Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-01-30
2001-09-18
Yucel, Remy (Department: 1636)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C536S024300
Reexamination Certificate
active
06291667
ABSTRACT:
FIELD OF INVENTION
The invention relates to the pharmacological use of VEGF antagonists antisense oligonucleotides (Veglin-1 (SEQ ID NO. 1) and Veglin-3 (SEQ ID NO. 2)) in a specific disease state. More particularly this invention relates to the use of VEGF inhibitors in the treatment of Kaposi's sarcoma (KS) in patients by administrating to the patients an effective amount of VEGF antagonist which is capable of inhibiting the growth of KS cells in culture. The VEGF agonist may be administered topically, orally or parenterally.
The invention also relates to the use of novel VEGF inhibitor antisense oligonucleotides (Veglin-1 (SEQ ID NO. 1 and Veglin-3 (SEQ ID NO. 2)) in the treatment of other diseases in which vascular proliferation plays a role, such as cancers, proliferative retinal diseases, collagen vascular diseases such as rheumatoid arthritis and lupus erythematosis, psoriasis and pemphigus etc. The invention also includes the use of KS cell lines as a rapid method to screen for compounds that inhibit VEGF effects.
BACKGROUND OF THE INVENTION
Kaposi's sarcoma (KS) is the most common tumor seen in patients with HIV-1 infection (Lifson AR et al. American Journal of Epidemiology 1990, 131:221-231. Reynolds P et al. American Journal of Epidemiology 1993,137:19-30.). KS causes significant morbidity and mortality through involvement of the skin and visceral organs. While the etiologic agent, if any, is unknown, substantial knowledge has been gained regarding the factors regulating the growth of tumor cells (Reynolds et al).
Kaposi's sarcoma most frequently presents as skin lesions (Lifson et al). Mucosal (oral cavity) involvement is the second most common site of disease, occurring on the palate and gums and can cause tooth loss, pain and ulceration. Lymph node involvement is common with KS. However, the precise frequency is not known due to the lack of routine lymph node biopsies.
Visceral involvement occurs frequently, (in nearly 50% of the cases) especially in patients with advanced disease (Laine L et al. Arch Intern Med 1987, 147:1174-1175.). Advanced gastrointestinal (GI) KS can cause enteropathy, diarrhea, bleeding, obstruction and death. Pulmonary involvement is common and significant pulmonary KS occurs in nearly 20% of the cases (Laine L et al. Arch Intern Med 1987, 147-:1174-1175. Gill PS et al. Am J Med 1989, 87:57-61). The symptoms vary from no symptoms to dry cough, exertional dyspnea, hemoptysis and chest pain. Pulmonary function studies may show varying degree of hypoxemia. The overall survival of patients with symptomatic pulmonary KS is less than 6 months (Gill et al).
While the skin, lung, and GI tract are common sites of disease, nearly every organ can be involved with KS, including liver, spleen, pancreas, omentum, heart, pericardium, etc.
Phenotypic studies to define the cell of origin of KS have been performed extensively. KS spindle cells express phenotypic features of mesenchymal cells and share some markers with endothelial cell, vascular smooth muscle cells, and dermal dendrocytes. The markers shared with endothelial cells include lectin binding sites for Ulex Europeaus Agglutinin-1 (UEA-1), CD34, EN-4, and PAL-E. The expression of several factors markers in HUVEC, AIDS-KS cells and trans differentiated HUVEC was confirmed by histochemistry and RT-RCR message analysis for expression of IL-6, IL-8, GM-CSF, TGF-&bgr; etc.
AIDS-KS spindle cell isolation have allowed the determination of factors secreted by the tumor cells and their effects on the tumor cell itself Both IL-1 &bgr; and IL-6 are produced by tumor cells. Further, the inhibition of their effects either through blocking their binding to the cognate receptors (IL-1 receptor antagonist, soluble IL-1 receptor) or inhibition of gene expression through antisense olignucleotides (for IL-6) inhibits the growth of tumor cells. More importantly, both IL-1 and IL-6 induce VEGF expression. Thus endogenous production of these factors may in part be responsible for high levels of VEGF production by KS cells.
