Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
2000-05-26
2003-02-11
Wortman, Donna (Department: 1642)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C536S023500, C530S350000, C435S320100, C514S04400A
Reexamination Certificate
active
06517828
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of cancer biology and molecular biology. More particularly, it relates to methods for inhibiting hyperproliferative cell growth and anti-angiogenic effects of C-CAM1.
2. Description of Related Art
Normal tissue homeostasis is achieved by an intricate balance between the rate of cell proliferation and cell death. Disruption of this balance, either by increasing the rate of cell proliferation or decreasing the rate of cell death, can result in the abnormal growth of cells and is thought to be a major event in the development of cancer. The effects of cancer are catastrophic, causing over half a million deaths per year in the United States alone. Conventional strategies for the treatment of cancer, chemotherapy, radiotherapy, surgery, biological therapy or combinations thereof are often ineffective.
In nearly 50% of patients, surgical excision of primary neoplasms is ineffective because metastasis has occurred by the time the tumor is large enough for resection (Sugarbaker, 1977; Fidler and Balch, 1987). Metastases can be located in different organs as well as different regions of the same organ, making complete eradication by surgery, radiation, drugs, or biotherapy difficult. Furthermore, the organ microenvironment significantly influences the response of tumor cells to therapy (Fidler, 1995), as well as the efficiency of anticancer drugs, which must be delivered to tumor foci in amounts sufficient to destroy cells without leading to undesirable side effects (Fidler and Poste, 1985). In addition, the treatment of metastatic cancer is greatly hindered due to the biological heterogeneity of cancer cells, and the rapid emergence of tumor cells that become resistant to most conventional anticancer agents (Fidler and Poste, 1985).
Conventional therapy for malignancy, such as chemotherapy and radiation, has focused on mass cell killing without specific targeting, often resulting in damaging side effects. With advances in molecular genetics and biology, it has become evident that altered expression of normal genes leads to initiation of cancer cells. Cells can be regulated in a positive (stimulatory) or negative (suppressive) manner. Loss of negative regulation of cell growth is often found in malignant cells which exhibit loss of cell proliferation control. Most negative regulators (Marx, 1993; Grunicke and Maly, 1993), referred to as tumor suppressors, have been found to be involved either in direct control of the cell cycle (e.g., Rb, p53, WT-1) or in the signaling pathway leading to cell growth and differentiation (e.g., NF-1).
Thus, the new direction in cancer therapy is to deliver a normal gene to replace or correct the mutated gene, thereby altering the malignant phenotype of transformed cells. However, the transfer of genetic material into cells has limitations. As such, there clearly remains a need for improved methods of anti-hyperproliferative cell therapy.
SUMMARY OF THE INVENTION
The present invention addresses the need for improved compositions and methods for anti-hyperproliferative and anti-angiogenic cell therapies. In one embodiment, an objective of the present invention is to provide a composition comprising a cytoplasmic domain of C-CAM1, free from other C-CAM1 domains. In particular embodiments, a composition comprising a cytoplasmic domain of C-CAM1, is provided, wherein the cytoplasmic domain has or comprises the sequence of SEQ ID NO:1. In addition to providing C-CAM1 to a cell or subject, the methods of the invention may further include one or more additional antihyperproliferative or anti-angiogenic therapies, such as surgery, chemotherapy, radiotherapy, hormone therapy, immunotherapy, or gene therapy with other therapeutic genes.
In certain embodiments, a cytoplasmic domain of C-CAM1 further comprises a non-C-CAM1 molecule. In other embodiments, a cytoplasmic domain of C-CAM1 comprises a non-C-CAM1 molecule, wherein the non-C-CAM1 molecule is linked to the C-CAM1 cytoplasmic domain. In additional embodiments, the non-C-CAM1 molecule is selected from the group consisting of a tumor suppressor, an inducer of apoptosis, a cytokine, a targeting sequence, a single chain antibody, an antisense construct, a ribozyme and a chemotherapeutic agent. In one embodiment, the non-C-CAM1 molecule is a tumor suppressor selected from the group consisting of p53, p16, p21, MMAC1, p73, zac1, BRCAI, and Rb. In another embodiment, the non-C-CAM1 molecule is an the inducer of apoptosis selected from the group consisting of Bax, Bak, Bim, Bik, Bid, Bad, Harakiri, Ad E1B, and an ICE-CED3 protease. In yet other embodiments, the non-C-CAM1 molecule is a cytokine selected from the group consisting of IL-2, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, TNF, GMCSF &bgr;-interferon, and &ggr;-interferon. In still further embodiments, the non-C-CAM1 molecule is a target sequence, wherein the target sequence is a substrate for integrins, proteoglycans, glycoproteins, cell surface receptors, nuclear receptors, or transporters. In a particular embodiment, the non-C-CAM1 molecule is a chemotherapeutic agent, wherein the chemotherapeutic agent is selected from the group consisting of verapamil, podophyllotoxin, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, bisulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, TAXOL (paclitaxel), transplatinum, 5-fluorouracil, vincristine, vinblastine, and methotrexate.
In certain embodiments, the invention involves methods of inhibiting a hyperproliferative cell by administering a C-CAM1 cytoplasmic domain, free from other C-CAM1 domains, to the cell such that the domain inhibits hyperproliferative cell growth. In particular embodiments, the hyperproliferative cell may be a cancer cell, wherein the cancer is selected from the group consisting of lung, breast, melanoma, colon, renal, testicular, ovarian, lung, prostate, hepatic, germ cancer, epithelial, prostate, head and neck, pancreatic cancer, glioblastoma, astrocytoma, oligodendroglioma, ependymomas, neurofibrosarcoma, meningia, liver, spleen, lymph node, small intestine, blood cells, colon, stomach, thyroid, endometrium, prostate, skin, esophagus, bone marrow, and blood. It is contemplated that any of the compounds of the invention may be administered as a pharmaceutical composition to a cell or subject. Components of the composition are pharmaceutically acceptable and are described elsewhere in this disclosure.
In further embodiments, the invention concerns methods of inhibiting a hyperproliferative cell by administering a C-CAM1 cytoplasmic domain, free from other C-CAM1 domains, to the cell, and by also administering a second anti-hyperproliferative agent. The second anti-hyperproliferative agent may be selected from the group consisting of tumor irradiation, chemotherapeutic agent, and a nucleic acid encoding an anti-hyperproliferative polypeptide. In one embodiment, the second anti-hyperproliferative agent is a chemotherapeutic agent selected from the group consisting of verapamil, podophyllotoxin, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, bisulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, TAXOL (paclitaxel), transplatinum, 5-fluorouracil, vincristine, vinblastine, and methotrexate. In another embodiment, the second anti-hyperproliferative agent is radiation, selected from the group consisting of X-ray radiation, UV-radiation, &ggr;-radiation, or microwave radiation In a further embodiment, the second anti-hyperproliferative agent is a polypeptide selected from the group consisting of p53, p16, p21, MMAC1, p73, zac1, BRCAI, Rb, Bax, Bak, Bim, Bik, Bid, Bad, Harakiri, Ad E1B, and an ICE-CED3 protease.
In other embodiments of the invention, methods involve a polypeptide that
Lin Sue-Hwa
Logothetis Christopher
Luo Weiping
Board of Regents , The University of Texas System
Fulbright & Jaworski L.L.P.
Rawlings Stephen L.
Wortman Donna
LandOfFree
C-CAM as an angiogenesis inhibitor does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with C-CAM as an angiogenesis inhibitor, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and C-CAM as an angiogenesis inhibitor will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3137523