• Calotropis procera
• Human angiogenic antibody array
• Natural anti-angiogenic compounds
• TG (fli1:EGFP)
• Xerophytic plants

• Calotropis/chemistry
• Humans
• Plant Extracts/pharmacology
• Plant Extracts/chemistry
• Zebrafish
• Liver Neoplasms/drug therapy
• Animals
• Cell Line, Tumor
• Breast Neoplasms/drug therapy
• Antineoplastic Agents, Phytogenic/pharmacology
• Antineoplastic Agents, Phytogenic/chemistry
• Plant Leaves/chemistry
• Female
• Angiogenesis Inhibitors/pharmacology
• Angiogenesis Inhibitors/chemistry
• Computer Simulation
• Phytochemicals/pharmacology
• Phytochemicals/chemistry
• Phytochemicals/analysis
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/analysis

• axitinib
• hepatocellular carcinoma
• mechanism
• survival
• tyrosine kinase

• Humans
• Axitinib/therapeutic use
• Carcinoma, Hepatocellular/pathology
• Sorafenib/therapeutic use
• Vascular Endothelial Growth Factor A
• Programmed Cell Death 1 Receptor
• Indazoles/pharmacology
• Liver Neoplasms/pathology
• Imidazoles/pharmacology

• Wellcome Trust
• R01 HD097068 NICHD NIH HHS
• Simons Foundation
• Wellcome
• NIH
• NSF
• BBSRC
• Swiss National Foundation
• Henri Seydoux Fund

• naphthopyran
• multitargeting
• c-myb
• microtubule
• antiangiogenesis

• Wilhelm Sander-Stiftung

• Breast cancer
• Cardiovascular disease
• Oncology
• Therapeutics

• Antioxidants/pharmacology
• Cardiotoxicity/prevention & control
• Constitutive Androstane Receptor
• Cyclophosphamide
• Cytochrome P-450 CYP2B6
• Doxorubicin/pharmacology
• Humans
• NF-E2-Related Factor 2/metabolism
• Triple Negative Breast Neoplasms/drug therapy

• R01 CA262084 NCI NIH HHS
• R01 GM121550 NIGMS NIH HHS
• UL1 TR003098 NCATS NIH HHS
• National Cancer Institute

• Angiogenesis
• Anti-angiogenic agents
• Combination therapy
• Resistance
• Tumor

• Angiogenesis Inhibitors/pharmacology
• Angiogenesis Inhibitors/therapeutic use
• Humans
• Immunotherapy
• Neoplasms/drug therapy
• Neoplasms/pathology
• Neovascularization, Pathologic/metabolism

• Anti-angiogenics
• Cancer
• Chemotherapy
• Dosing schedule
• Immunotherapy
• Innate and adaptive immunity
• Low and medium dose
• Metronomic

• Administration, Metronomic
• Angiogenesis Inhibitors/administration & dosage
• Angiogenesis Inhibitors/immunology
• Angiogenesis Inhibitors/therapeutic use
• Antineoplastic Agents, Hormonal/administration & dosage
• Antineoplastic Agents, Hormonal/immunology
• Antineoplastic Agents, Hormonal/therapeutic use
• Delayed-Action Preparations
• Dose-Response Relationship, Drug
• Drug Carriers
• Drug Liberation
• Humans
• Neoplasms/drug therapy
• Neovascularization, Pathologic/drug therapy
• Vascular Endothelial Growth Factor A/drug effects

• Adolescent
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Argentina
• Brazil
• Child
• Cyclophosphamide/administration & dosage
• Cyclophosphamide/adverse effects
• Disease Progression
• Disease-Free Survival
• Europe
• Female
• Humans
• Israel
• Maintenance Chemotherapy/adverse effects
• Maintenance Chemotherapy/mortality
• Male
• Remission Induction
• Rhabdomyosarcoma, Alveolar/drug therapy
• Rhabdomyosarcoma, Alveolar/mortality
• Rhabdomyosarcoma, Alveolar/pathology
• Rhabdomyosarcoma, Embryonal/drug therapy
• Rhabdomyosarcoma, Embryonal/mortality
• Rhabdomyosarcoma, Embryonal/pathology
• Risk Assessment
• Risk Factors
• Time Factors
• Vinorelbine/administration & dosage
• Vinorelbine/adverse effects
• Young Adult

