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The invention relates to the treatment of diseases and conditions exacerbated by the development of blood vessels and concomitant blood flow. More specifically the invention relates to the use of metal chelating materials including, picolinic acid, fusaric acid and their derivatives as pharmacological response modifiers to reduce angogenesis in the presence of cancers, tumors and in the eye.
It will be appreciated that hereinafter the use of the term xe2x80x9cresponse modifierxe2x80x9d is intended to encompass all of the intended functions of the invention and method including antiviral, antiinfective, antiinflammatory, anticancer, vaccine and so on. Further, it will be appreciated that the broad term xe2x80x9cantiinfectivexe2x80x9d is intended to include antibacterial, antifungal, antiparasitic functions, as well as actions against any other infective agent or organism including viruses not encompassed by the term xe2x80x9cantiviralxe2x80x9d. It will also be appreciated that the term xe2x80x9cantiinflammatoryxe2x80x9d is intended to include an inflammatory response modifier, including all inflammatory responses such as production of stress proteins, white blood cell infiltration, fever, pain, swelling and so forth. Furthermore, the term xe2x80x9canalgesicxe2x80x9d is intended to include a pain reliever, whether the pain incurred is a result of disease, inflammation, trauma or psychosomatic reaction.
Researchers recently have come to appreciate the role of metal containing proteins in physiological actions and responses including pain, inflammation, proliferative and infectious diseases. Generally speaking, the inventor has studied the important function of proteins having amino acid sequences which bind metals, particularly transition metal ions therein. For example, the inventor has determined the important role zinc finger or zinc ring proteins as hormone-receptor proteins and in proliferative, inflammatory and infectious diseases. Moreover, the inventor has determined the role of other metal ion containing protein complexes, such as the role of iron finger proteins such as iron-finger hormone-receptor proteins in aging and carcinogenesis.
Likewise, researchers have come to understand the role of certain elements, particularly copper, zinc and iron in angiogenesis. Angiogenesis is implicated in certain diseases states such as cancer and diabetic retinopathy. Zinc, iron and copper are cofactors in angiogenesis.
The inventor and others have recognized at least three efficient approaches to inhibiting zinc finger proteins: 1) disruption of the zinc finger by modification of the cysteines which are at least one of the four binding sites for Zn2+ in the zinc finger protein which results in the ejection of zinc ion; 2) removal of the zinc from the zinc finger moiety by specific chelating agents; and 3) specific chelating agents that form a ternary complex at the site of zinc binding on zinc finger proteins, resulting in inhibition of the DNA or RNA binding activity of zinc finger proteins.
Papilloma virus infection results in a number of proliferative diseases in subjects including warts induced by type 4 human papilloma virus (common warts). Moreover, papilloma virus can cause plantar ulcers as well as plantar warts. Human papilloma virus infection of the uterine cervix is the most common of all sexually transmitted diseases. Commonly known as genital warts, this wide spread virus infection is a serious disease that potentially can develop into cervical cancer. Since the virus is permanently present in cells, infection recurs in a significant percentage of patients. In many instances, conization of the uterine cervix is required to remove the infected tissue.
Condylomata acuminata, also denoted genital warts, are benign epithelial growths that occur in the genital and perianal areas and caused by a number of human papilloma viruses (HPV) including types 6, 11 and 54. These are low risk viruses which rarely progress to malignancy. However, high risk viruses such as HPV-16 and HPV-18 are associated with cervical intraepithelial cancer.
The actions of HPV are mediated by specific viral-encoded proteins which interact and/or modulate cellular DNA and proteins to produce abnormal growth and differentiation of cells. Two proteins of the HPV viral genome, E6 and E7, are well conserved among anogenital HPVs and both may contribute to the uncontrolled proliferation of basal cells characteristics of the lesions. The E7 oncoprotein is a multi-functional protein with transcriptional modulatory and cellular transforming properties. The E7 oncoprotein is denoted as a xe2x80x9czinc fingerxe2x80x9d protein because it posesses a sequence motif that is implicated in zinc binding. A strong correlation between zinc binding and the transactivation activity of E7 has been documented. The HPV-16 E6 protein is a xe2x80x9czinc fingerxe2x80x9d protein that binds DNA and may have transcriptional properties such that its function may be dependent upon the formation of zinc fingers. E6 protein can complex with the cellular tumor suppressor protein p53 and it is necessary with E7 protein for the immortalization of primary human squamous cells. Only two proteins of HPV are consistently expressed and integrated in keratinocytes, the E6 and E7 zinc finger proteins. The E6 and E7 proteins are responsible for continuous cell proliferation. About twenty HPVs are associated with ano-genital lesions and all transformed keratinocytes of these lesions contain E6 and E7 zinc finger proteins. The E6 and E7 regulate growth and transformation by interfering with cellular p53 and pRb proteins, respectively. Thus, one should be able to control or cure HPV by inactivating E6 and E7, the critical zinc finger proteins which are required for replication. When replication of the virus is halted, apoptosis of the virally-infected cells must occur. Thus, one can alter the epidemiology of, for example, carcinoma of the uterine cervix by interfering with the function of zinc finger or zinc ring proteins.
