A tumor is developed by uncontrollable disordered abnormal cell proliferation. If this tumor shows a destructive growth, invasiveness and metastasis, it is regarded as a malignant cancer. Invasiveness is a character to infiltrate or destroy surrounding tissues, and in particular, a basal layer forming a boundary of tissues is destroyed by the character, resulting in the local spread and sometimes inflow of a tumor through circulatory system. Metastasis means the spread of tumor cells from the original birthplace to other areas through lymphatic or blood vessels. In a broad sense, metastasis also means the direct extension of tumor cells through serous body cavity or other space.
Cancer is caused not only by hereditary factors but also by acquired environmental factors. And advanced countries have higher cancer development rate. The reasons might be the increase of the amounts of pesticides and insecticides used and remaining in foods; the increase of consumption of processed foods containing food preservatives, antiseptics and coloring agents; the increase of water, soil and air pollution; the increase of stress in modern people; the decrease of activity; and obesity resulted from bountiful dietary life (Kim H J, et al., Liv Sci of Tj Univ. 3:99-130, 1997; Jacobs M M, Nutr Tod, 28(3):19-23, 1993).
Angiogenesis is essential for the growth and metastasis of tumor (Folkman J, J Natl Cancer Inst, 82:4-6, 1990). Angiogenesis plays a role in providing nutrition and oxygen to the growing tumor and also enables permeation and metastasis of tumor cells from primary lesion through blood vessel wall to remote organs (Kim K J, et al., Nature, 362:841-844, 1993).
As of today, surgical operation, radiotherapy and chemotherapy have been used for the treatment of cancer singly or jointly. The surgical operation is a way to remove diseased tissues. Thus, tumors in specific regions such as breast, colon and skin can be effectively removed by the surgical operation. However, a tumor in vertebra or dispersive tumor like leukemia cannot be properly treated by the surgical operation.
Chemotherapy blocks cell replication or metabolism, and has been used for the treatment of breast cancer, lung cancer and testicular cancer. Though, patients with cancers who have been treated by chemotherapy have seriously suffered from the side effects of systemic chemotherapy. Motion sickness and vomiting are common but serious examples of all. The side effects of chemotherapy can even affect the life of a patient since they might drop the adaptability of a patient rapidly. Besides, DLT (Dose Limiting Toxicity) is also one of major side effects of chemotherapy, which draws a careful attention in the administration of a medicine. Mucositis is an example of DLT against anticancer agents such as 5-fluoruracil which is an antimetabolic cytotoxic agent, and methotrexate, and anticancer antibiotics like doxorubicin. If a patient suffers seriously from such side effects of chemotherapy, he or she should be hospitalized and given an anodyne for reducing pain. So, side effects of chemotherapy and radiotherapy are the biggest problem for the treatment of cancer patients. The conventional anticancer agents kill not only tumor cells but also normal cells. Therefore, recent studies have been focused on the development of a novel anticancer agent that can kill tumor cells only, leaving normal cells untouched.
The present inventors tried to develop a novel protease. As a result, the inventors separated the novel microorganism Aranicola proteolyticus HY-3 (Accession No: KCTC 0268BP; WO 01/57222) from Nephila clavata. And arazyme, a novel protease, was isolated from the strain. Arazyme showed high enzyme activity at low temperature and at high salt concentration; particularly it exhibited the highest activity at human body temperature 37° C. and stable enzyme activity in wide range of pH. So, the inventors identified the gene of this promising novel protease (WO 01/57222).
The present inventors investigated the effect of arazyme originated from Aranicola proteolyticus. As a result, the inventors found out that arazyme increases weight but inhibits tumor cell growth in nude mice transplanted with human lung adenocarcinoma cell line (A549), reduces the expressions of MMP-9, NF-κB and PCNA, reduces the expressions of p21, PCNA (Proliferating Cell Nuclear Antigen), VEGF (Vascular Endothelial Growth Factor), BCl2 (B-cell CLL/lymphoma 2), p-p38, PKC (Protein Kinase C) and MMP-1 (Matrix MetalloProteinase-1) but increases the expression of catalase in human breast cancer cell line (MDA-MB-231). Based on this founding, the present inventors completed this invention by confirming that arazyme can be effectively used for a composition for the prevention and treatment of cancer.
USPTO Backgrounds
USPTO Backgrounds