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Background: This study aimed to examine the clinical characteristics of bone metastasis (BoM) in patients with non‐small cell lung cancer (NSCLC) who have an epidermal growth factor receptor (EGFR) mutation and to identify the most effective treatment strategy using EGFR–tyrosine kinase inhibitors (TKIs). Methods: The study included patients with stage IV EGFR‐mutated NSCLC who were receiving first‐line treatment with EGFR–TKIs between January 2014 and December 2020. These patients were divided into two groups based on the presence or absence of BoM at the time of initial diagnosis. The BoM group was further subdivided based on whether they received denosumab or not. Results: The final analysis included 247 patients. Those with BoM at initial diagnosis had shorter progression‐free survival (12.6 vs. 10.5 months, p = 0.002) and overall survival (OS) (49.7 vs. 30.9 months, p = 0.002) compared to those without BoM. There was a difference in the location of metastatic sites between the two groups, with a higher incidence of extrathoracic metastasis in the BoM group (p < 0.001). The incidence of T790M was higher in patients with BoM than in those without (47.4% vs. 33.9%, p = 0.042). Multivariate Cox regression analysis revealed that sequential osimertinib treatment and the addition of antiangiogenic therapy (AAT) and denosumab therapy improved OS in patients with BoM. Conclusions: The presence of BoM is a negative prognostic factor for NSCLC patients with an EGFR mutation, possibly due to the presence of extrathoracic metastases. However, adding AAT and denosumab, along with sequential osimertinib, to the treatment regimen for patients with BoM can improve survival outcomes. [ABSTRACT FROM AUTHOR]

Coevolution of tumor cells and surrounding stroma results in protective protumoral environment, in which abundant vessel, stiff structure and immunosuppression promote each other, cooperatively incurring deterioration and treatment compromise. Reversing suchenvironment may transform tumors from treatment‐resistant to treatment‐vulnerable. However, effective reversion requires synergistic comprehensive regression of such environment under precise control. Here, the first attempt to collaboratively retrograde coevolutionary tumor environment to pre‐oncogenesis status, defined as tumor environment regression therapy, is made for vigorous immune response eruption by a switchable prune‐to‐essence nanoplatform (Pres) with simplified composition and fabrication process. Through magnetic targeting and multimodal imaging of Pres, tumor environment regression therapy is guided, optimized and accomplished in a trinity way: Antiangiogenesis is executed to rarefy vessels to impede tumor progression. By seizing the time, cancer associated fibroblasts are eliminated to diminish collagen and loosen the stiff structure for deep penetration of Pres, which alternately functioned in deeper tumors, forming a positive feedback loop. Through this loop, immune cell infiltration, immunosuppression mitigation and immunogenic cells death induction are all fulfilled and further escalated in the regressed environment. These transformations consequently unleashed systemic immune responses and generated immune memory against carcinoma. This study provides new insights intotreatment of solid tumors. [ABSTRACT FROM AUTHOR]

A 67‐year‐old male patient presented with extensive‐stage small cell lung cancer with the primary lesion located in the right upper lung, accompanied by multiple metastases to the pleura and abdominal cavity with enlarged mediastinal lymph nodes. A combination therapy approach was used to target the patient's multiple systemic metastases after localized radiotherapy. The approach involved adoptive transfer of programmed death ligand 1 (PD‐L1) enhanced exogenous natural killer (NK) cells, along with antiangiogenic treatment. Allogeneic cord blood NK cells were infused back into the patient over two consecutive days. On the first day, the treatment was followed by a dose of 1200 mg of atezolizumab. Subsequently, the patient received a daily dose of 10 mg of anlotinib administered orally for 14 days. This was followed by a 7‐day break, and each cycle lasted 21 days. After delivering localized radiation to the primary lesion in the right lung and metastatic mediastinal lymph nodes, complete remission was achieved in the local lesion, effectively avoiding the risk of superior vena cava syndrome. Following six cycles of combined therapy, most of the metastatic lesions had disappeared, and the remaining metastatic lesions had significantly reduced in size. The recent therapeutic effect resulted in partial remission. The combination therapy of immune checkpoint inhibitor PD‐L1‐enhanced exogenous adoptive transfer NK cells, along with antiangiogenic targeted treatment, demonstrated a satisfactory short‐term effect, with disappearance of most of the metastases and noticeable shrinkage in the remaining metastatic lesions. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor receptor 2 (VEGFR2)/KDR plays a critical role in tumor growth, diffusion, and invasion. The amino acid sequence homology of KDR between mouse and human in the VEGF ligand‐binding domain was low, thus the WT mice could not be used to evaluate Abs against human KDR, and the lack of a suitable mouse model hindered both basic research and drug developments. Using the CRISPR/Cas9 technique, we successfully inserted different fragments of the human KDR coding sequence into the chromosomal mouse Kdr exon 4 locus to obtain an hKDR humanized mouse that can be used to evaluate the marketed Ab ramucirumab. In addition, the humanized mAb VEGFR‐HK19 was developed, and a series of comparative assays with ramucirumab as the benchmark revealed that VEGFR‐HK19 has higher affinity and superior antiproliferation activity. Moreover, VEGFR‐HK19 selectively inhibited tumor growth in the hKDR mouse model but not in WT mice. The most important binding epitopes of VEGFR2‐HK19 are D257, L313, and T315, located in the VEGF binding region. Therefore, the VEGFR2‐HK19 Ab inhibits tumor growth by blocking VEGF‐induced angiogenesis, inflammation, and promoting apoptosis. To our best knowledge, this novel humanized KDR mouse fills the gaps both in an animal model and the suitable in vivo evaluation method for developing antiangiogenesis therapies in the future, and the newly established humanized Ab is expected to be a drug candidate possibly benefitting tumor patients. [ABSTRACT FROM AUTHOR]

Development of monoclonal antibody therapeutics against vascular endothelial growth factor receptor 2 (VEGFR‐2) protein, which is the main regulator in angiogenesis, has been a major challenge for years. In the current study, we engineer an inclusion body forming single‐chain variable fragment (scFv) against VEGFR‐2 by using complementarity determining regions (CDR) grafting technique to improve its solubility and investigate the activity of the engineered molecule. CDR sequences of the target scFv were grafted into the framework of another intrinsically soluble scFv molecule. Based on the computational results, CDR grafting has increased the solubility of the grafted scFv molecule. Results confirmed that the grafting approach increased in vivo folding properties of the target scFv molecule compared with the original scFv molecule. Similar binding affinities to the VEGFR‐2 were observed for the original and the grafted scFv by surface plasmon resonance assays. Biological activity assays, including human umbilical vein endothelial cells proliferation and wound healing assays, showed that grafted scFv molecule has an antiangiogenic property. This study suggests that an antiangiogenic scFv fully expressed as an inclusion body can be rescued by grafting its CDR regions to a scFv expressed in a soluble form without any loss in its binding property and its activity. [ABSTRACT FROM AUTHOR]