Herpes viruses, for example, Herpes Simplex Virus (HSV), has two important viral metalloproteins, a zinc finger protein and ribonucleotide reductase, an iron-containing enzyme, which are necessary for replication and propagation of the viruses. One can alter the course of herpes diseases, such as xe2x80x9cfever blistersxe2x80x9d and genital herpes, by inhibiting the two viral metalloproteins.
The human immunodeficiency virus (HIV) encodes several regulatory proteins that are not found in other retroviruses. The tat protein, which is one of these proteins, trans-activates genes that are expressed from the HIV long terminal repeat and tat is essential for viral replication. The tat protein of the HIV-1 is a zinc finger protein that when added to certain cells in tissue culture, specifically promotes growth. It has been shown that the tat protein of HIV-1 stimulates growth of cells derived from Kaposi""s sarcoma lesions of AIDS patients. Other experiments raised the possibility that tat might act as a viral growth factor to stimulate replication in latently infected cells or alter expression of cellular genes.
The nucleocapsid p7 protein of HIV has been targeted by the inventor for treatment of HIV viral infections. The p7 protein is required for the correct assembly of newly formed virus particles during the viral life cycle. Moreover, the p7 protein contains two zinc fingers that are required for the recognition and packaging of the viral RNA. Because the zinc finger domain is essential for nucleic acid binding, p7 resistant mutants are highly unlikely to occur. Thus, agents that effectively attack the two zinc finger domains of the HIV virus nucleocapsid p7 in vivo will decrease the overall number of viral particles that bud off and exit the cells to infect other cells.
The hepatitis C virus is not integrated with DNA and thus may be vulnerable to attack by specific antivirals. The hepatitis C viruses are dependent upon the Zn2+ metalloproteinases for specific viral functions. Processing at the C terminus portion of the NS2 protein of hepatitis C virus is mediated by virus encoded protease (metalloproteinases). Modification of the metalloproteinases presents an opportunity for controlling the progression of hepatitis C mediated disease.
It is of interest to note that the breast cancer susceptibility gene BRCA1 includes a zinc ring domain that is involved in protein-protein interactions or protein-DNA interactions. It also is of interest to note that the zinc ring domain of the BRCA1 has a 54% sequence similarity and 38% sequence identity with a zinc ring domain encoded by the genome of the equine herpes virus. (R. Bienstock, xe2x80x9cMolecular Modeling of Proteins Structures, Science and Medicine, January/February 1997, p.56).
From the foregoing it appears that it would be beneficial to have a product that can interfere with the formation or action of certain zinc finger proteins or zinc ring proteins to stop the progress of certain virally induced or mediated proliferative diseases or to halt the progress of viruses or malignancies dependent upon zinc finger or zinc ring proteins for their transformation and immortalization. Furthermore, it would be beneficial to provide a product that can halt the growth of other proliferative cells, such as malignant cells by chelating metal ions from zinc-dependent or iron-dependant, transition metal ion (e.g. copper, iron, etc.) dependent proteins, hormones and enzymes necessary for the replication of the malignant cells. Likewise, it would be beneficial to retard angiogenesis in certain disease states, such as cancers and diabetic retinopathy and post-ophthalmic surgery.
It is among the general objects of the present invention to provide a pharmacological response modifier which can retard the growth and proliferation of target cells by blocking the activity of metal ion-containing proteins and enzymes.
Another object of the present invention is to provide a compound which can retard the growth and proliferation of cells by blocking the activity of transition metal ion-containing protein structures such as zinc finger, zinc ring proteins, iron-finger or iron-ring proteins or enzymes associated with replication of the cells.
Another object of the invention is to provide such a compound to retard angiogenesis, particularly angiogenesis in tumors and in the eye following ophthalmologic surgery.
Yet another object of the invention is to provide such a compound that inhibits fibroblast production after cataract surgery which results from an inflammatory response to artificial lenses.
Another object of the invention to provide a method of halting the function of metal containing protein structures containing metals other than zinc, metal-containing ring proteins structures, such as iron-finger or iron-ring proteins and other proteins with metal binding motifs heretofore unidentified by the administration of a metal chelating agent, both topically and systemically.
Yet another object of the invention is to provide such chelating agents in a relatively safe and nontoxic form such as picolinic acid or its derivatives for both topical and systemic use.
According to the invention, briefly stated, a method or treatment and compound used in the method, for example, metal chelating compounds, such as picolinic acid or derivative thereof, for the treatment of diseases which have, as a mode of progression or as a symptom or sequelae, angiogenesis or enhanced angiogenesis, as well as the method of treatment. The invention can be used orally or topically to treat or control a number of diseases. The metal chelating compounds bind metal, for example iron or transition metal ions such as zinc or copper required by cells for angiogenesis. In one preferred embodiment, an oral dose of 500 mg of picolinic acid is administered over a five week escalation from approximately 500 mg daily to approximately four (4) grams daily, in divided doses.
Various active derivatives that maintain their activity and stability when after systemic administration are provided. Slow release oral formulations can be used to treat diseases for the digestive tract. The active derivatives can be administered orally, parenterally, by inhalation, transdermally, intrathecally, implantation under the skin or by any other appropriate method to control proliferation or blood vessels in the disease state.