. One trial compared different doses of acetonide anecortave acetate with placebo, a second trial compared triamcinolone acetonide versus placebo, and the third trial compared anecortave acetate against photodynamic therapy (PDT). We did not conduct a meta-analysis owing to heterogeneity of interventions and comparisons. The risk ratio for loss of 3 or more lines of vision at 12 months follow-up was 0.8 (95% confidence interval (CI) 0.45 to 1.45) with 3 mg anecortave acetate, 0.45 (95% CI = 0.21 to 0.97) with 15 mg anecortave acetate, 0.91 (0.52 to 1.58) with 30 mg anecortave acetate, 0.97 (95% CI 0.74 to 1.26) with triamcinolone acetonide, all compared to placebo and 1.08 (95% CI 0.91 to 1.29) with anecortave acetate compared with PDT. Based on the included trials, we found no evidence that antiangiogenic steroids prevent visual loss in patients with neovascular AMD. With the emergence of anti-vascular endothelial growth factor modalities, based on evidence summarized in this review, it is unclear what role steroids have in treating patients with neovascular AMD.

Serum Prolactin Level and Diabetic Retinopathy in Type 2 Diabetes Prolactin and Diabetic Retinopathy

Retinopathy is a common complication of type 2 diabetes. Several factors including hyperglycemia and hypertension play important roles in retinopathy progression. However, the actual mechanistic pathways are not yet discovered. Prolactin via its antiangiogenic characteristics may exert protective effects on retina. We performed a case- control study in order to investigate the potential role of 23KD prolactin in retinopathy. A total of 212 type 2 diabetics were recruited in this study. According to retinopathy they were divided into two groups. Group one (70 patients) suffered diabetic retinopathy and group two (142 patients) did not have retinopathy. There were significant differences in diabetes duration and hyperglycemia and systolic hypertension between two groups (p 0.05). Serum 23 KD prolactin does not seem to have protective role in diabetes retinopathy.

Antiangiogenic Characteristics of Astrocytes From Optic Nerve Heads With Primary Open-angle Glaucoma

To evaluate the angiogenic status of the human optic nerve head (ONH) with primary open-angle glaucoma (POAG). Using real-time reverse transcription-polymerase chain reaction and Western blot, we analyzed the expression of proangiogenic and antiangiogenic factors in cultured ONH astrocytes from healthy donors and donors with POAG. Immunohistochemical analysis was used to localize those factors in human ONHs from healthy donors and donors with POAG. Cocultures of normal and POAG astrocytes with human umbilical vein endothelial cells were performed to obtain functional data on angiogenesis. The ONH astrocytes from donors with POAG decreased expression of proangiogenic factors (vascular endothelial growth factor C and platelet-derived growth factor A) and increased expression of antiangiogenic factors (collagen XVIII and ADAMTSL-3) when compared with normal ONH astrocytes. Vascular endothelial growth factor C and platelet-derived growth factor A were markedly reduced in the lamina cribrosa of the ONHs of donors with POAG. Endostatin immunolabeling increased in the lamina cribrosa of the ONHs of donors with POAG. When cocultured with human umbilical vein endothelial cells, POAG astrocytes induced less tube formation than normal ONH astrocytes. The ONH astrocytes from donors with POAG display antiangiogenic characteristics when compared with normal ONH astrocytes. The study supports the clinical observation of decreased angiogenesis in patients with POAG.

A recombinant human RNASET2 glycoprotein with antitumorigenic and antiangiogenic characteristics

Human RNASET2 is a T2-RNase glycoprotein encoded by the RNASET2 gene, which is located on chromosome 6 (6q27). Deletion in 6q27 is associated with several human malignancies. A synthetic RNASET2 gene that was optimized for expression in the yeast Pichia pastoris was designed according to the cDNA sequence and was cloned under the control of the methanol-induced promoter fused to the alpha-mating secretion peptide. The recombinant protein was purified from the culture supernatant of transformed P. pastoris through an affinity Sepharose-concanavalin A column. Actin-binding activity was examined by membrane blotting using monoclonal mouse antiactin immunoglobulin M and by cross-linking in solution to G-actin using 1-[3-(dimethylamino)propyl]-3-ethyl-carboimide methiodide. The antiangiogenic activity of RNASET2 (from 0.5 microM to 10 microM) was assessed by a human umbilical vein endothelial (HUVE) cell assay in the presence of 1 microg/mL angiogenin, basic fibroblast growth factor (bFGF), or recombinant human vascular endothelial growth factor (VEGF). Cell colony formation was examined in human colon HT29 cancer cells to assess the antitumorigenic activity of RNASET2 or the enzymatic-inactivated RNASET2 (EI-RNASET2) (1 microM each). In an athymic mouse xenograft model, LS174T human cancer cells were injected subcutaneously. When tumors were palpable, the mice were treated for 3 weeks with RNASET2 (1 mg/kg), paclitaxel (10 mg/kg or 15 mg/kg), or a combination of the 2 drugs. The recombinant RNASET2 was identified as a 27-kilodalton glycoprotein that possessed the ability to bind actin in vitro. RNASET2 significantly inhibited clonogenicity in HT29 cells. EI-RNASET2 produced a similar effect, suggesting that its antitumorigenic activity is unrelated to its RNase activity. In HUVE cells, RNASET2 inhibited angiogenin-, bFGF-, and VEGF-induced tube formation in a dose-dependent manner. In athymic mice, RNASET2 inhibited the development of an LS174T-derived xenograft by 40%. A synergistic effect was obtained with combined RNASET2 and paclitaxel treatments. The current results suggested that RNASET2 represents a new class of antitumorigenic and antiangiogenic drugs, and the findings of this study emphasize the advantage of using agents like RNASET2 in combined therapy.

Novel benzimidazole derivatives selectively inhibit endothelial cell growth and suppress angiogenesis in vitro and in vivo

We discovered a novel benzimidazole derivative, named compound (comp.) 1, with unique antiangiogenic characteristics. Comp.1 cytostatically inhibited the vascular endothelial growth factor- and basic fibroblast growth factor-induced growth of endothelial cells (50% inhibitory concentration: 29–79 nM) without a cytotoxic phase, but did not affect the growth of other types of cells up to 90 μM. Comp.1 also inhibited the tube formation derived from a rat aorta fragment, but the oral (p.o.) treatment of comp.1 (46 mg/kg, administered twice daily (b.i.d.)) did not inhibit aniogenesis in a mouse sponge model. Comp.8, an analogue of comp.1, showed a specific inhibitory effect on endothelial cell growth. Comp.8 also suppressed angiogenesis (15 mg/kg, b.i.d., p.o., 70% inhibition) in the sponge model without body weight loss.