We analyze a mathematical model for the combination of chemotherapy with antiangiogenic treatment as a multi‐input optimal control problem. Assuming that the total amounts of both agents to be given have been determined a priori based on a medical assessment of side effects, we consider the problem to minimize a weighted average of tumor volume and the carrying capacity of the tumor vasculature. For medically realistic initial conditions and data, based on a thorough theoretical analysis of the necessary conditions for optimality given by the Pontryagin maximum principle, in this paper, the optimal administration regimen for the antiangiogenic agent is determined. [ABSTRACT FROM AUTHOR]

Advanced hepatocellular carcinoma (HCC) was considered an inherently refractory tumor in the chemotherapy era (1950–2000). However, systemic therapy has evolved to molecular targeted therapy and immunotherapy, and nine treatment regimens have been approved worldwide during the past 20 years. The approved regimens target tumor angiogenesis or tumor immunity, the two cancer hallmarks. Recently, the combination of atezolizumab (antiprogrammed cell death ligand 1) and bevacizumab (anti‐vascular endothelial growth factor) has improved the efficacy of systemic therapy in treating advanced HCC without excessive toxicities or deterioration of quality of life. This review summarizes the major advances in systemic therapy and provides future perspectives on the next‐generation systemic therapy for advanced HCC. [ABSTRACT FROM AUTHOR]

Lichens are symbiotic organisms which are composed fungi and algae and/or cyanobacteria. They produce a variety of characteristic secondary metabolites. Such substances have various biological properties including antimicrobial, antiviral, and antitumor activities. Angiogenesis, the growth of new vessels from pre‐existing vessels, contributes to numerous diseases including cancer, arthritis, atherosclerosis, infectious, and immune disorders. Antiangiogenic therapy is a promising approach for the treatment of such diseases by inhibiting the new vessel formation. Technological advances have led to the development of various antiangiogenic agents and have made possible antiangiogenic therapy in many diseases associated with angiogenesis. Some lichens and their metabolites are used in the drug industry, but many have not yet been tested for their antiangiogenic effects. The cytotoxic and angiogenic capacities of lichen‐derived small molecules have been demonstrated in vivo and in vitro experiments. Therefore, some of them may be used as antiangiogenic agents in the future. The secondary compounds of lichen whose antiangiogenic effect has been studied in the literature are usnic acid, barbatolic acid, vulpinic acid, olivetoric acid, emodin, secalonic acid D, and parietin. In this article, we review the antiangiogenic effects and cellular targets of these lichen‐derived metabolites. [ABSTRACT FROM AUTHOR]

Accumulated evidence has shown that pre‐eclampsia (PE) is related to both maternal and utero‐placental antiangiogenesis and inflammation. Remarkably, an elevated cell‐free fetal DNA (cffDNA) level has been found in maternal circulation; however, it remains unclear whether this DNA can induce activation of cytosolic DNA sensor signaling pathways and lead to the development of PE. In this study, we found that trophoblast cells constitutively expressed the cytosolic DNA sensors, absent in melanoma 2 (AIM2) and interferon‐inducible protein 16 (IFI16). The cffDNA and pro‐inflammatory and antiangiogenic factors were present at higher concentrations in PE compared with the control group and correlated with the severity of PE. DNA stimulation significantly increased the AIM2 and IFI16 levels, consistent with the elevated AIM2 and IFI16 expression in women with PE, and elicited increased production of AIM2‐mediated interleukin IL‐8 (IL‐8), IL‐6 and CC chemokine ligand 2 (CCL2) and IFI16‐mediated sEndoglin, sFlt‐1 and CXCL10. Furthermore, enhancement of the inflammatory response was found to be induced by DNA exposure, but DNA exposure did not induce PE‐like symptoms in pregnant mice. It is possible that elevated cffDNA could reflect the degree of placental damage and trigger cytosolic DNA sensor activation, which disrupts the immunity balance and, consequently, contributes to inflammatory and antiangiogenic responses. In conclusion, the results of this study suggest that circulating cffDNA levels are increased in preeclamptic women and act through AIM2 and IFI16 activation to promote the production of pro‐inflammatory and antiangiogenic factors, which correlate with the severity of the disease, and may offer insights into the etiology and pathogenesis of PE. [ABSTRACT FROM AUTHOR]

In this study, we newly designed and synthesized a small library of ten structurally related C,N‐cyclometalated ruthenium(II) complexes containing various pyridine‐functionalized NHC ligand and chelating bipyridyl ligands (e.g. 2,2′‐bipyridine, 5,5′‐dimethyl‐2,2′‐bipyridine, and 1,10‐phenanthroline (phen)). The complexes were well characterized by NMR, electrospray ionization‐mass spectrometry, and single‐crystal X‐ray structure analyses. Among the new ruthenium(II) derivatives, we identified that the complex Ru8 bearing bulky moieties (i.e. phen and pentamethyl benzene) had the most potent cytotoxicity against all tested cancer cell lines, generating dose‐ and cell line‐dependent IC50 values at the range of 3.3–15.0 μm. More significantly, Ru8 not only efficiently inhibited the metastasis process against invasion and migration of tumor cells but also exhibited potent antivascular effects by suppressing HUVEC cells migration and tube formation in vitro and blocking vessel generation in vivo (chicken chorioallantoic membrane model). In a metastatic A2780 tumor xenograft‐bearing mouse model, administration of Ru8 outperformed antimetastatic agent NAMI‐A and clinically approved cisplatin in terms of antitumor efficacy and inhibition of metastases to other organs. Overall, these data provided compelling evidence that the new cyclometalated ruthenium complex Ru8 is an attractive agent because of synergistically suppressing bulky tumors and metastasized tumor nudes. Therefore, the complex Ru8 deserves further investigations. [ABSTRACT FROM AUTHOR]