• 28028 Cancer Research UK
• 5943 Cancer Research UK

Antiangiogenic strategies have not shown striking antitumor activities in the majority of glioma patients so far. It is unclear which antiangiogenic combination regimen with standard therapy is most effective. Therefore, we compared anti-VEGF-A, anti-Ang2, and bispecific anti-Ang-2/VEGF-A antibody treatments, alone and in combination with radio- or temozolomide (TMZ) chemotherapy, in a malignant glioma model using multiparameter two-photon in vivo microscopy in mice. We demonstrate that anti-Ang-2/VEGF-A lead to the strongest vascular changes, including vascular normalization, both as monotherapy and when combined with chemotherapy. The latter was accompanied by the most effective chemotherapy-induced death of cancer cells and diminished tumor growth. This was most probably due to a better tumor distribution of the drug, decreased tumor cell motility, and decreased formation of resistance-associated tumor microtubes. Remarkably, all these parameters where reverted when radiotherapy was chosen as combination partner for anti-Ang-2/VEGF-A. In contrast, the best combination partner for radiotherapy was anti-VEGF-A. In conclusion, while TMZ chemotherapy benefits most from combination with anti-Ang-2/VEGF-A, radiotherapy does from anti-VEGF-A. The findings imply that uninformed combination regimens of antiangiogenic and cytotoxic therapies should be avoided.

• Ang-2
• VEGF-A
• antiangiogenic therapy
• in vivo imaging
• radio- and chemotherapy

Tumor vascular normalization theory opened the door for the rational use of antiangiogenic agents and chemotherapeutics.

• angiogenesis
• inhibitors
• isomerization
• kinases
• photochemistry

The 5^th Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6^th – 8^th May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians and researchers interested in metronomic chemotherapy, anti-angiogenics, drug repurposing and combinations thereof. Clinical experiences, including many from India, were reported and discussed in three symposia covering breast cancer, head and neck cancers and paediatrics. On the pre-clinical side research into putative mechanisms of action, and the interactions between low dose metronomic chemotherapy and angiogenesis and immune responses, were discussed in a number of presentations. Drug repurposing was discussed both in terms of clinical results, particularly with respect to angiosarcoma and high-risk neuroblastoma, and in pre-clinical settings, particularly the potential for peri-operative interventions. However, it was clear that there remain a number of key areas of challenge, particularly in terms of definitions, perceptions in the wider oncological community, mechanisms of action and predictive biomarkers. While the potential for metronomics and drug repurposing in low and middle income countries remains a key theme, it is clear that there is also considerable potential for clinically relevant improvements in patient outcomes even in high income economies.

• LMIC
• Metronomic chemotherapy
• anti-angiogenics
• cancer
• drug repurposing

• Metronomic chemotherapy
• Nanomedicine
• Paclitaxel
• Tumor priming
• Tumor vascular normalization

Cyclophosphamide treatment on a six-day repeating metronomic schedule induces a dramatic, innate immune cell-dependent regression of implanted gliomas. However, little is known about the underlying mechanisms whereby metronomic cyclophosphamide induces innate immune cell mobilization and recruitment, or about the role of DNA damage and cell stress response pathways in eliciting the immune responses linked to tumor regression.

Untreated and metronomic cyclophosphamide-treated human U251 glioblastoma xenografts were analyzed on human microarrays at two treatment time points to identify responsive tumor cell-specific factors and their upstream regulators. Mouse microarray analysis across two glioma models (human U251, rat 9L) was used to identify host factors and gene networks that contribute to the observed immune and tumor regression responses.

Metronomic cyclophosphamide increased expression of tumor cell-derived DNA damage, cell stress, and cell death genes, which may facilitate innate immune activation. Increased expression of many host (mouse) immune networks was also seen in both tumor models, including complement components, toll-like receptors, interferons, and cytolysis pathways. Key upstream regulators activated by metronomic cyclophosphamide include members of the interferon, toll-like receptor, inflammatory response, and PPAR signaling pathways, whose activation may contribute to anti-tumor immunity. Many upstream regulators inhibited by metronomic cyclophosphamide, including hypoxia-inducible factors and MAP kinases, have glioma-promoting activity; their inhibition may contribute to the therapeutic effectiveness of the six-day repeating metronomic cyclophosphamide schedule.

