Louisiana State University and Agricultural & Mechanical College

The Ohio State University

The Administrators of the Tulane Educational Fund

Children's Hospital

Tulane University

Eugene A Woltering

Zhijun Liu

Conrad A Hornick

David H Coy

William A Murphy

Frank L Greenway

Gregory D Espenan

Thomas M O'Dorisio

M Sue O'Dorisio

Amy E Myers

Edward W Martin

Joseph A Fuselier

George J Drouant

Seza A Gulec

The present invention is directed to methods for extracting and isolating extracts having angiogenesis inhibiting activity from a latex-containing portion of avariant, pharmaceutical and nutraceutical compositions comprising the extracts, methods of administering the extracts to treat angiogenesis-dependent diseases and to reduce or inhibit neovessel growth in a subject in need thereof, and the use of the extracts in the manufacture of a composition for reducing or inhibiting neovessel growth.

Ficus extracts having angiogenesis inhibiting activity and methods of isolating and using the same

Noni juice and a protein-free, alcohol precipitate of Noni juice inhibited angiogenesis in in vitro human angiogenesis models. When growth medium contained Noni juice at least over the range from about 2.5% to about 33% (by volume), angiogenesis was blocked. Moreover, Noni juice and an ethanol precipitate were able to destroy a pre-existing angiogenic response as well as prevent the development of new vessels. Noni juice was effective in inhibiting the growth of angiogenic vessels from breast cancer explants. It will also be effective in treating cancers and non-cancerous diseases whose response includes an increase in angiogenesis, e.g., retinopathy of prematurity, neovascular glaucoma, diabetic retinopathy, and psoriasis. In an initial experiment, Noni juice was effective in treating lesions associated with psoriasis. The primary antiangiogenic component is believed to be a carbohydrate with a molecular weight less than about 6000 Daltons. In an initial experiment, oral administration of Noni juice appeared to adversely affect the antiangiogenic component(s) in the juice.

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An extract of Chinese blackberry () has been found to inhibit angiogenesis, and two active fractions isolated. Gallic acid was shown to be one of the active anti-angiogenic compounds by an in vitro human angiogenesis model. Aqueous extracts from other plants either known or found to have gallic acid were also found to have anti-angiogenic activity. Various derivatives of gallic acid were found to inhibit angiogenesis. The extract from Chinese blackberry also slowed the growth of a pancreatic tumor and of corneal neovascularization in rats. Extracts from pomegranate were shown to inhibit angiogenesis in fat tissue. Extracts fromspp, and other plants with gallic acid, and gallic acid and its derivatives will be useful for treating various diseases associated with neovascularization, including diabetic retinopathy, psoriasis, tumors, obesity, cancer, rheumatoid arthritis, etc.

Anti-angiogenic extracts from pomegranate

Noni juice and a protein-free, alcohol precipitate of Noni juice inhibited angiogenesis in in vitro human angiogenesis models. When growth medium contained Noni juice at least over the range from about 2.5% to about 33% (by volume), angiogenesis was blocked. Moreover, Noni juice and an ethanol precipitate were able to destroy a pre-existing angiogenic response as well as prevent the development of new vessels. Noni juice was effective in inhibiting the growth of angiogenic vessels from breast cancer explants. It will also be effective in treating cancers and non-cancerous diseases whose response includes an increase in angiogenesis, e.g., retinopathy of prematurity, neovascular glaucoma, diabetic retinopathy, and psoriasis. The primary antiangiogenic component is believed to be a carbohydrate with a molecular weight less than about 6000 Daltons. In an initial experiment, oral administration of Noni juice appeared to adversely affect the antioangiogenic component(s) in the juice.

Angiogenic agents from plant extracts, gallic acid, and derivatives

Apolipoprotein A-I-rich Lhigh-density Lipoprotein 2 (HDL2) and Apolipoprotein A-I (ApoA-I) was discovered to inhibit angiogenesis in an in vitro human angiogenesis model, the human placental vein angiogenesis model. Apolipoprotein A-I was able to destroy a pre-existing angiogenic response as well as prevent the development of new vessels. Application of Apolipoprotein A-I will be effective in inhibiting tumor growth dependent on angiogenesis, and in decreasing existing blood vessels formed by tumors. It will also be effective in treating non-cancerous diseases which symptoms include an increase in angiogenesis, e.g., psoriasis, retinopathy of prematurity, neovascular glaucoma, diabetic retinopathy, obesity, and psoriasis.

Inhibition of angiogenesis and destruction of angiogenic vessels by apolipoprotein A-I and high density lipoprotein

A one-step procedure for sentinel lymph node identification and biopsy using a single compound, a radiolabeled, low molecular weight dye (e.g.,I-labeled methylene blue). This radiolabled dye is mixed with an unlabeled, similar molecular weight dye (e.g., isosulfan or methylene blue). The mixture is injected at the time of surgery, and rapidly migrates to reach the lymph nodes in less than 20 min, more preferably in less than 15 min and most preferably in less than 10 min. Using rabbits, rapid transit ofI-methylene blue to regional lymph nodes with limited systemic biodistribution has been confirmed. By admixing small amounts of radiolabeled dye with a large amount of unlabeled dye, the sentinel lymph node identification was similar to that for the prior two-step dual mapping process, but with enhanced SLN localization because of the lower energy gamma emission ofI as compared withTc.