Thymic carcinoma is a rare and highly aggressive mediastinal tumor. Most patients are diagnosed at surgically unresectable stages. Current prospective and retrospective studies have indicated that platinum and anthracycline‐based chemotherapy are the first choice drugs of first‐line therapy for advanced thymic carcinoma. However, there is no optimal treatment after progression for patients who have undergone first‐line and subsequent chemotherapy. Anlotinib, a novel small molecule tyrosine kinase multitarget inhibitor, was approved by the China Food and Drug Administration as a third‐line treatment for advanced non‐small cell lung cancer (NSCLC) in May 2018. Herein we report a case of an advanced thymic squamous cell carcinoma patient harboring EGFR exon 20 insertion who had previously received multiline therapy, including chemotherapy, radiotherapy as well as antiangiogenic therapy. Also as an angiogenesis inhibitor, anotinib had controlled his mediastinal mass after failure of the apatinib treatment. To date, over 23 months of progression‐free survival (PFS) and six years of overall survival (OS) have been achieved. Compared with apatinib, the adverse reactions have been mild and tolerable and the patient's quality of life has improved. To our knowledge, this is the first report where anlotinib has been effective in controlling the progression of thymic carcinoma. In the multiline treatment of advanced thymic carcinoma, anlotinib appears to show great potential when utilized as a salvage treatment. [ABSTRACT FROM AUTHOR]

Background: Anlotinib showed significant survival benefits in advanced non‐small cell lung cancer (NSCLC) patients as a third‐ or further‐line treatment in the ALTER0303 trial. We aimed to evaluate the efficacy of anlotinib in patients with different histologies. Methods: The ALTER0303 trial was a randomized, open‐label, phase 3 study of anlotinib in NSCLC patients previously treated with at least two lines of chemotherapy or a tyrosine kinase inhibitor (TKI) in 31 centers in China. Patients were randomly assigned at a 2:1 ratio to receive anlotinib (12 mg QD from days 1 to 14 of a 21‐day cycle) or placebo until progression or intolerable toxicity. The primary endpoint was overall survival (OS). We assessed the efficacy of anlotinib in histological subgroups in the full analysis set. Results: In the ALTER0303 trial, 336 patients had the histological subtype of adenocarcinoma (ACC), 86 patients had the histological subtype of squamous cell carcinoma (SCC), and 15 patients had another subtype. In the ACC subgroup, the median OS time was significantly improved with anlotinib compared with placebo (9.6 months vs 6.9 months, P =.0051), as was the median progression‐free survival (PFS) time (5.5 months vs 1.4 months, P <.0001). In the SCC subgroup, the median OS time was 10.7 months in the anlotinib group and 6.5 months in the placebo group (P =.2570), and the median PFS time was 4.8 months and 2.7 months (P =.0004), respectively. The common adverse events observed in the SCC and ACC subgroups were similar. Conclusions: Our findings suggest that anlotinib significantly improves PFS and OS in ACC patients and has a tendency to prolong survival in SCC patients. [ABSTRACT FROM AUTHOR]

Patients with tongue squamous cell carcinoma (TSCC) and cervical lymph node metastasis are particularly difficult to treat. This is the first report of about anlotinib combined with docetaxel chemotherapy for chemotherapy‐refractory TSCC with cervical lymph node metastasis, may provide a new, suitable therapeutic option for these patients. [ABSTRACT FROM AUTHOR]

A number of antiangiogenic drugs have been approved by the Food and Drug Administration which are used in cancer therapy, and variety of other agents in several stages of clinical development or in preclinical assessment. Among these, combretastatin A4 (CA‐4) is an under‐researched inhibitor of angiogenesis that shows potential activity in the treatment of advanced tumors with migration capacity. However, its clinical application has been limited due to poor water solubility, low bioavailability, rapid metabolism, and systemic elimination. During the last decade, numerous investigations have been done to overcome these problems by using different CA‐4 delivery systems or developing produgs of CA‐4 or its structural analogs. Nevertheless, these strategies could not be efficient out of the undesired side effects on normal tissues. Nanoliposomal CA‐4 not only benefits from the advantage of using liposomal drugs as opposed to free drugs but also can accumulate in the tumor site via specific targeting ligands, which leads to efficient targeting and enhancement of bioavailability. To the best of our knowledge, we consider an important attempt to understand different factors that might influence the CA‐4 loading and release pattern of liposomes and the consequent results in tumor therapy. In this review, we shed light on various studied liposomal CA‐4 formulations showing application thereof in cancer treatment. [ABSTRACT FROM AUTHOR]

Galbanic acid (GBA) is an active sesquiterpene coumarin derivative, with various medicinal benefits, including anticancer properties. However, the low solubility of GBA is the main limitation of its clinical applications. In this study, we used a nanosystem based on poly (D, l‐lactide)–polyethylene glycol (PLA–PEG), for the delivery of GBA to C26 colon carcinoma cells. The physicochemical characteristics of nanoparticles (NPs) prepared by the emulsification–evaporation method were evaluated. MTT assay was used to compare the anticell proliferation of GBA and PLA–PEG–GBA against C26 cell lines. PLA–PEG‐NPs with an average size of about 140 nm had an enhanced release of GBA at a pH of 5.5 compared with a pH of 7.4. Cytotoxicity studies showed that the IC 50 of the PLA–PEG–GBA NPs (8 µM) was significantly lower than free GBA (15 µM). In the in vivo study, PLA–PEG–GBA NPs exhibited remarkable efficacy and reduced in vivo toxicity in C26 colon carcinoma tumor‐bearing female BALB/c mice. To study the antiangiogenesis effect of the NPs, tumor sections were stained with an anti CD34 antibody. The results show the CD34 (+) vessels were decreased in the GBA and PLA–PEG–GBA treated mice by more than 75% and 90%, respectively. These results suggest that the encapsulation of GBA into the PLA–PEG could potentially be used for the treatment of colorectal cancer. In this study, we used a nanosystem based on poly (D, l‐lactide)–polyethylene glycol (PLA–PEG), for the delivery of galbanic acid (GBA) to C26 colon carcinoma cells. The results suggest that the encapsulation of GBA into the PLA–PEG could potentially be used for the treatment of colorectal cancer [ABSTRACT FROM AUTHOR]