Large numbers of responsive cytokines, chemokines and immune regulatory genes linked to innate immune cell recruitment and tumor regression were identified, as were several immunosuppressive factors that may contribute to the observed escape of some tumors from metronomic CPA-induced, immune-based regression. These factors may include useful biomarkers that facilitate discovery of clinically effective immunogenic metronomic drugs and treatment schedules, and the selection of patients most likely to be responsive to immunogenic drug scheduling.

The online version of this article (doi:10.1186/s12885-015-1358-y) contains supplementary material, which is available to authorized users.

Tumor vasculature is known to be poorly organized leading to increased leakage of molecules to the extravascular space. This process can potentially increase interstitial fluid pressure impairing intra-tumoral blood flow and oxygen supply, and can affect drug uptake. Anti-angiogenic therapies are believed to reduce vascular permeability, potentially reducing interstitial fluid pressure and improving the extravasation of small molecule-based chemotherapeutics. Here we show that pretreatment of human ovarian carcinoma tumors with sub-optimal doses of the VEGFR targeting tyrosine kinase inhibitor axitinib, but not the EGFR targeting kinase inhibitor erlotinib, induces a transient period of increased tumor oxygenation. Doxorubicin administered within this window was found to enter the extravascular tumor space more rapidly compared to doxorubicin when applied alone or outside this time window. Treatment with the chemotherapeutics, doxorubicin and RAPTA-C, as well as applying photodynamic therapy during this period of elevated oxygenation led to enhanced tumor growth inhibition. Improvement of therapy was not observed when applied outside the window of increased oxygenation. Taken together, these findings further confirm the hypothesis of angiostasis-induced vascular normalization and also help to understand the interactions between anti-angiogenesis and other anti-cancer strategies.

Chemotherapy given in a metronomic manner can be administered with less adverse effects which are common with conventional schedules such as myelotoxicity and gastrointestinal toxicity and thus may be appropriate for older patients and patients with decreased performance status. Efficacy has been observed in several settings. An opportunity to improve the efficacy of metronomic schedules without significantly increasing toxicity presents with the addition of anti-angiogenic targeted treatments. These combinations rational stems from the understanding of the importance of angiogenesis in the mechanism of action of metronomic chemotherapy which may be augmented by specific targeting of the vascular endothelial growth factor (VEGF) pathway by antibodies or small tyrosine kinase inhibitors. Combinations of metronomic chemotherapy schedules with VEGF pathway targeting drugs will be discussed in this paper.

• Metronomic chemotherapy
• Vascular endothelial growth factor
• Angiogenesis
• Bevacizumab
• Vascular endothelial growth factor receptor

Metronomic cyclophosphamide given on an intermittent, 6-day repeating schedule, but not on an exposure dose-equivalent daily schedule, activates an anti-tumor innate immune response that leads to major regression of large implanted gliomas, without anti-angiogenesis.

Mice bearing implanted 9L gliomas were used to investigate the effects of this 6-day repeating, immunogenic cyclophosphamide schedule on myeloid-derived suppressor cells, which are pro-angiogenic and can inhibit anti-tumor immunity, and to elucidate the mechanism whereby the innate immune cell-dependent tumor regression response to metronomic cyclophosphamide treatment is blocked by several anti-angiogenic receptor tyrosine kinase inhibitors.

Intermittent metronomic cyclophosphamide scheduling strongly increased glioma-associated CD11b⁺ immune cells but not CD11b⁺Gr1⁺ myeloid-derived suppressor cells, while bone marrow and spleen reservoirs of the suppressor cells were decreased. The inhibition of immune cell recruitment and tumor regression by anti-angiogenic receptor tyrosine kinase inhibitors, previously observed in several brain tumor models, was recapitulated in the 9L tumor model with the VEGFR2-specific inhibitory monoclonal antibody DC101 (p < 0.01), implicating VEGFR2 signaling as an essential step in metronomic cyclophosphamide-stimulated immune cell recruitment. In contrast, sorafenib, a multi-receptor tyrosine kinase inhibitor with comparatively weak VEGF receptor phosphorylation inhibitory activity, was strongly anti-angiogenic but did not block metronomic cyclophosphamide-induced innate immunity or tumor regression (p > 0.05).