VEGF was first discovered as a molecule that is a secreted protein with biological effects which include the following. VEGF in vitro induces the growth of endothelial cells and induces migration of endothelial cells. VEGF induces new vessel formation in model systems, such as the chick chorioallantoic membrane and the rat or rabbit cornea avascular zone. VEGF induces permeability of the existing blood vessels, in model systems, such as the mice of guinea pig skin vessels. It was later shown that a number of tumor cells produce VEGF and the secreted protein induces the regional blood vessels to produce more blood vessel network to support the tumor growth and metastasis. In addition inhibition of VEGF function was shown to reduce the growth potential of tumor explants in immunodeficient mice. VEGF expression is increased by hypoxia as noted in the deepest part of the tumor, and by certain cytokines, such as IL-1 and IL-6. VEGF functions through the cognate tyrokinase receptors, Flt-1 and Flk-1/KDR. Flt-1 is an intermediate affinity receptor and Fik-1/KDR is a low affinity receptor. Expression of both receptors results in high affinity binding of the homodimer of VEGF to the target cells. Signal transduction however occurs through Fik-1/KDR only. The expression of VEGF receptors thus is essential for its biological activity and the restricted expression in activated endothelial cells lining the blood vessels.
VEGF is expressed as four different spliced variants. VEGF 165 and VEGF 121 are secreted proteins. Four other members of the VEGF family have been described recently. These include VEGF-B, VEGF-C, VEGF-D, and placental derived growth factor (PIGF). KS cells express all members of the VEGF family, as well as the receptors for VEGF and VEGF-C (Flt-4). PIGF has 47% homology to VEGF and binds to Flt-1 as a homodimer or a heterodimer with VEGF. VEGF-B is a 167 amino acid secreted protein and has 43% and 30% homology with VEGF and PIGF. VEGF-C also called VEGF related protein (VRP) has 32% and 27% homology to VEGF and PIGF. It binds to Flt-4 as a homodimer and to Flk-1/KDR as a VEGF heterodimer.
The hallmark of KS is the aberrant and enhanced proliferation of vascular structures. Various angiogenic factors have been isolated for their ability to enhance endothelial cell proliferation and migration in-vitro. The analysis of AIDS-KS cells have revealed the expression of basic fibroblast growth factor (bGFG) and vascular endothelial cell growth factor (VEGF). The latter is a secreted molecule with capability to induce capillary permeability, a prominent feature of a subset of AIDS-KS. Inhibition of VEGF expression may have therapeutic efficacy in KS. In addition, the isolation of several members of the VEGF family reveals that there is a redundancy and modulation of VEGF function. It is thus conceivable, that the inhibition of VEGF alone may be active as a therapeuric strategy to inhibit tumor growth, while inhibition of several or all members of this family may be more effective.
The treatment of AIDS-related Kaposi's sarcoma is palliative. Localized KS can be managed with local therapy including radiation therapy. Radiation therapy produces local toxicity and has a cumulative dose limiting toxicity. Other options for the cosmetic treatment of localized disease include cryotherapy, photodynamic therapy, intralesional vinblastine, and intralesional sclerosing agents, all of which result in local toxicity of pigmentation which may at times be worse than the lesions itself.
Progressive KS especially with local complications of pain, edema, and ulceration and symptomatic visceral KS, require therapy which will result in rapid response. Systemic cytotoxic chemotherapy is the only treatment modality that produces rapid response. The frequency of response however depends on the agent, dose, and schedule. The response to therapy varies from 25% to over 50%. The most active agents include vinca alkaloids (vincristine, vinblastine), etoposide, anthracyclines and bleomycin. Combination therapie
Gill Parkash S.
Masood Rizwan
Gansheroff Lisa
McCutchen, Doyle, Brown & Enersen
Yucel Remy
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