The chick embryo chorioallantoic membrane (CAM) has long been a favored system for the study of tumor angiogenesis because at the stage of development when generally tumor grafts are placed (6–10 days of incubation), the chick's immunocompetent system is not fully developed and the conditions for rejection have not yet been established. All studies for mammalian neoplasms, including neuroblastoma, have used tumor cell lines, tumor bioptic specimens, cell suspensions derived from tumors, and mouse tumor xenografts bioptic specimens. CAM can also be used to study the effects of antiangiogenic molecules on tumor cell suspensions of tumor bioptic specimens. This review article summarizes and discusses the literature data on the use of the CAM as an in vivo experimental model to study human neuroblastoma. Two histological sections of a gelatin sponge soaked with a cell suspension of a human neuroblastoma cell line implanted in the chorioallantoic membrane surface. Indirect immunoperoxidase using a monoclonal antibody against neuroblastoma and aminoethylcarbazole as a chromogen (red staining). Note several neuroblastoma positive cells in a perivascular (a) and in an intravascular (b) position. [ABSTRACT FROM AUTHOR]

To investigate the suppressive effects of xanthatin on glioma growth in a nude mouse xenograft model and rat orthotopic implantation model using magnetic resonance imaging (MRI) to dynamically monitor the antitumour growth and antiangiogenesis effects of xanthatin. The nude mouse xenograft tumour model and rat orthotopic implantation model were established to observe the antitumour effects of xanthatin in vivo. In the rat orthotopic implanted tumour model, MRI scanning was used to dynamically monitor the antitumour growth effect and evaluate the antiangiogenesis effect of xanthatin. We found that xanthatin at a dose of 0.4 mg/10 g dramatically decreased the growth of xenograft tumours in nude mice. The antiangiogenesis effect of xanthatin C6 glioma was evaluated by dynamic contrast-enhanced (DCE) MRI via comparison of the volume transfer constant (Ktrans ) value, a parameter that reflects vessel permeability. We found that xanthatin at the doses of 8 and 16 mg/kg significantly decreased the Ktrans value, which suggests that xanthatin has antiangiogenesis effects. These data demonstrate the suppressive effects of xanthatin on C6 glioma occur via antiangiogenesis. Meanwhile, this study also provides evidence for the application of quantitative parameters of DCE-MRI for dynamically evaluating the growth and angiogenesis of intracranial tumours and for experimental and clinical research. [ABSTRACT FROM AUTHOR]

Objectives: Mucocele of the minor salivary gland is usually caused when the duct is injured, mucus leaks into the tissue space and the mucous gland are obstructed, which lead to cystic lesion formation and dilatation. Currently, there are multiple therapeutic methods available with various outcomes. This study aims to provide clinical evidence of polidocanol sclerotherapy for the treatment of mucocele of the minor salivary gland.Methods: In this study, we injected polidocanol into 112 patients who were diagnosed with mucocele of the minor salivary gland and evaluated the treatment efficacy and safety systematically.Results: Of the 122 cases, 102 cases were cured, eight cases showed remarkable remission, and two cases had partial remission. No recurrence was found during follow-up, and none of the cases showed an invalid effect, resulting in a total cure rate of 91.07%. No severe side effects were observed during treatment or the follow-up period. No significant difference in efficacy between different genders was found (P = 0.490). Polidocanol sclerotherapy for mucocele on the lower lip was more effective compared to mucocele on the inferior surface of the lingual apex (P = 0.035).Conclusion: Polidocanol sclerotherapy showed satisfying curative effects for mucocele of the minor salivary gland without causing side effects of anesthesia, trauma, or severe pain. [ABSTRACT FROM AUTHOR]

Angiogenesis is critical for tumor growth and mediated mainly by vascular endothelial growth factor (VEGF) signaling. Inhibition of the VEGF signaling pathway has emerged as one of the promising approaches for cancer therapy. VEGF receptor 2 (VEGFR-2) is considered as a major mediator of angiogenic effects of VEGF. We describe herein the discovery of a series of potent VEGFR-2 tyrosine kinase (KDR) inhibitors from a new 2-(2-aminopyrimidin-4-yl)phenol scaffold. The KDR activity was reduced appreciably by a series of compounds with a benzoyl group at position 4 of phenol ring. The structure-activity relationships for a series of (3-(2-aminopyrimidin-4-yl)-4-hydroxyphenyl)phenyl methanones revealed compound 9 (KDR IC50 = 25 nM) as the most potent inhibitor in the series. Compound 22 had a potent cellular activity on VEGF-induced HUVEC cell growth (IC50 < 0.1 μM) with high selectivity over HCT116. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) are receptor tyrosine kinases known to play critical roles in the development and progression of tumors. Based on the cross-talk between EGFR and VEGFR2 signal pathways, we designed and produced a bispecific diabody (bDAb) targeting both EGFR and VEGFR2 simultaneously. The bispecific molecule (EK-02) demonstrated that it could bind to HUVEC (VEGFR2 high-expressing) and A431 (EGFR overexpressing) cells. Additionally, similar to the parental antibodies, it was able to inhibit proliferation and migration, and induced apoptosis in these cells (HUVECs and A431), demonstrating that it had retained the functional properties of its parental antibodies. Furthermore, the efficacy of EK-02 was evaluated using the human colon adenocarcinoma cell line HT29 (VEGFR2 and EGFR coexpressing). In vitro assay showed that EK-02 could bind to HT29 cells, restrain cell growth and migration, and induce apoptosis with enhanced efficacy compared to both parental antibodies. Further, it inhibited the neovascularization and tumor formation on an HT29 cell bearing chicken chorioallantoic membrane (CAM) tumor model in vivo. In conclusion, these data suggest that the novel bDAb (EK-02) has antiangiogenesis and antitumor capacity both in vitro and in vivo, and can possibly be used as cotargeted therapy for the treatment of EGFR and VEGFR2 overexpressing tumors. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:294-302, 2016 [ABSTRACT FROM AUTHOR]