The interference by receptor tyrosine kinase inhibitors in the immunogenic actions of intermittent metronomic chemotherapy is not a consequence of anti-angiogenesis per se, as demonstrated in an implanted 9L tumor model. Furthermore, this undesirable interaction with tyrosine kinase inhibitors can be avoided by using anti-angiogenic drugs that spare the VEGFR2 pathway.

The efficacy and safety of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 in combination with pemetrexed and cisplatin was evaluated in patients with advanced non-squamous non–small-cell lung cancer (NSCLC).

Overall, 170 patients were randomly assigned to receive axitinib at a starting dose of 5-mg twice daily continuously plus pemetrexed 500 mg/m² and cisplatin 75 mg/m² on day 1 of up to six 21-day cycles (arm I); axitinib on days 2 through 19 of each cycle plus pemetrexed/cisplatin (arm II); or pemetrexed/cisplatin alone (arm III). The primary endpoint was progression-free survival (PFS).

Median PFS was 8.0, 7.9, and 7.1 months in arms I, II, and III, respectively (hazard ratio: arms I vs. III, 0.89 [P = 0.36] and arms II vs. III, 1.02 [P = 0.54]). Median overall survival was 17.0 months (arm I), 14.7 months (arm II), and 15.9 months (arm III). Objective response rates (ORRs) for axitinib-containing arms were 45.5% (arm I) and 39.7% (arm II) compared with 26.3% for pemetrexed/cisplatin alone (arm III). Gastrointestinal disorders and fatigue were frequently reported across all treatment arms. The most common all-causality grade ≥3 adverse events were hypertension in axitinib-containing arms (20% and 17%, arms I and II, respectively) and fatigue with pemetrexed/cisplatin alone (16%).

Axitinib in combination with pemetrexed/cisplatin was generally well tolerated. Axitinib combinations resulted in non-significant differences in PFS and numerically higher ORR compared with chemotherapy alone in advanced NSCLC.

ClinicalTrials.gov: NCT00768755 (October 7, 2008).

Numerous angiogenesis-vascular targeting agents have been admitted to the ranks of cancer therapeutics; most are used in polytherapy regimens. This review looks at recent progress and our own preclinical experience in combining angiogenesis inhibitors, mainly acting on VEGF/VEGFR pathways, and vascular targeting agents with conventional chemotherapy, discussing the factors that determine the outcome of these treatments. Molecular and morphological modifications of the tumor microenvironment associated with drug distribution and activity are reviewed. Modalities to improve drug delivery and strategies for optimizing combination therapy are examined.

• angiogenesis inhibitors
• combination therapies
• drug delivery
• paclitaxel
• tumor microenvironment
• tyrosine kinase receptor inhibitors
• vascular disrupting agents

• axitinib
• dacarbazine
• melanoma

• CNS
• blood-brain barrier
• brain drug delivery
• brain tumor
• brain tumor therapy
• clinical practice
• drug development
• drug efflux mechanism

• Angiogenesis Inhibitors/pharmacology
• Animals
• Anthraquinones/administration & dosage
• Anthraquinones/pharmacology
• Anthraquinones/therapeutic use
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Axitinib
• Cell Hypoxia/drug effects
• Cell Line, Tumor
• Cell Survival/drug effects
• Drug Therapy, Combination
• Enzyme Inhibitors/pharmacology
• Humans
• Hydralazine/pharmacology
• Imidazoles/pharmacology
• Indazoles/pharmacology
• Male
• Mice
• Mice, Nude
• Mice, SCID
• NAD(P)H Dehydrogenase (Quinone)/antagonists & inhibitors
• NAD(P)H Dehydrogenase (Quinone)/biosynthesis
• Neoplasms/blood supply
• Neoplasms/drug therapy
• Neoplasms/enzymology
• Neovascularization, Pathologic/prevention & control
• Rats
• Regional Blood Flow/drug effects
• Vasodilator Agents/pharmacology
• Xenograft Model Antitumor Assays

• R01 CA049248 NCI NIH HHS
• CA049248 NCI NIH HHS

• glioblastoma
• angiogenesis
• bevacizumab
• vascular endothelial growth factor
• metronomic chemotherapy

