https://www.cell.com/cell/pdf/0092-8674(91)90642-C.pdf

Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation.

Localization of Matrix Metalloproteinase MMP-2 to the Surface of Invasive Cells by Interaction with Integrin αvβ3

To reveal the antiangiogenic capability of cancer chemotherapy, we developed an alternative antiangiogenic schedule for administration of cyclophosphamide. We show here that this antiangiogenic schedule avoided drug resistance and eradicated Lewis lung carcinoma and L1210 leukemia, an outcome not possible with the conventional schedule. When Lewis lung carcinoma and EMT-6 breast cancer were made drug resistant before therapy, the antiangiogenic schedule suppressed tumor growth 3-fold more effectively than the conventional schedule. When another angiogenesis inhibitor, TNP-470, was added to the antiangiogenic schedule of cyclophosphamide, drug-resistant Lewis lung carcinomas were eradicated. Each dose of the antiangiogenic schedule of cyclophosphamide induced the apoptosis of endothelial cells within tumors, and endothelial cell apoptosis preceded the apoptosis of drug-resistant tumor cells. This antiangiogenic effect was more pronounced in p53-null mice in which the apoptosis of p53-null endothelial cells induced by cyclophosphamide was so vigorous that drug-resistant tumors comprising 4.5% of body weight were eradicated. Thus, by using a dosing schedule of cyclophosphamide that provided more sustained apoptosis of endothelial cells within the vascular bed of a tumor, we show that a chemotherapeutic agent can more effectively control tumor growth in mice, regardless of whether the tumor cells are drug resistant.

https://cancerres.aacrjournals.org/content/canres/60/7/1878.full.pdf

Antiangiogenic Scheduling of Chemotherapy Improves Efficacy against Experimental Drug-resistant Cancer

Neovascularization is critical for the growth of tumours and is a dominant feature in a variety of angiogenic diseases such as diabetic retinopathy, haemangiomas, arthritis and psoriasis. Recognition of the potential therapeutic benefit of controlling unabated capillary growth has led to a search for safe and effective angiogenesis inhibitors. We report here the synthesis of a family of novel inhibitors that are analogues of fumagillin, a naturally secreted antibiotic of Aspergillus fumigatus fresenius. We first isolated this fungus from a contaminated culture of capillary endothelial cells. Purified fumagillin inhibited endothelial cell proliferation in vitro and tumour-induced angiogenesis in vivo; it also inhibited tumour growth in mice, but prolonged administration was limited because it caused severe weight loss. Synthesis of fumagillin analogues yielded potent angiogenesis inhibitors ('angioinhibins') which suppress the growth of a wide variety of tumours with relatively few side-effects.

Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth.

The present invention provides compositions comprising an anti-angiogenic factor, and a polymeric carrier. Representative examples of anti-angiogenic factors include Anti-Invasive Factor, Retinoic acids and derivatives thereof, and paclitaxel. Also provided are methods for embolizing blood vessels, and eliminating biliary, urethral, esophageal, and tracheal/bronchial obstructions.

Anti-angiogenic compositions and methods of use

Certain tissues such as cartilage are resistant to vascular invasion, yet no single tissue-derived molecule that can inhibit angiogenesis has been reported. A protein derived from cartilage was purified that inhibits angiogenesis in vivo and capillary endothelial cell proliferation and migration in vitro in three separate bioassays. This protein is also an inhibitor of mammalian collagenase. These findings may help elucidate the mechanisms by which neovascularization is controlled in both normal and pathological states.

Identification of an inhibitor of neovascularization from cartilage

An inhibitor of neovascularization from the conditioned media of scapular chondrocytes established and maintained in serum-free culture has been isolated and characterized. To determine whether this chondrocyte-derived inhibitor (ChDI) was capable of inhibiting neovascularization in vivo, this protein was assayed in the chick chorioallantoic membrane assay. ChDI was a potent inhibitor of angiogenesis in vivo (4 micrograms = 87% avascular zones). This inhibitor is also an inhibitor of fibroblast growth factor-stimulated capillary endothelial cell (EC) proliferation and migration, as well as being an inhibitor of mammalian collagenase. ChDI significantly suppressed capillary EC proliferation in a dose-dependent, reversible manner with an IC50 (the inhibitory concentration at which 50% inhibition is achieved) of 2.025 micrograms/ml. Inhibition by ChDI of growth factor-stimulated capillary EC migration was also observed using a modified Boyden chamber assay (IC50 = 255 ng/ml). SDS-PAGE analysis followed by silver staining of ChDI purified to apparent homogeneity revealed a single band having an M(r) of 35,550. Gel elution experiments demonstrated that only protein eluting at this molecular weight was anti-angiogenic. These studies are the first demonstration that chondrocytes in culture can produce a highly enriched, potent inhibitor of neovascularization which also inhibits collagenase.

/pdf/isolation-and-characterization-of-an-inhibitor-of-z3lngen0wn.pdf

Isolation and characterization of an inhibitor of neovascularization from scapular chondrocytes

Pharmaceutical compositions for delivering an effective dose of an angiogenesis inhibitor consisting of a specific inhibitor of collagenase, for inhibition of blood vessel ingrowth and tube formation in vivo and capillary endothelial cell proliferation and migration in vitro, which is non-cytotoxic to normal cells. The compositions are delivered topically or locally using implants or injection. Examples of specific collagenase inhibitors include purified cartilage-derived inhibitor, collagenase binding peptides and antibodies which block the active site or metal binding regions of collagenase, and compounds which inhibit enzymes activating collagenase, such as plasmin inhibitor.

Method and compositions for inhibiting angiogenesis

Compositions pharmaceutiques permettant d'administrer une dose efficace d'un inhibiteur de l'angiogenese, consistant en un inhibitgeur specifique de la collagenese, pour l'inhibition de la croissance interne et de la formation de tube dans les vaisseaux sanguins in vivo et de la proliferation et de la migration de cellules endotheliales capillaires in vitro, qui est non cytotoxique pour les cellules normales. Lesdites compositions sont administrees de maniere topique ou locale en utilisant des implants ou des injections. Les inhibiteurs specifiques de la collagenase sont par exemple l'inhibiteur purifie derive de cartilage, les peptides et anticorps liant la collagenase qui bloquent le site actif ou les regions de liaison metallique de la collagenase, et des composes qui inhibent les enzymes activant la collagenase, tels que l'inhibiteur de la plasmine.

Judith Sudhalter

Papers

Identification of an inhibitor of neovascularization from cartilage

Isolation and characterization of an inhibitor of neovascularization from scapular chondrocytes

Method and compositions for inhibiting angiogenesis

Procede et compositions destines a inhiber l'angiogenese