The Functional Assessment of Cancer Therapy ( FACT)-Antiangiogenesis (AntiA) Subscale was developed and validated to enhance treatment decision-making and side effect management for patients receiving anti-angiogenesis therapies. Side effects related to anti-angiogenesis therapies were identified from the literature, clinician input, and patient input. Fifty-nine possible patient expressions of side effects were generated. Patient and clinician ratings of the importance of these expressions led us to develop a 24-item questionnaire with clinical and research potential. To assess the scale's reliability and validity, 167 patients completed the AntiA Subscale, the Functional Assessment of Cancer Therapy-general ( FACT-G), the FACT-Kidney Symptom Index ( FKSI), the FACIT-Fatigue Subscale, the Global Rating of Change Scale ( GRC), and the PROMIS Global Health Scale. Patient responses to the AntiA were analyzed for internal consistency, test-retest reliability, convergent and discriminant validity, and responsiveness to change in clinical status. All tested scales were found to have good internal consistency reliability (Cronbach's alpha 0.70-0.92). Test-retest reliability was also good (0.72-0.88) for total and subscale scores and lower for individual items. The total score, subscale scores, and all single items (except nosebleeds) significantly differentiated between groups defined by level of side effect bother. Evaluation of responsiveness to change in this study was not conclusive, suggesting an area for further research. The AntiA is a reliable and valid measure of side effects from anti-angiogenesis therapy. [ABSTRACT FROM AUTHOR]

Noninvasive imaging has been widely applied for monitoring antiangiogenesis therapy in cancer drug discovery. In this report, we used different imaging modalities including high-frequency ultrasound ( HFUS), dynamic contrast enhanced- MR ( DCE- MR), and fluorescence molecular tomography ( FMT) imaging systems to monitor the changes in the tumor vascular properties after treatment with γ-secretase inhibitor PF-03084014. Sunitinib was tested in parallel for comparison. In the MDA- MB-231Luc model, we demonstrated that antiangiogenesis was one of the contributing mechanisms for the therapeutic effect of PF-03084014. By immunohistochemistry and FITC-lectin perfusion assays, we showed that the vascular defects upon treatment with PF-03084014 were associated with Notch pathway modulation, evidenced by a decrease in the HES1 protein and by the changes in VEGFR2 and HIF1 α levels, which indicates down-stream effects. Using a 3D power Doppler scanning method, ultrasound imaging showed that the% vascularity in the MDA- MB-231Luc tumor decreased significantly at 4 and 7 days after the treatment with PF-03084014. A decrease in the tumor vessel function was also observed through contrast-enhanced ultrasound imaging with microbubble injection. These findings were consistent with the PF-03084014-induced functional vessel changes measured by suppressing the Ktrans values using DCE- MRI. In contrast, the FMT imaging with the AngioSence 680 EX failed to detect any treatment-associated tumor vascular changes. Sunitinib demonstrated an outcome similar to PF-03084014 in the tested imaging modalities. In summary, ultrasound and DCE- MR imaging successfully provided longitudinal measurement of the phenotypic and functional changes in tumor vasculature after treatment with PF-03084014 and sunitinib. [ABSTRACT FROM AUTHOR]

Advanced gastric cancer is a common disease, but the conventional treatments are unsatisfactory because of the high recurrence rate. One of the promising new therapies is oncolytic virotherapy, using oncolytic herpes simplex viruses (HSVs). Thrombospondin-1 (TSP-1) suppresses tumor progression via multiple mechanisms including antiangiogenesis. Our approach to enhance the effects of oncolytic HSVs is to generate an armed oncolytic HSV that combines the direct viral oncolysis with TSP-1-mediated function for gastric cancer treatment. Using the bacterial artificial chromosome (BAC) system, a 3rd generation oncolytic HSV (T-TSP-1) expressing human TSP-1 was constructed for human gastric cancer treatment. The enhanced efficacy of T-TSP-1 was determined in both human gastric cancer cell lines in vitro and subcutaneous tumor xenografts of human gastric cancer cells in vivo. In addition, we examined the apoptotic effect of T-TSP-1 in vitro, and the antiangiogenic effect of T-TSP-1 in vivo compared with a non-armed 3rd generation oncolytic HSV, T-01. No apparent apoptotic induction by T-TSP-1 was observed for human gastric cancer cell lines TMK-1 cells but for MKN1 cells in vitro. Arming the viruses with TSP-1 slightly inhibited their replication in some gastric cancer cell lines, but the viral cytotoxicity was not attenuated. In addition, T-TSP-1 exhibited enhanced therapeutic efficacy and inhibition of angiogenesis compared with T-01 in vivo. In this study, we established a novel armed oncolytic HSV, T-TSP-1, which enhanced the antitumor efficacy by providing a combination of direct viral oncolysis with antiangiogenesis. Arming oncolytic HSVs may be a useful therapeutic strategy for gastric cancer therapy. [ABSTRACT FROM AUTHOR]

Orthosiphon stamineus Benth. (Family: Lamiaceae), a famous traditional medicinal plant in tropical and sub-tropical region, is being used for treating various ailments including inflammatory conditions. Since anti-inflammation and antiangiogenesis involve cyclooxygenase-II pathway, the present study is aimed to carry out antiangiogenic studies and bioassay-guided isolation on aqueous extract of the plant. After antiangiogenic activity studies on the extract, fractions were prepared by partitioning the extract with hexane, chloroform and ethyl acetate, which were then evaluated for antiangiogenic activity. The most active, hexane fraction (HF) upon activity-guided isolation gave three compounds, 1 (betulinic acid), 2 (oleanolic acid) and 3 (ursolic acid). The total contents of these three compounds were determined in the extract and its fractions using HPLC. The extract and HF exhibited 20% and 80% antiangiogenic activity, respectively, whereas, chloroform and ethyl acetate fractions were inactive. The three isolated compounds exhibited 100% antiangiogenic activity. Median effective concentrations (EC50s) of HF, 1, 2 and 3 were found to be 84, 32, 34 and 38 μg/mL, respectively. The results of this study indicate that hexane fraction and the isolated compounds have promising antiangiogenic activity. Additionally, the isolated compounds may be sued as analytical markers to standardize extracts and formulations prepared from O. stamineus. [ABSTRACT FROM AUTHOR]