• Antibodies, Monoclonal/administration & dosage
• Antibodies, Monoclonal/therapeutic use
• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Bevacizumab
• Brain Neoplasms/drug therapy
• Dacarbazine/administration & dosage
• Dacarbazine/analogs & derivatives
• Dacarbazine/therapeutic use
• Disease-Free Survival
• Etoposide/administration & dosage
• Etoposide/therapeutic use
• Female
• Glioblastoma/drug therapy
• Humans
• Kaplan-Meier Estimate
• Karnofsky Performance Status
• Male
• Middle Aged
• Neoplasm Recurrence, Local/drug therapy
• Temozolomide

• T32 AG027668 NIA NIH HHS
• 5 R37 CA11898 NCI NIH HHS
• P20 CA096890 NCI NIH HHS
• 5P50-NS-20023 NINDS NIH HHS
• R37 CA011898 NCI NIH HHS
• M01 RR 30 NCRR NIH HHS
• P50 NS020023 NINDS NIH HHS

• Angiogenesis Inhibitors/pharmacology
• Animals
• Axitinib
• Cell Line, Tumor
• Cyclophosphamide/analogs & derivatives
• Cyclophosphamide/pharmacokinetics
• Cyclophosphamide/pharmacology
• Drug Synergism
• Gliosarcoma/blood supply
• Gliosarcoma/drug therapy
• Gliosarcoma/metabolism
• Imidazoles/pharmacology
• Indazoles/pharmacology
• Male
• Mice
• Mice, Inbred ICR
• Mice, SCID
• Neovascularization, Pathologic/drug therapy
• Neovascularization, Pathologic/metabolism
• Random Allocation
• Rats
• Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors
• Transplantation, Heterologous

• R01 CA049248 NCI NIH HHS
• R01 CA049248-22 NCI NIH HHS
• CA49248 NCI NIH HHS

• Adenocarcinoma/drug therapy
• Adenocarcinoma/pathology
• Animals
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Celecoxib
• Cyclophosphamide/administration & dosage
• Cyclophosphamide/therapeutic use
• Drug Administration Schedule
• Female
• Mammary Neoplasms, Experimental/drug therapy
• Mammary Neoplasms, Experimental/pathology
• Mice
• Neoplasm Metastasis
• Pyrazoles/administration & dosage
• Pyrazoles/therapeutic use
• Sulfonamides/administration & dosage
• Sulfonamides/therapeutic use

• Angiogenesis Inhibitors/pharmacology
• Angiogenesis Inhibitors/therapeutic use
• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors
• Carcinogens/antagonists & inhibitors
• Cytochrome P-450 CYP1B1
• Cytochrome P-450 Enzyme Inhibitors
• Endothelial Cells/drug effects
• Endothelial Cells/pathology
• Enzymes/drug effects
• Enzymes/metabolism
• Female
• Humans
• Male
• Mice
• NF-E2-Related Factor 2/antagonists & inhibitors
• Neoplasms/drug therapy
• Neoplasms/pathology
• Neoplasms/prevention & control
• Pharmaceutical Preparations/metabolism
• Polycyclic Aromatic Hydrocarbons/antagonists & inhibitors
• Polycyclic Aromatic Hydrocarbons/toxicity
• Pregnancy
• Prodrugs/therapeutic use
• Prostatic Neoplasms/drug therapy
• Steroid 17-alpha-Hydroxylase/antagonists & inhibitors

• ES07060 NIEHS NIH HHS
• CA90890 NCI NIH HHS
• ES00210 NIEHS NIH HHS
• P30 ES005022 NIEHS NIH HHS
• CA11799101 NCI NIH HHS
• ES00726316A1 NIEHS NIH HHS
• CA02744028 NCI NIH HHS
• CA49248 NCI NIH HHS
• CA073674 NCI NIH HHS
• R01 CA049248 NCI NIH HHS
• R01 CA118947 NCI NIH HHS
• CA094828 NCI NIH HHS
• P01 CA090890 NCI NIH HHS
• R01 CA094828 NCI NIH HHS
• R01 CA073674 NCI NIH HHS
• CA118947 NCI NIH HHS
• R01 ES011295 NIEHS NIH HHS
• R03 CA125781 NCI NIH HHS
• T32 ES007060 NIEHS NIH HHS
• P30 ES000210 NIEHS NIH HHS