Injection of a radioactive dye for sentinel lymph node identification

An in vitro tissue angiogenesis and vasculogenesis system is disclosed that allows the outgrowth of microvessels from a three-dimensional tissue fragment implanted in a matrix. The matrix may, for example, be a fibrin- or collagen-based matrix fed by a growth medium, for example, a mixture of tissue culture medium, serum, or a layer of growth medium containing a defined mixture of growth factors. This system, which may be used with human or other mammalian or animal tissues, may be used in assaying tumor angiogenic potential, or in promoting angiogenesis in other tissues, e.g., promoting angiogenesis prior to transplantation of a tissue. The angiogenic potential of a tissue can be determined by measuring the growth of microvessels into the matrix. The three-dimensional structure of the tumor or other tissue is maintained in the matrix, including blood vessels. In another aspect, the method allows for the proliferation of a tissue specimen, thus increasing the mass of cells available for subsequent transplant; and the method also provides for the proliferation of blood vessels from the tissue mass, thus enhancing the chance of successful engraftment.

Three-dimensional ex vivo angiogenesis system

Administration of a radioisotopic compound by infusion over a period of time greater than two hours, preferably greater than twelve hours, greatly increases the maximum radioactivity that accumulates in the target cell. The efficacy of the administration of the radiolabeled compound can be increased about five times higher than prior bolus injection or short infusion methods. This method enhances the tumor to background ratio by increasing the actual radioligand accumulated inside the target cells. This technique works for any radiolabeled compound whose cellular uptake is limitedly a cellular process of either binding to a cellular receptor or to a transport protein. Once the radiolabeled compound is bound and internalized, the ability of an unlabeled compound to compete with the radioligand is markedly decreased. The primary factor governing residence time after internalization is the physical half-life of the radioisotope, not biologic half-life.

Method to enhance tissue accumulation of radiolabeled compounds

Hydrophilic somatostatin analogs

Administration of a radioisotopic compound by infusion over a period of time greater than two hours, preferably greater than twelve hours, greatly increases the maximum radioactivity that accumulates in the target cell. The efficacy of the administration of the radiolabeled compound can be increased about five times higher than prior bolus injection or short infusion methods. This method enhances the tumor to background ratio by increasing the actual radioligand accumulated inside the target cells. This technique works for any radiolabeled compound whose cellular uptake is limited by a cellular process of either binding to a cellular receptor or to a transport protein. Once the radiolabeled compound is bound and internalized, the ability of an unlabeled compound to compete with the radioligand is markedly decreased. The primary factor governing residence time after internalization is the physical half-life of the radioisotope, not biologic half-life.

Disclosed are methods and compositions for the diagnosis and treatment of diseases associated with aberrant expression of a somatostatin receptor (e.g., cancer) or with increased production of a factor regulatable by somatostatin (e.g., acromegaly). The compounds of the invention are of the general formulae: ##STR1## wherein P is a somatostatin peptide analog which binds to a somatostatin receptor,

Multi-tyrosinated somatostatin analogs

Broadly, the present invention is directed to a method for the detection and differentiation of neoplastic tissue in a patient suspected of having neoplastic tissue. The method includes the administration of a radiolabeled somatostatin congener to the patient and accessing the patient with a radiation detection probe for determining tissue exhibiting elevated levels of radiation, viz., neoplastic tissue. However, before subjecting the patient to such administration, an initial determination preferably is made as to whether the radiolabeled somatostatin congener will bind to the tumor site, i.e., whether somatostatin receptors are associated with the neoplastic tissue. This is conveniently done with a wide variety of endocrine tumors, which release peptides or hormones, referred to as 'biochemical markers. ' In order to make this determination, initially a biochemical marker-inhibiting dose of unlabeled somatostatin congener is administered to the patient. The biochemical marker associated with the neoplastic tissue then is monitored to determine whether the administered somatostatin congener reduces the presence of the marker in the patient. If the monitored presence of the marker was reduced, then the surgeon can be confident that the neoplastic tissue or tumor contains receptors to which the somatostatin will bind. Thus, the administration of radiolabeled somatostatin congener is appropriate for such patient. If the biochemical marker associated with the neoplastic tissue is not appropriately reduced following the administration of the unlabeled somatostatin congener, then the neoplastic tissue may not be determinable by the use of radiolabeled somatostatin congener and alternative modalities of treatment should be considered, such as the use of radiolabeled antibodies as proposed in U.S. Pat. No. 4,782,840. If the tumor is of a type that does not release a biochemical marker, the presence of somatostatin receptors can be confirmed by other means, such as pathology, immunohistochemistry, radioreceptor assay, or such other means as will be apparent to those skilled in the art.

Growing community of inventors

Kenner, LA, United States of America

Eugene A Woltering