BACKGROUND Sunitinib ( SUTENT, Pfizer Inc., New York, NY) is a multitargeted inhibitor of selected receptor tyrosine kinases, which produces an antiproliferative and antiangiogenic effect by blocking pathways fundamental to tumor growth and survival. We investigated the effects of sunitinib on male and female fertility and early embryonic development in the rat. METHODS In the female fertility and early embryonic development phase, untreated males were paired with treated females dosed at 0 (control), 0.5, 1.5, and 5 mg/kg/day from 14 days premating, through mating, to gestation day 7. In the male fertility phase, the same males were then treated 58 days at doses of 0 (control), 1, 3, and 10 mg/kg/day, mated with untreated females, with continued daily dosing for a total of 74 days. RESULTS There was no systemic toxicity- or treatment-related effects on fertility in female rats. Females exposed at 5 mg/kg/day had an increase in the number of early resorptions with associated decrease in viable embryos. In the males, body weight and food consumption were decreased at 10 mg/kg/day compared to the controls. Male reproductive capacity, as assessed by copulation, fertility, and conception indices, was not impacted at any dose level. Sperm morphology, concentration, and motility were also unaffected by treatment. CONCLUSIONS There were no effects on male reproduction. An increase in corpora lutea and an increase in early resorptions with associated reduction in viable embryos was noted in the females dosed 5 mg/kg/day. Sunitinib at doses up to 1.5 and 10 mg/kg/day had no effects on female and male reproduction, respectively. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the toxicoses and antitumor activity of metronomic chlorambucil at a dosage of 4 mg m−2 daily in dogs with naturally occurring cancer. Thirty-six dogs were enrolled in the study. The protocol was well tolerated with no grade 3 or 4 toxicoses noted. Complete remission was achieved, and lasted over 35 weeks in three dogs (mast cell tumour, soft tissue sarcoma and thyroid carcinoma). Partial remission was noted in 1 dog with histiocytic sarcoma (39 weeks duration) for an overall remission rate of 11% (4 of 36). Stable disease was noted in 17 dogs (47%) with various other cancers. The median progression-free interval was 61 days, and the median survival time was 153 days. Chlorambucil given in a metronomic protocol showed antitumor activity in dogs with a variety of naturally occurring cancers. [ABSTRACT FROM AUTHOR]

The article details a study which examined the activity and tolerability of combined bevacizumab and everolimus in patients with metastatic melanoma. The study included patients with metastatic melanoma who received up to two previous chemotherapy or immunotherapy, who were given bevacizumab and everolimus. Study authors concluded that combined bevacizumab and everolimus has moderate activity and was well tolerated in patients with metastatic melanoma.

The article offers information on the clinical use and efficacy of bevacizumab in patients with high-grade glioma (HGG), along with the issues surrounding its administration. A description of the role of angiogenesis in HGG is presented. The clinical use of bevacizumab in the treatment of malignant gliomas is explained, including the development of bevacizumab-based treatment. Evidence on the efficacy and safety of bevacizumab are also given.

The article presents a study which probes the effects of the combination of AZD6244, a medicine for cancer treatment and mammalian target of rapamycin (mTOR) inhibitor rapamycin (RAPA) in the preclinical models of human hepatocellular carcinoma (HCC). The study treated patient-derived HCC xenografts with RAPA, MEK inhibitor AZD6244 (ARRY-142886), and AZD6244 plus RAPA. Conclusions suggest that AZD6244/RAPA combination had antiangiogenic and antitumor effects in preclinical models of human HCC.

The article discusses the medical challenges of thalidomide. It notes that thalidomide is a glutamic acid derivative which consists of a glutaramide ring and pthalimido ring. Thalidomide is originally marketed as a sedative and anti-hypnotic in 1957 by Chemie-Grunenthal for the effective relief of morning sickness during early pregnancy. However, thalidomide was the reason behind the increase in birth defects especially in the limbs, ears and eyes.

• Introduction • The importance of angiogenesis in physiological and pathological conditions • The contribution of immune cells to angiogenesis in inflammation and tumour growth • Neutrophils • Basophils • Eosinophils • Monocytes-macrophages • Lymphocytes • Dendritic cells • The contribution of progenitor cells and adult cell transdifferentiation • Mast cells • Platelets • Conclusions Both innate and adaptive immune cells are involved in the mechanisms of endothelial cell proliferation, migration and activation, through the production and release of a large spectrum of pro-angiogenic mediators. These may create the specific microenvironment that favours an increased rate of tissue vascularization. In this review, we will focus on the immune cell component of the angiogenic process in inflammation and tumour growth. As angiogenesis is the result of a net balance between the activities exerted by positive and negative regulators, we will also provide information on some antiangiogenic properties of immune cells that may be utilized for a potential pharmacological use as antiangiogenic agents in inflammation as well as in cancer. [ABSTRACT FROM AUTHOR]

Objectives: Human head and neck squamous cell carcinoma (HNSCC) in addition to lung, skin, ovarian, and other cancers overexpress fibroblast growth factor (FGF) receptors on both individual tumor cells and endothelial cells within the tumor microenvironment. The purpose of this study was to investigate whether FGF2-targeted gene therapy could redirect adenoviral vectors encoding the herpes simplex virus thymidine kinase gene (Ad-TK) to FGF receptors on tumor and endothelial cells with the intent of improving both the efficiency of transgene expression and the antitumor response. Study Design and Methods: An Ad-TK vector consisting of a conjugate of FGF2 linked to a Fab′ fragment against the adenoviral knob region was directly delivered to human HNSCC xenograft tumors in nude mice, which were subsequently dosed with ganciclovir. Tumor specimens were assessed for herpes simplex virus thymidine kinase (HSV- tk) transgene mRNA expression, FGF1/2 receptor expression, terminal deoxynucleotidyl transferase biotin-deoxy uridine triphosphate nick end labeling assay for apoptosis, CD31 immunohistochemistry to estimate tumor microvessel density, and tumor volume change. Results: FGF2-retargeted Ad-TK gene therapy demonstrated significant increases in both HSV- tk mRNA expression and cellular apoptosis levels, and a significant decrease in tumor volume size compared with all other groups. Furthermore, microvessel density was significantly lower in the FGF2-retargeted Ad-TK group, indicating a strong antiangiogenesis effect. Conclusions: These data suggest that FGF2-retargeted Ad-TK produces a combination of expected direct antitumor cytotoxicity and a newly reported antiangiogenesis effect that could prove promising as a novel therapeutic approach in the treatment of FGF receptor-expressing cancers. Laryngoscope, 2009 [ABSTRACT FROM AUTHOR]

Angiogenesis, the growth of new capillary blood vessels, is a central regulator of cancer growth, and a validated target for cancer therapy. The antiangiogenic agents in clinical use target one or more cellular pathways involved in the cascade of vascular growth. In haematological malignancies, angiogenesis occurs within a bone marrow ecosystem comprised of closely apposed malignant cells, endothelial cells, pericytes, fibroblasts, endothelial progenitor cells, dendritic cells, and extracellular matrix. Inhibition of angiogenesis therefore blocks not only the delivery of oxygen and micronutrients to cancer cells, but also disrupts the interdependency of these cellular players and the paracrine effects they exert to maintain the malignant phenotype. Agents such as thalidomide, lenalidomide, bortezomib, and bevacizumab, have demonstrated clinical activity in myeloma, myelodysplastic syndrome, and leukaemias. In leukaemia, vascular endothelial growth factor (VEGF) is emerging as a compelling biological target for therapy, as well as a potential predictive marker for disease relapse. Initial clinical studies suggest that the anti-VEGF strategies may advance the primary, sequential or adjunctive treatment for leukaemia, and establish the basis for other potential antiangiogenic strategies in haematological malignancies. [ABSTRACT FROM AUTHOR]

It is well appreciated that hepatocellular carcinoma (HCC) represents one of the most challenging malignancies of worldwide importance. In fact, HCC is the fifth most common cancer and the third most common cause of cancer-related death globally. The incidence rates for HCC in the U.S. and Western Europe have been rising. Unresectable or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit. Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed, molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, such as renal cell carcinoma, there has been renewed interest in developing novel systemic therapy in HCC. At the recent Annual Meeting of the American Society of Clinical Oncology, results of a phase 3, randomized, placebo-controlled trial were presented in which sorafenib demonstrated improved survival in patients with advanced HCC. This landmark study represents the first agent that has demonstrated an improved overall survival benefit in this disease and sets the new standard for first-line treatment of advanced HCC. For this review, the author concisely summarized the current status of molecularly targeted agents that are under clinical development in advanced HCC. [ABSTRACT FROM AUTHOR]

The immunomodulatory drugs (IMiDs) lenalidomide and actimid (also known as CC-4047) are thalidomide analogues which are more potent than their parental compound. In combination with rituximab, we have previously demonstrated that IMiDs have synergistic in vivo anti-tumour activity in preclinical studies in a human lymphoma severe combined immunodeficiency mouse model. This report further explored the mechanisms by which IMiDs exert their anti-lymphoma effects. Following exposure of subcutaneous lymphoma tumours in murine models to IMiDs, there was a significant increase in the recruitment of natural killer (NK) cells to tumour sites. This increase in NK cells was mediated via stimulation of dendritic cells and modification of the cytokine microenvironment associated with an increase in monocyte chemotactic protein-1, tumour necrosis factor-α and interferon-γ and probably augmented rituximab-associated antibody-dependent cellular cytotoxicity. IMiDs also had significant anti-angiogenic effects in our B-cell lymphoma models. Thus, by modulation of the immune system mediated via dendritic cells and NK cells, changing the cytokine milieu, as well as by their anti-angiogenic effects, IMiDs in combination with rituximab resulted in augmented in vivo anti-tumour effects against B-cell lymphoma. Our positive preclinical data adds additional support for the evaluation of IMiDs plus rituximab in patients with relapsed/refractory B-cell lymphoma. [ABSTRACT FROM AUTHOR]

We investigated whether transfer of the gene encoding the angiogenesis inhibitor endostatin into the NIH/3T3 fibroblast cell line could inhibit renal tumor growth in vivo. NIH/3T3 cells were transduced with retroviral vectors containing the murine endostatin (ES) gene. SCID mice bearing CaKi-1 derived tumors were given a subcutaneous injection of either ES-transduced cells or control cells and were monitored for tumor growth. At the end of the in vivo experiment, the mean tumor volume of treated mice was 51.6 ± 2.4 mm³, while the tumor volume of control was 234.5 ± 14.8 mm³. Microvascular density was significantly decreased on treatment (control 9.79 vs. ES 2.53%, <0.001) accompanied by a 23-fold increase in intraturmoral necrotic area and a 2.94-fold increase in the apoptotic index, determined by immunohistochemistry with anti- activated caspase-3. Apoptotic cells were found in foci enriched in infiltrating leukocytes. In conclusion, retroviral endostatin gene transfer led to secretion of functional endostatin that was sufficiently active to inhibit tumor angiogenesis and tumor growth. A second mechanism may also be implied in endostatindependent tumor regression, associated with tumor infiltration of leukocytes. Besides its antiangiogenic properties, endostatin may be a promising adjuvant to immunotherapy. [ABSTRACT FROM AUTHOR]

Angiogenesis, i.e. sprouting of new vessels, their remodelling and regression, is a prerequisite for growth and differentiation of organs and tissues. It is involved in many pathological processes, particularly growth and metastasis of tumours. Angiostatic therapy is a promising new strategy in the treatment of cancer. Angiogenesis inhibitors could intervene in the different phases of the angiogenic cascade, i.e. migration, proliferation, differentiation and three-dimensional organisation of endothelial cells, to inhibit the generation of tumour vessels. The aim of this study was to explore whether in a previously validated in vitro model for quantitation of angiogenesis the effects of the angiostatic factors angiostatin and suramin can be investigated and quantified. Examination of angiostatin and suramin showed that angiostatin-induced antiangiogenesis resulted in inverse angiogenesis. The addition of suramin initially resulted in increased angiogenesis. However, long-term incubation ultimately led to disintegration of endothelial structures, thus establishing the angiostatic effects of suramin. Antiangiogenesis was not only quantified using the previously validated method. It also lent itself to assessment of the extent of antiangiogenesis within the various phases of the angiogenic cascade. This method may therefore be employed in trial studies of potential angiostatic substances and related cellular mechanisms. [ABSTRACT FROM AUTHOR]

The antiangiogenic and antitumor properties of Grateloupia longifolia polysaccharide (GLP), a new type of polysaccharide isolated from the marine alga, were investigated with several in vitro and in vivo models. Possible mechanisms underlying its antiangiogenic activity were also assessed.GLP dose-dependently inhibited proliferation of human microvascular endothelial cells (HMEC-1) and human umbilical vein endothelial cells (HUVEC), with IC50 values of 0.86 and 0.64 mg ml−1, respectively. In tube formation and cell migration assays using HMEC-1 cells, noncytotoxic doses of GLP significantly inhibited formation of intact tube networks and reduced the number of migratory cells. Inhibition by GLP was VEGF-independent.In the chick chorioallantoic membrane (CAM) assay, GLP (2.5 μg egg−1) reduced new vessel formation compared with the vehicle control. GLP (0.1 mg plug−1) also reduced the vessel density in Matrigel plugs implanted in mice.The levels of pan and phosphorylated recptors for VEGF, VEGFR-1 (flt-1) and VEGFR-2 (KDR) were not significantly altered by 5 mg ml−1 GLP treatment of HMEC-1, although tissue factor (TF) showed significant decreases at both mRNA and protein levels following GLP treatment.In mice bearing sarcoma-180 cells, intravenous administration of GLP (200 mg kg−1) decreased tumor weight by 52% without obvious toxicity. Vascular density in sections of the tumor was reduced by 64% after GLP treatment.Collectively, these results indicate that GLP has antitumor properties, associated at least, in part, with the antiangiogenesis induced by downregulation of TF.British Journal of Pharmacology (2006) 148, 741–751. doi:10.1038/sj.bjp.0706741; published online 22 May 2006 [ABSTRACT FROM AUTHOR]

Lennernäs B, Albertsson P, Damber JE, Norrby K. Antiangiogenic effect of metronomic paclitaxel treatment in prostate cancer and non-tumor tissue in the same animals: a quantitative study. APMIS 2004;112:201–9. Well-tolerated continuous or metronomic chemotherapy can exert a marked antiangiogenic and thus superior antitumor effect compared with conventional high-dose, temporarily spaced-out chemotherapy, as shown in preclinical studies. There is, however, no means of directly assessing the antiangiogenic effect in a tumor, a serious impediment to assessing the effects of putative antiangiogenic chemotherapeutics or treatments. In an attempt to circumvent or minimize this impediment we studied the antiangiogenic effect of well-tolerated metronomic paclitaxel therapy in a surrogate tumor-free tissue that allows true quantitative analysis as well as in syngeneic At-1 prostate cancer in the same rat. This novel model allows an accurate comparison of the angiogenesis-modulating effect of chemotherapy in the two tissues to be made. The effect of chemotherapy on -mediated angiogenesis, a characteristic of most tumors, was assessed truly quantitatively by microscopic morphometry and image analysis in the tumor-free mesentery. The chemotherapy significantly suppressed -mediated angiogenesis in the mesentery to an extent that closely mirrored the significant increase in tumor necrosis measured morphometrically and the significant decrease in tumor growth rate. This finding opens an avenue to study quantitatively and systematically the antiangiogenic effect of chemotherapeutic modalities and treatments that approximately mirror their antiangiogenic effect in the At-1 tumor. [ABSTRACT FROM AUTHOR]

The hypothesis that the combination of two known antiangiogenic agents TNP-470 and interferon (IFN)-α exerts synergistic effects has been investigated in vitro and in vivo. In vitro, TNP-470 and recombinant human IFN-α2a (rhIFN-α2a) resulted in a dose-dependent inhibition of proliferation of human umbilical vein endothelial cells (HUVECs) and EA.hy926 endothelial cells. Compared with the two agents used singly at their lowest or ineffective doses, combined treatment with the same doses inhibited more intensely in the absence of cytotoxicity and displayed similar behaviour on cell chemotaxis and capillary morphogenesis on Matrigel. However, the secretion of matrix metalloproteinase 2 (MMP-2) and MMP-9 was not influenced by the two agents, either alone or in combination, even when they were applied at their lowest efficacious doses or at higher cytotoxic doses. Experiments in vivo with the chick embryo chorioallantoic membrane (CAM)–sponge assay revealed the same dose-dependent inhibition and synergy. As the basic fibroblast growth factor (bFGF)-induced angiogenesis in the CAM–sponge model was strongly inhibited by the combined treatment, TNP-470 and rhIFN-α2a would appear to exert antiangiogenesis synergistically, perhaps by interfering with the bFGF-mediated pathway. [ABSTRACT FROM AUTHOR]

Since the recognition of the importance of the vascular bed for growth and metastasis of solid tumours, many researchers have investigated the approach of attacking the tumour vascular bed instead of the tumour cells themselves in anti-cancer therapy. Such approaches have become possible with the increasing knowledge of the angiogenic process and the factors that regulate it. Especially the potent angiogenic factor VEGF has been the subject of extensive study in this regard. A number of studies showed that inactivation of this factor or its receptors led to a profound negative effect on the development of experimental tumours. However, despite the encouraging results obtained in animal studies, it remains to be established whether human tumours, which might be in a state of relative quiescence, are as sensitive to anti-VEGF treatment as the fast-growing tumours that are generally used in animal studies. If so, anti-VEGF treatment might certainly represent a powerful tool in anti-cancer therapy, either or not in combination with other blockers of angiogenesis. [ABSTRACT FROM AUTHOR]

Keywords: antiangiogenesis; antimetastasis; cancer chemotherapy; cytotoxicity; ruthenium(II) complexes EN antiangiogenesis antimetastasis cancer chemotherapy cytotoxicity ruthenium(II) complexes 15050 15050 1 11/28/20 20201126 NES 201126 B Three birds with one stone b : New therapies are needed to facilitate synergistic combinations that span distinct antitumor mechanisms. Antiangiogenesis, antimetastasis, cancer chemotherapy, cytotoxicity, ruthenium(II) complexes. [Extracted from the article]

Applying a bioactivity-guided isolation approach, staurosporine was separated and identified as the active principle in the culture extract of the new isolate Streptomyces sp. BV410 collected from the chamomile rhizosphere. The biotechnological production of staurosporine by strain BV410 was optimized to yield 56 mg/L after 14 days of incubation in soy flour-glucose-starch-mannitol-based fermentation medium (JS). The addition of FeSO 4 significantly improved the staurosporine yield by 30%, while the addition of ZnSO 4 significantly reduced staurosporine yield by 62% in comparison with the starting conditions. Although staurosporine was first isolated in 1977 from Lentzea albida (now Streptomyces staurosporeus) and its potent kinase inhibitory effect has been established, here, the biological activity of this natural product was assessed in depth in vivo using a selection of transgenic zebrafish (Danio rerio) models, including Tg(fli1:EGFP) with green fluorescent protein-labeled endothelial cells allowing visualization and monitoring of blood vessels. This confirmed a remarkable antiangiogenic activity of the compound at doses of 1 ng/ml (2.14 nmol/L) which is below doses inducing toxic effects (45 ng/ml; 75 nmol/L). A new, efficient producing strain of commercially significant staurosporine has been described along with optimized fermentation conditions, which may lead to optimization of the staurosporine scaffold and its wider applicability., (© 2020 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)